Active COVID-19, Clinical Pathway — All Settings

Remdesivir

Background

Remdesivir is an antiviral medication that has received Food and Drug Administration (FDA) approval for treatment of hospitalized COVID-19 patients ≥ 28 days of age and ≥ 3 kg. The mechanism of action of remdesivir is through inhibition of the viral RNA polymerase, and as a result, it retains activity against variants of concern reported to date, including omicron.

The ACCT-1 trial ¹ demonstrated that remdesivir may result in a modest reduction in time to clinical improvement (10 vs 15 days) in adults hospitalized with COVID-19.These benefits appear greatest in those requiring supplemental oxygen and for those with < 10 days of symptoms; remdesivir did not appear to benefit patients requiring invasive mechanical ventilation or ECMO. The Solidarity trial enrolled adults hospitalized with COVID-19 who were randomized to receive remdesivir versus usual care. While there was no mortality benefit with remdesivir in the overall study population, mortality was reduced in those treated with remdesivir in the subgroup of patients not requiring mechanical ventilation at enrollment (14.6% vs 16.3%). Finally, in the Discovery trial, no differences in clinical outcomes were detected in patients treated with remdesivir versus standard care.

Among unvaccinated outpatients with mild disease, the PINETREE study demonstrated a reduction in need for hospital admission in adolescents and adults treated within 7 days of symptom onset with remdesivir as compared to placebo. Notably, only 8 adolescents and no children < 12 years old were included, with most subjects being adults with comorbid medical conditions (including obesity, diabetes, and hypertension) who were unvaccinated. The benefit of outpatient remdesivir in children with mild disease is therefore uncertain - but it is unlikely to carry significant benefit given that children generally experience a milder course of illness than adults with significant comorbidities.

Pediatric data evaluating remdesivir are limited. A phase 2/3 study evaluating safety, tolerability, and pharmacokinetics of remdesivir was performed in 53 hospitalized children < 12 years and weighing between 3.5 kg and 40 kg. The dose evaluated in this trial was 5 mg/kg on day 1, followed by 2.5 mg/kg/day thereafter. Adverse events included acute kidney injury (11%) and increase in alanine transaminase (8%); no conclusions regarding efficacy can be made given that there was no control group.

Indication

Hospitalized patients

Use of remdesivir can be considered for select hospitalized patients with laboratory confirmed SARS-CoV-2 infection, with criteria for administration summarized in the table below. Remdesivir should be started as soon as possible after symptom onset in patients meeting these indications. Please also review the “Therapies by Illness Severity” table.

Illness severity	No high risk condition	High risk condition
Asymptomatic	Not recommended	Not recommended
Mild symptoms (e.g., cough, fever, tachypnea) without supplemental oxygen requirement (patients in this group are generally admitted for non-COVID-19 reasons)	Not recommended	Symptoms ≤ 7 days AND not fully vaccinated1: remdesivir not routinely recommended, can consider on a case-by-case basis
	Not recommended	Symptoms ≥ 7 days OR fully vaccinated: not recommended
Supplemental oxygen requirement, HFNC, or non-invasive mechanical ventilation attributable to COVID-19 lower respiratory tract disease²	Symptoms ≤ 10 days: Suggest remdesivir	Symptoms ≤ 10 days: Suggest remdesivir
Mechanical ventilation or ECMO	Not recommended	Not recommended

¹ Fully vaccinated is defined as an immunocompetent patient ≥ 14 days after the second dose of either mRNA vaccine against COVID-19 OR a single dose of the Johnson and Johnson vaccine
² Remdesivir is not routinely recommended for patients with asthma or bronchiolitis on low-flow oxygen, whose oxygen requirement is likely multifactorial in etiology.

Non-hospitalized patients

Remdesivir is not available for outpatients because there are no pediatric data supporting its effectiveness in this setting. Further, since it is only administered as a 3-day IV infusion, the risks of this therapy outweigh its uncertain benefits. Patients should not be admitted to the hospital for the purpose of receiving remdesivir (or any other COVID-19 therapy). Providers should instead review the “Therapies by Illness Severity” table for treatment recommendations for non-hospitalized patients.

Instructions for Front Line Providers

ID consultation is not required for use of remdesivir, but is available upon request at the discretion of the primary treating team.

All Patients > 28 Days and > 3 kg (FDA Approved April 2022):

Obtain baseline CMP.
Verify that ALT are < 10x the upper limit of normal before starting remdesivir.
Order remdesivir using COVID-19 inpatient orderset. Written consent is no longer required.
Obtain daily ALT/AST if clinical concern for hepatotoxicity (e.g., for patients receiving concurrent hepatotoxic medications, patients with abnormal baseline LFTs, patients in shock), other labs as clinically indicated. Daily LFTs are no longer routinely required.

Remdesivir Dosing and Administration
Category	Dose/duration (see also CHOP formulary)	Dose/duration (see also CHOP formulary)	Comments (see also CHOP formulary)
< 3 kg or < 28 days	Discuss with infectious diseases/Antimicrobial Stewardship Program/Clinical Pharmacy		Baseline labs: CMP, pregnancy test (if applicable) Follow up labs: CMP daily. as clinically indicated if there is concern for hepatotoxicity (e.g., for patients receiving concurrent hepatotoxic medications, patients with abnormal baseline LFTs, patients in shock). Renal impairment: No dose adjustment. If eGFR < 30 ml/minute, duration should be limited to 5 days and lyophilized powder should be used preferentially to minimize risk of toxicity from cyclodextrin accumulation. Hepatic impairment: No dose adjustment. Do not use if ALT is > 10x upper limit of normal.
> 28 days and 3 kg - 40 kg	5 mg/kg IV loading dose (maximum 200 mg) on day 1; followed by 2.5 mg/kg IV q24h (maximum 100 mg) daily Use lyophilized powder only	Mild/moderate disease (no respiratory support): up to 3 days Severe: up to 5 days Remdesivir should be stopped when the patient is otherwise ready for discharge; patients should not remain hospitalized solely to complete the above durations.
≥ 40 kg	200 mg IV loading dose on day 1; followed by 100 mg IV q24h on days 2-5

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The clinical pathways are based upon publicly available medical evidence and/or a consensus of medical practitioners at The Children’s Hospital of Philadelphia (“CHOP”) and are current at the time of publication. These clinical pathways are intended to be a guide for practitioners and may need to be adapted for each specific patient based on the practitioner’s professional judgment, consideration of any unique circumstances, the needs of each patient and their family, and/or the availability of various resources at the health care institution where the patient is located.

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