TRANSFORM HOW YOU USE DRUG INFORMATION

It is unknown if dosage adjustments are needed in patients with hepatic disease. Consider discontinuing treatment if ALT increases to more than 10-times ULN. Discontinue treatment if ALT elevations are accompanied by signs or symptoms of hepatic inflammation.[66063]

Adult and Pediatric patients

eGFR 30 mL/minute or more: No dosage adjustment needed.

eGFR less than 30 mL/minute: Treatment is not recommended.

Term neonates 7 days and older

Serum creatinine less than 1 mg/dL: No dosage adjustment needed.

Serum creatinine 1 mg/dL or more: Treatment is not recommended.[65365]

Term neonates 0 to 6 days

Recommendations are not available.[65365]

Remdesivir is an antiviral medication approved for use in adults and pediatric patients (12 years and older and weighing at least 40 kg) to treat coronavirus disease 2019 (COVID-19) requiring hospitalization.[66063] Although remdesivir is not FDA-approved for use in patients younger than 12 years or weighing less than 40 kg, the FDA has issued an Emergency Use Authorization (EUA) which allows the drug to be used to treat suspected or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing 3.5 to 39 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg.[66064] Remdesivir is also part of an EUA allowing for the combined use of remdesivir and baricitinib to treat suspected or laboratory confirmed COVID-19 in hospitalized patients (2 years and older) who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[66126]

The National Institutes of Health (NIH) COVID-19 treatment guidelines have recommendations for the use of remdesivir based on disease severity.[65314]

• The NIH guideline recommends remdesivir for use in the following patients with COVID-19:
• For hospitalized patients who require supplemental oxygen BUT NOT on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO, the NIH recommends 5 days of remdesivir either alone (patients requiring minimal oxygen) or in combination with a corticosteroid (patients requiring increasing amounts of oxygen). Remdesivir therapy may be stopped early if a patient is discharged from the hospital or may be extended up to 10 days if no improvement is observed at day 5.
• For hospitalized patients who require high-flow oxygen or noninvasive ventilation, the NIH recommends remdesivir be given in combination with a corticosteroid.
• For hospitalized patients who initially started on remdesivir monotherapy and then progressed to requiring invasive mechanical ventilation or ECMO, the NIH recommends adding a corticosteroid and continuing remdesivir until the treatment course is completed. Due to questionable clinical benefit, treatment with remdesivir alone is not recommended.
• The NIH recommends against continuing the use of remdesivir in COVID-19 patients discharged from inpatient hospital settings in stable condition who do not require supplemental oxygen.
• The NIH states there is insufficient evidence to recommend for or against the use of remdesivir in the following patients with COVID-19:
• Patients with mild to moderate COVID-19 (i.e., non-hospitalized patients or hospitalized patients that do not require supplemental oxygen).
• Patients discharged from inpatient hospital settings who require supplemental oxygen.
• Patients discharged from the emergency department despite new or increasing need for supplemental oxygen when hospital resources are limited or inpatient admission is not possible.

The World Health Organization (WHO) has issued a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of disease severity. According to the WHO, there is currently no evidence that remdesivir improves survival or other outcomes (e.g., need for mechanical ventilation, time to clinical improvement) in these patients. The WHO does support continued enrollment in clinical trials evaluating the use of remdesivir for COVID-19.[66125]

Data from a randomized, double-blind, placebo-controlled trial [i.e., Adaptive COVID-19 Treatment Trial (ACTT-1)] found remdesivir to be superior to placebo in shortening the time to recover in hospitalized adults with COVID-19 and lung involvement. In this study, the median time to recovery was 10 days in the remdesivir-treated group compared to 15 days in the placebo group (rate ratio for recovery: 1.29; 95% CI: 1.12 to 1.49, p less than 0.001); and the Kaplan-Meier estimates of mortality by day 29 were 11.4% and 15.2% for remdesivir and placebo, respectively (hazard ratio: 0.73; 95% CI: 0.52 to 1.03). Remdesivir was most beneficial when administered early in the course of the disease; however, in most analyses, clinical benefit persisted throughout the duration of symptoms. In patients treated within 10 days of symptom onset, the rate ratio for recovery was 1.37 (95% CI, 1.14 to 1.64); whereas, for those whose treatment was initiated more than 10 days after symptom onset, the rate ratio for recovery was 1.20 (95% CI, 0.94 to 1.52).[65474][66001]

Data from another randomized, double-blind, placebo-controlled, multicenter trial of hospitalized patients with severe COVID-19 found treatment with remdesivir was not associated with statistically significant benefits. Included in this trial were adult patients admitted to the hospital with the following: laboratory-confirmed SARS-CoV-2 infection, symptom onset 12 days or less, SpO₂ of 94% or less or a PaO₂/FiO₂ of 300 mmHg or less, and radiologically confirmed pneumonia. Patients were randomized to receive remdesivir (n = 158) or placebo (n = 79); both treatment groups were allowed concurrent use of corticosteroids, interferons, and lopinavir; ritonavir. The study found no difference in the time to clinical improvement (median, 21 vs. 23 days; hazard ratio: 1.23; 95% CI: 0.87 to 1.75) or in the 28-day mortality rate (14% vs. 13%; 95% CI: 8.1 to 10.3). Additionally, 66% of remdesivir patients and 64% of placebo patients reported adverse events, with 12% of remdesivir recipients and 5% in the placebo group stopping treatment early.[65408]

Preliminary data from an open-label, randomized, multicenter trial conducted by the World Health Organization (WHO), the SOLIDARITY trial, found treatment with remdesivir was not associated with clinical benefit in adults hospitalized with COVID-19. In this trial, a 10-day course of remdesivir (n = 2,743), as compared to a control group (n = 2,708), did not reduce overall in-hospital mortality (10.9% vs. 11.1%; death rate ratio, 0.95; 95% CI, 0.81 to 1.11; p = 0.5), initiation of ventilation in those not already ventilated (295 for remdesivir vs. 284 for the control group), or duration of hospitalization (hospitalized at day 7, 69% for remdesivir and 59% for the control group).[66045]

A manufacturer-sponsored, open-label trial evaluated the use of 5-day (n = 200) and 10-day (n = 197) courses of remdesivir to treat hospitalized patients with severe COVID-19 pneumonia (i.e., lung infiltrates and either receiving supplemental oxygen or a SpO₂ of 94% or less on room air); data showed no significant difference in efficacy between the 2 treatment groups. On day 14, clinical improvement of at least 2 points on the 7-point ordinal scale was achieved by 65% in the 5-day group and 54% in the 10-day group. Other data showed numerically more patients discharged from the hospital in the 5-day group than in the 10-day group (60% vs. 52%, respectively), and lower mortality in the 5-day group (8% vs. 11%, respectively). Of note, this study excluded patients who were receiving mechanical ventilation and ECMO at baseline, as well as patients with signs of multiorgan failure. Also, although patients were randomly assigned on a 1:1 basis, those assigned to the 10-day group had significantly worse clinical status at baseline (p = 0.02).[65486]

A multicenter study compared the efficacy of remdesivir vs. standard of care alone in adults with severe COVID-19 using data from an ongoing phase 3 trial (n = 312) and a retrospective cohort of patients (n = 818). Patients had confirmed SARS-CoV-2 infection, were hospitalized, had SpO₂ 94% or lower on room air or required supplemental oxygen, and had pulmonary infiltrates. On day 14, 74.4% of remdesivir patients had recovered vs. 59% of patients receiving standard of care (aOR, 2.03; 95% CI, 1.34 to 3.09; p less than 0.01). On day 14, an improvement in clinical status of at least 2-points (or being discharged alive) was noted in 71.9% of remdesivir patients compared to 58.8% of patients receiving standard of care (aOR 1.64; 95% CI, 1.10 to 2.43; p = 0.001). On day 14, 7.6% of remdesivir patients had died vs. 12.5% of patients receiving standard of care (aOR, 0.38; 95% CI, 0.22 to 0.68; p = 0.001).[65755]

Efficacy and safety of remdesivir in patients hospitalized with moderate COVID-19 pneumonia (i.e., pulmonary infiltrates and SpO₂ greater than 94% on room air) was evaluated in a randomized, open-label, multicenter trial, in which remdesivir 5-day (n = 191) and 10-day (n = 193) therapies were compared against standard care alone (n = 200). In this trial, the 5-day remdesivir group had significantly higher odds of a better clinical status (defined as clinical status at day 11 on a 7-point ordinal scale) as compared to standard care (OR, 1.65; 95% CI, 1.09 to 2.48; p = 0.02); however, the clinical status on day 11 was not significantly different between the 10-day remdesivir group and standard care (p = 0.18). The proportion of patients who developed an adverse event were 51% in the 5-day group, 59% in the 10-day group, and 47% in the standard care group. The difference in safety between the 5-day and standard care groups was not statistically significant (4.8%; 95% CI, -5.2% to 14.7%; p = 0.36), but was significant between the 10-day group and standard care (12%; 95% CI, 1.6% to 21.8%; p = 0.02).[65849]

For storage information, see the specific product information and study protocols.

NOTE: Prior to administering remdesivir under the Emergency Use Authorization (EUA) to pediatric patients (younger than 12 years or less than 40 kg), the health care provider must communicate to the patient and parent/caregiver information consistent with the "Fact Sheet for Parents and Caregivers", including:

• Remdesivir has been authorized for emergency use by the FDA. It is not an FDA approved drug for this population.
• The parent/caregiver has the option to accept or refuse remdesivir.
• The significant known and potential risks and benefits of remdesivir, and the extent to which such risks and benefits are unknown.
• Information on available alternative treatments and the risks and benefits of those alternatives.

If providing this information will delay treatment to a degree that would endanger the lives of patients, the information must be provided to the parent/caregiver as soon as practicable after remdesivir is administered.[65365]

Maintain records showing the receipt, use, and disposition of remdesivir.[65365]

Remdesivir is contraindicated in patients with hypersensitivity to remdesivir or any components of the product.[66063]

Remdesivir is a monophosphoramidate prodrug of remdesivir triphosphate (RDV-TP), an adenosine analog that acts as an inhibitor of RNA-dependent RNA polymerases (RdRps). Remdesivir triphosphate competes with adenosine-triphosphate for incorporation into nascent viral RNA chains. Once incorporated into the viral RNA at position i, RDV-TP terminates RNA synthesis at position i+3. Because RDV-TP does not cause immediate chain termination (i.e., 3 additional nucleotides are incorporated after RDV-TP), the drug appears to evade proofreading by viral exoribonuclease (an enzyme thought to excise nucleotide analog inhibitors). Remdesivir causes delayed RNA chain termination during the process of viral replication.

Remdesivir has a broad spectrum of in vitro antiviral activity against RNA viruses, including viruses belonging to Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae families. The 50% effective concentration (EC₅₀) against a clinical isolate of SARS-CoV-2 in primary human airway epithelial (HAE) cells is 9.9 nM after 48 hours of treatment. The EC₅₀ against SARS-CoV-2 in the continuous human lung epithelial cell lines Calu-3 and A549-hACE2 is 280 nM after 72 hours of treatment and 115 nM after 48 hours of treatment, respectively. No clinical data are available regarding the development of SARS-CoV-2 resistance to remdesivir.[65120][65133][65134][65135][65136][65137][65156][65161][65247][65248][65365][66063]

Remdesivir is administered via intravenous infusion.

Preliminary data show that remdesivir is extensively metabolized. The rapid decline in remdesivir plasma concentrations is accompanied by the sequential appearance of the intermediate metabolite GS-704277 and the nucleoside metabolite GS-441524. Within cells, the GS-441524 monophosphate undergoes rapid conversion to the pharmacologically active analog of adenosine triphosphate, GS-443902.[65365] The pharmacokinetic parameters of remdesivir and its metabolites (GS-441524 and GS-704277) were evaluated in a multiple dose study involving healthy adults. In this study, the percent bound to human plasma proteins and the blood-to-plasma ratio were 88% to 93.6% and 0.68 to 1 for remdesivir, 2% and 1.19 for GS-441524, and 1% and 0.56 for GS-704277, respectively. Remdesivir is predominately metabolized by carboxylesterase 1 (CES1, 80%), with minor contributions from cathepsin A (10%) and CYP3A (10%). The metabolite GS-704277 is further metabolized by histidine triad nucleotide-binding protein 1 (HINT1), while GS-441524 is not significantly metabolized. The elimination half-lives for remdesivir, GS-441524, and GS-704277 are 1 hour, 27 hours, and 1.3 hours, respectively. The major route of elimination for remdesivir and GS-704277 is via metabolism, with only 10% of remdesivir and 2.9% of GS-704277 being excreted in the urine. GS-441524 is primarily eliminated via glomerular filtration and active tubular secretion (49% in urine and 0.5% in feces).[66063]

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, OATP1B1, OATP1B3, MATE1, P-gp

In vitro, remdesivir is a substrate for CYP3A4 and the drug transporters organic anion transporting polypeptide 1B1 (OATP1B1) and p-glycoprotein (P-gp). Remdesivir is an in vitro inhibitor of CYP3A4, OATP1B1, OATP1B3, and the multidrug and toxin extrusion protein 1 (MATE1). The metabolite GS-704277 is a substrate of OATP1B1 and OATP1B3. The clinical relevance has not been established.[66063]