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What are the indications and dosing regimens for remdesivir for COVID-19 treatment?

Comment by InpharmD Researcher

The FDA has released dosing instructions under the EUA for remdesivir (Table 1). In summary, the recommended dose for adults and pediatrics ≥ 40 kg requiring mechanical ventilation and/or ECMO is remdesivir 200 mg IV over 30 to 120 min on day 1 followed by 100 mg IV over 30 to 120 min. Pediatrics weighing between 3.5 and <40 kg undergo weight-based dosing; 5 mg/kg IV over 30 to 120 min on day 1 followed by 2.5 mg/kg/IV over 30 to 120 min. Treatment course up to 5 days is recommended if not on invasive mechanical ventilation or ECMO, otherwise 10 days therapy is recommended including if clinical improvements are not seen at day 5. Only severe COVID-19 patients with an oxygen saturation (SpO2) ≤ 94% or requiring supplemental oxygen, mechanical ventilation, or ECMO are eligible to receive remdesivir under the EUA.
Background

The Food and Drug Administration (FDA) emergency use authorization (EUA) of remdesivir defines severe COVID-19 disease as patients with an oxygen saturation (SpO2) ≤ 94% on room air or requiring: supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). [1-3]

References:

[1] Food and Drug Administration. Remdesivir EUA Letter of Authorization. Available: https://www.fda.gov/media/137564/download. Published May 1, 2020. Accessed May 11, 2020.
[2] Food and Drug Administration. Frequently Asked Questions on the Emergency Use Authorization for Remdesivir for Certain Hospitalized COVID-19 Patients. https://www.fda.gov/media/137574/download. Published May 1, 2020. Accessed May 11, 2020.
[3] Gilead. FACT SHEET FOR HEALTH CARE PROVIDERS: EMERGENCY USE AUTHORIZATION (EUA) OF REMDESIVIR (GS-5734™). Available: https://www.gilead.com/-/media/files/pdfs/remdesivir/eua-fact-sheet-for-hcps_01may2020.pdf?la=en&hash=B56F8C441364B7EDA15543F75E8EC88F. Accessed: May 11, 2020.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What are the indications and dosing regimens for remdesivir for COVID-19 treatment?

Please see Table 1 for your response.


The Food and Drug Administration (FDA) dosing instructions for Remdesivir in the setting of COVID-19
 

Adult and Pediatrics with bodyweight > 40 kg

Pediatrics with bodyweight between 3.5 kg and < 40 kg.

Requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO)

Single loading dose of 200 mg IV over 30 to 120 minutes on Day 1

Once-daily maintenance doses of 100 mg IV over 30 to 120 minutes for 9 days (days 2 through 10)

Use remdesivir for injection, 100 mg, lyophilized powder only.

Administer a body weight-based dosing regimen of one loading dose of remdesivir 5 mg/kg IV (infused over 30 to 120 min) on Day 1 followed by remdesivir 2.5 mg/kg IV (infused over 30 to 120 min) once daily for 9 days (days 2 through 10)

Not requiring invasive mechanical ventilation and/or ECMO

Single loading dose of 200 mg IV over 30 to 120 minutes on Day 1

Once-daily maintenance doses of 100 mg IV over 30 to 120 minutes for 4 days (days 2 through 5)

If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e., up to a total of 10 days). 

Use remdesivir for injection, 100 mg, lyophilized powder only.

Administer a body weight-based dosing regimen of one loading dose of remdesivir 5 mg/kg IV (infused over 30 to 120 min) on Day 1 followed by remdesivir 2.5 mg/kg IV (infused over 30 to 120 min) once daily for 4 days (days 2 through 5)

If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e., up to a total of 10 days). 

Special populations 

Pregnancy

Remdesivir should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus 

Renal impairment

The pharmacokinetics of remdesivir have not been evaluated in patients with renal impairment.

Use in patients with renal impairment are based on potential risk and potential benefit considerations. Patients with eGFR greater than or equal to 30 mL/min have received remdesivir for treatment of COVID-19 with no dose adjustment of remdesivir.

All patients must have an eGFR determined before dosing. Remdesivir is not recommended in adult and pediatric patients (>28 days old) with eGFR less than 30 mL/min or in full-term neonates (≥7 days to ≤28 days old) with serum creatinine greater than or equal to 1 mg/dL unless the potential benefit outweighs the potential risk.

 
Hepatic impairment

The pharmacokinetics of remdesivir have not been evaluated in patients with hepatic impairment.

It is not known if dosage adjustment is needed in patients with hepatic impairment and remdesivir should only be used in patients with hepatic impairment if the potential benefit outweighs the potential risk. Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir.

 

 Other information and warnings

Dose preparation

Care should be taken during admixture to prevent inadvertent microbial contamination.

As there is no preservative or bacteriostatic agent present in this product, aseptic technique must be used in preparation of the final parenteral solution. It is always recommended to administer IV medication immediately after preparation when possible. 

Remdesivir for Injection, 100 mg: Reconstitute remdesivir for injection lyophilized powder with 19 mL of Sterile Water for Injection and dilute in 0.9% saline prior to administration.

Remdesivir injection, 5 mg/mL: Dilute remdesivir injection concentrated solution in 0.9% saline prior to administration

Administer remdesivir as an intravenous infusion over 30 to 120 minutes. 

After infusion is complete, flush with at least 30 mL of 0.9% saline. 

Discard any remaining reconstituted remdesivir lyophilized powder, reconcentrated solution, and diluted solution.

 
Storage and handling

Store diluted remdesivir solution for infusion up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

This product contains no preservative. Any unused portion of a single-dose remdesivir vial should be discarded after a diluted solution is prepared.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Should either be observed, the solution should be discarded and fresh solution prepared.

The prepared diluted solution should not be administered simultaneously with any other medication. The compatibility of remdesivir injection with IV solutions and medications other than 0.9% saline is not known.

Warnings

There are limited clinical data available for remdesivir. Serious and unexpected adverse events may occur that have not been previously reported with remdesivir use.

Infusion-Related Reactions: Infusion-related reactions have been observed during, and/or have been temporally associated with, administration of remdesivir. Signs and symptoms may include hypotension, nausea, vomiting, diaphoresis, and shivering. If signs and symptoms of a clinically significant infusion reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. The use of remdesivir is contraindicated in patients with known hypersensitivity to remdesivir.

Increased Risk of Transaminase Elevations: Transaminase elevations have been observed in the remdesivir clinical development program, including in healthy volunteers and patients with COVID19. In healthy volunteers who received up to 150 mg daily for 14 days, alanine aminotransferase (ALT) elevations were observed in the majority of patients, including elevations up to 10 times baseline values in one subject without evidence of clinical hepatitis; no ≥ Grade 3 adverse events were observed. Transaminase elevations have also been reported in patients with COVID-19 who received remdesivir, including one patient with ALT elevation up to 20 times the upper limit of normal. As transaminase elevations have been reported as a component of COVID-19 in some patients, discerning the contribution of remdesivir to transaminase elevations in this patient population is challenging. 

Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir.

Remdesivir should not be initiated in patients with ALT ≥ 5 times the upper limit of normal at baseline.

Remdesivir should be discontinued in patients who develop:

ALT ≥ 5 times the upper limit of normal during treatment with remdesivir. Remdesivir may be restarted when ALT is < 5 times the upper limit of normal

OR

ALT elevation accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR

Serious side effects

An adverse reaction associated with remdesivir in clinical trials in healthy adult subjects was increased liver transaminases. Additional adverse reactions associated with the drug, some of which may be serious, may become apparent with more widespread use.

References:

The Food and Drug Administration (FDA). FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF REMDESIVIR (GS-5734™). Available: https://www.fda.gov/media/137566/download. Accessed: May 11, 2020.