Remdesivir

Edina Avdic, Pharm.D.
Pediatric Dosing Author: Bethany Sharpless Chalk, Pharm.D., BCPPS

INDICATIONS

FDA

  • Remdesivir is an investigational agent (not FDA approved) that has been authorized for use (EUA) in the U.S. by FDA under an Emergency Use Authorization (EUA) for treatment of suspected or laboratory-confirmed SARS-Co-2 infection (COVID-19) in adults and children hospitalized with severe diseases.
  • 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)

FORMS

brand name

preparation

manufacturer

route

form

dosage^

cost*

N/A

Remdesivir

Gilead Sciences Inc.

IV

vial

100 mg

n/a

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

USUAL ADULT DOSING

COVID-19: 200 mg IV once, followed by 100 mg IV q24h for 5 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 the recent open-label study, serious adverse events were observed at higher rate in patients receiving 10-day of 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[3].

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 LFTs 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

No data

DOSING IN PERITONEAL DIALYSIS

No data

DOSING IN RENAL REPLACEMENT THERAPY

No data

Other Adult Renal Dosing Information

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 (this is the same issue with voriconazole IV).

PEDIATRIC DOSING

USUAL PEDIATRIC DOSING

COVID-19:

  • 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 risks.

ADVERSE DRUG REACTIONS

GENERAL

  • 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 10-day duration of treatment compared to 5 days.
  • Remdesivir is contraindicated in patients with hypersensitivity to any ingredient of remdesivir.

COMMON

  • GI:
    • 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%)

OCCASIONAL

  • Transaminase elevations (4-7%)
    • Remdesivir should be discontinued in patients who develop ALT ≥ 5 times the upper limit of normal during treatment with Remdesivir or ALT elevation accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.
  • Prothrombin time (PT) elevation without a change in INR
  • Rash -7%
  • Renal: AKI (2-8%), decreased CrCl (3-12%). Rates are higher with 10-day course compared to 5 days.
  • Pyrexia (5%)
  • Hypoglycemia (4%)
  • Insomnia (5%)

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.
  • 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.

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. EC50 for SARS-CoV2 was 0.77 μM in one in vitro study[1].

RESISTANCE

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

PHARMACOLOGY

MECHANISM

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.

PHARMACOKINETIC PARAMETERS

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.

Protein Binding

The free fraction in humans was 12.1%.

Cmax, Cmin, and AUC

  • Remdesivir exhibits linear PK profile.

T1/2

  • Remdesivir : ~1 h
  • Metabolite GS-441524: ~25 h

Distribution

Widely distributed

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.

PREGNANCY RISK

  • Remdesivir should be used in pregnancy only if benefits outweigh the risk to the mother and fetus. In nonclinical reproductive toxicity studies, no adverse effect on embryofetal development where observed when Remdesivir was administered to pregnant animals. In the reproductive studies, at a systemically toxic dose a decrease in implantation sites and viable embryos; lower ovary and uterus/cervix/oviduct weights in the rats.
  • 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[9].

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.

COMMENTS

  • Remdesivir is an investigational agent (not FDA approved) that has been authorized for use in the U.S. by FDA under an Emergency Use Authorization (EUA) for the treatment of suspected or laboratory-confirmed SARS-Co-2 infection (COVID-19) in adults and children hospitalized with severe disease.
    • There are two formulations: solution formulation and lyophilized powder formulation

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, suggest shorter time (by 4 days) to recovery in patients receiving Remdesivir compared to placebo (median time, 11 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)[4]. 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[1]. 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 significant difference in the clinical status at 14 days after adjusting for baseline difference 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[3].
  • Remdesivir is also recommended by NIH guidelines (updated May 12, 2020) for the treatment of COVID-19 in hospitalized patients with severe disease (per EUA criteria). They do not recommend Remdesivir for the treatment of mild or moderate COVID-19 outside the setting of clinical trials.

Other viruses

  • In animal studies when Remdesivir was used as prophylaxis, it prevented MERS-CoV clinical disease, reduced MERS-CoV levels and lung injury[7][5].
  • 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)[9].
  • In a mouse model, Remdesivir was effective when tested as a treatment for SARS-CoV-1[10].

Basis for recommendation

  1. 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:[Epub ahead of print]. https://doi.org/10.1016/S0140-6736(20)31022-9

    Comment:
    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.


  2. FDA. Fact sheet for health care providers emergency use authorization (EUA) of remdesivir (GS-5734™). https://www.fda.gov/media/137566/download. Published 2020. Accessed 2020 May 11.

    Comment: FDA Fact Sheet provides details on FDA EUA remdesivir criteria for use, the responsibility of the provider and necessary documentation. The fact sheet also provide details on the remdesivir mechanism of action, dosing, monitoring, safety and warning precautions as well as the instruction for the preparation of the product.



  3. Goldman JD, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2015301; Accessed May 28, 2020.

    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%).


  4. Beigel JH et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. Available at : https://www.nejm.org/doi/pdf/10.1056/NEJMoa2007764?articleTools=true; Accessed, May 28, 2020.

    Comment: In this 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 preliminary analysis of 1059 patients (538 in remdesivir and 521 in placebo), the median time to recovery was significantly shorter remdesivir group compared to placebo, 11 days vs. 15 days respectively (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; p< 0.001). 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. There was no difference in mortality by 14 days between the two groups (7.1% in remdesivir vs, 11.9% in the placebo group; HR for death, 0.70; 95% CI, 0.47 to 1.04). Adverse events were observed in 21.1% of remdesivir compared to 27% in the placebo group.



References

  1. 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/ritanovir 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/ritanovir with interferon beta was not as effective as remdesivir reduced viral loads, but had no impact on improving clinical status of mice.

  2. 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.

  3. 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.

  4. 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.  [PMID:32020029]

    Comment: In this letter to the editor, the authors note that remdesivir was highly effective against 2019-nCoV infection in vitro using Vero E6 cells. EC50 was 0.77 mM.

  5. 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 were not related to the underlying Ebola virus disease.
    Rating: Important

  6. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396).  [PMID:28659436]

    Comment: Remdesivir was effective in inhibiting both SARS-CoV and MERS-CoV replication in vitro systems (human airway epithelial cell culture, bat-CoVs, and circulating contemporary human CoV in primary human lung cells).

  7. https://www.ema.europa.eu/en/documents/other/summary-compassionate-use-rem...

    Comment: Summary of compassionate use from the European Medicines Agency. The document includes information on Remdesivir mechanism of action, a summary of in vitro activity, pharmacology (including PK studies in humans and animals that have not been published at this time), toxicity and summary of the currently available clinical trials.



    Rating: Important

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Last updated: June 6, 2020