Remdesivirum

Uses

Emergency use of Remdesivirum for treatment of suspected or laboratory confirmed Corona Virus Disease 2019 (COVID-19). Severe disease is defined as patients with an oxygen saturation (Sp02) <94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO). Specifically, Remdesivirum is only authorized for hospitalized adult and pediatric patients for whom use of an intravenous agent is clinically appropriate.

Remdesivirum is also used to associated treatment for these conditions: Coronavirus Disease 2019 (COVID‑19)

How Remdesivirum works

COVID-19 is caused by the positive-sense RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of the viral genome is a key step in the infectious cycle of RNA viruses, including those of the Filoviridae, Paramyxoviridae, Pneumoviridae, and Coronaviridae families, and is carried out by viral RNA-dependent RNA polymerase (RdRp) enzymes or enzyme complexes. For both SARS-CoV and SARS-CoV-2, the RdRp comprises nsp7, nsp8, and nsp12 subunits under physiological conditions, although functional RdRp complexes can be reassembled in vitro that incorporate only the nsp8 and nsp12 subunits, similar to the Middle East respiratory syndrome coronavirus (MERS-CoV).

Remdesivirum is a phosphoramidite prodrug of a 1'-cyano-substituted adenosine nucleotide analogue that competes with ATP for incorporation into newly synthesized viral RNA by the corresponding RdRp complex. Remdesivirum enters cells before being cleaved to its monophosphate form through the action of either carboxylesterase 1 or cathepsin A; it is subsequently phosphorylated by undescribed kinases to yield its active triphosphate form remdesivir triphosphate (RDV-TP or GS-443902). RDV-TP is efficiently incorporated by the SARS-CoV-2 RdRp complex, with a 3.65-fold selectivity for RDV-TP over endogenous ATP. Unlike some nucleoside analogues, remdesivir provides a free 3'-hydroxyl group that allows for continued chain elongation. However, modelling and in vitro experiments suggest that at i + 4 (corresponding to the position for the incorporation of the fourth nucleotide following RDV-TP incorporation), the 1'-cyano group of remdesivir sterically clashes with Ser-861 of the RdRp, preventing further enzyme translocation and terminating replication at position i + 3. This mechanism was essentially identical between SARS-CoV, SARS-CoV-2, and MERS-CoV, and genomic comparisons reveal that Ser-861 is conserved across alpha-, beta-, and deltacoronaviruses, suggesting remdesivir may possess broad antiviral activity.

Considerations for the use of nucleotide analogues like remdesivir include the possible accumulation of resistance mutations. Excision of analogues through the 3'-5' exonuclease (ExoN) activity of replication complexes, mediated in SARS-CoV by the nsp14 subunit, is of possible concern. Murine hepatitis viruses (MHVs) engineered to lack ExoN activity are approximately 4-fold more susceptible to remdesivir, supporting the proposed mechanism of action. However, the relatively mild benefit of ExoN activity to remdesivir resistance is proposed to involve its delayed chain termination mechanism, whereby additional endogenous nucleotides are incorporated following RDV-TP. In addition, serial passage of MHV in increasing concentrations of the remdesivir parent molecule GS-441524 led to the development of resistance mutations F476L and V553L, which maintain activity when transferred to SARS-CoV. However, these mutant viruses are less fit than wild-type in both competition assays and in vivo in the absence of selective pressure. To date, no clinical data on SARS-CoV-2 resistance to remdesivir have been described.

Dosage

Remdesivirum dosage

General Information-

• Adult and pediatric patients (>28 days and old) must have an eGFR determined and full-term neonates (≥7 days to ≤28 days old) must have serum creatinine determined before dosing of Remdesivirum.
• Hepatic laboratory testing should be performed in all patients prior to starting Remdesivirum and daily while receiving Remdesivirum.
• Remdesivirum should be administered via intravenous infusion only. Do not administer as intramuscular injection.

• The recommended dosage in adults requiring invasive mechanical ventilation and/or ECMO is a single loading dose of Remdesivirum 200 mg on day 1 followed by once daily maintenance dose of Remdesivirum 100 mg for 9 days.
• The recommended dose in adults not requiring invasive mechanical ventilation and/or ECMO is a single dose of Remdesivirum 200 mg on day 1 followed by once daily maintenance dose of Remdesivirum 100 mg for 4 days. If a patient dose not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e. up to a total of 10 days)
• Remdesivirum is to be administered via intravenous infusion in a total volume of up to 250 ml 0.9% saline over 30 to 120 minutes.

• The recommended pediatric dose for pediatric patients weighing between 3.5 kg <40 kg should be calculated using the mg/kg dose according to the patient’s weight.
• For pediatric patients with body weight between 3.5 kg <40 kg use Remdesivirum for injection 100 mg lyophilized powder only. Administer a body weight-based dosing regimen of one loading dose of Remdesivirum 5 mg/kg IV (infused over 30 to 120 minutes) on day 1 followed by Remdesivirum 2.5 mg/kg IV (infused over 30 to 120 minutes) once daily for 9 days (for pediatric patients requiring invasive mechanical ventilation and/or ECMO, days 2 through 5). If a patient dose not demonstrate clinical improvement, treatment may be extended for up to 5 additional days (i.e. up to a total of 10 days)
• For pediatric patients with body weight ≥40 kg requiring invasive mechanical ventilation and/or ECMO, the adult dosage regimen of one loading dose of Remdesivirum 200 mg IV (infused over 30 to 120 minutes) on day 1 followed by Remdesivirum 100 mg IV (infused over 30 to 120 minutes) once daily for 9 days will be administered.
• For pediatric patients with body weight ≥40 kg requiring invasive mechanical ventilation and/or ECMO, the adult dosage regimen of one loading dose of Remdesivirum 200 mg IV (infused over 30 to 120 minutes) on day 1 followed by Remdesivirum 100 mg IV (infused over 30 to 120 minutes) once daily for 4 days (days 2 through 5) will be administered. 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).

The prepared dilution should not be administered simultaneously with any other medication. The compatibility of Remdesivirum injection with IV solutions and medications other than saline is not known. Please administered the diluted solution with the infusion rate described in the below table. Recommended Rate of Infusion- Diluted Remdesivirum for Injection Lyophilized Powder in Adults and Pediatric Patients Weighing > 40 kg

Infusion bag 250 ml:

• Infusion Time: 30 min, Rate of Infusion: 8.33 ml/min
• Infusion Time: 60 min, Rate of Infusion: 4.17 ml/min
• Infusion Time: 120 min, Rate of Infusion: 2.08 ml/min

• Infusion Time: 30 min, Rate of Infusion: 3.33 ml/min
• Infusion Time: 60 min, Rate of Infusion: 1.67 ml/min
• Infusion Time: 120 min, Rate of Infusion: 0.83 ml/min

Side Effects

An adverse reaction associated with Remdesivirum in clinical trials in healthy adult subjects was increased liver transaminases.

Toxicity

Data regarding overdoses of remdesivir are not readily available. Overdoses of other nucleoside analogs like acyclovir can be managed with symptomatic and supportive treatment.

Precaution

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

Food Interaction

Remdesivirum Alcohol interaction

[Moderate] GENERALLY AVOID:

Concomitant use of remdesivir with other agents that are known to induce hepatotoxicity may theoretically increase the risk of liver injury.

Data from investigational use and clinical studies suggest that remdesivir may be associated with hepatotoxic effects.

Transient treatment-emergent Grade 1 or Grade 2 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed during multiple-dose Phase 1 studies in healthy volunteers.

Some ALT and AST elevations were associated with graded PT elevations, but there were no graded changes in international normalized ratio (INR).

Laboratory results for these subjects indicated no systemic sign of drug reaction.

Liver transaminase elevations, including grade 3 or higher, were also observed in some participants during compassionate or investigational use of remdesivir and clinical studies for the treatment of COVID-19.

The mechanism of potential hepatotoxicity is unknown and the contribution of remdesivir is difficult to determine, as transaminase elevations have also been reported as a component of COVID-19, including in patients receiving placebo in clinical trials of remdesivir.

Until more information is available, concomitant use of remdesivir with known hepatotoxic drugs should be avoided when possible.

Liver function should be evaluated prior to starting remdesivir and monitored during treatment as clinically appropriate.

Remdesivirum should not be initiated in patients with ALT greater than or equal to 5 times the upper limit of normal (ULN) at baseline.

Likewise, remdesivir should be discontinued immediately if ALT increases to 5 times ULN or greater during treatment (may be restarted when ALT falls below 5 times ULN), or if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR.

Remdesivirum Drug Interaction

Moderate: rosuvastatin, acetaminophen, nirmatrelvir / ritonavir, acetaminophenUnknown: diphenhydramine, ubiquinone, dexamethasone, apixaban, fluticasone nasal, enoxaparin, pregabalin, metoprolol, guaifenesin, sars-cov-2 mrna , bioflavonoids, cyanocobalamin, ascorbic acid, cholecalciferol, zinc sulfate, cetirizine

Remdesivirum Disease Interaction

Major: renal dysfunctionModerate: liver dysfunction

Volume of Distribution

Data regarding the volume of distribution of remdesivir is not readily available.

Elimination Route

Remdesivirum is absorbed quickly; maximal plasma concentrations following a single 30-minute intravenous infusion are reached within 0.67-0.68 hours (T_max). Repeated dosing yields a C_max (coefficient of variation as a percent) of 2229 (19.2) ng/mL and an AUC_tau of 1585 (16.6) ng*h/mL.

Remdesivirum metabolite GS-441524 has measured values: T_max 1.51-2.00 hours, C_max 145 (19.3) ng/mL, AUC_tau 2229 (18.4) ng*h/mL, and C_trough 69.2 (18.2) ng/mL. Another metabolite, GS-704277, has measured values: T_max 0.75 hours, C_max 246 (33.9) ng/mL, AUC_tau 462 (31.4) ng*h/mL, and an undetermined C_trough.

A 10mg/kg intravenous dose given to cynomolgus monkeys distributes to the testes, epididymis, eyes, and brain within 4h.

Half Life

Remdesivirum has an elimination half-life of 1 hour following a single 30-minute intravenous infusion. Under the same conditions, the elimination half-lives of the remdesivir metabolites GS-441524 and GS-704277 are 27 hours and 1.3 hours, respectively.

A 10mg/kg intravenous dose in non-human primates has a plasma half-life of 0.39h. The nucleoside triphosphate metabolite has a half-life of 14h in non-human primates. The nucleoside triphosphate metabolite has a half-life of approximately 20 hours in humans.

Clearance

Data regarding the clearance of remdesivir is not readily available.

Elimination Route

Remdesivirum is 74% eliminated in the urine and 18% eliminated in the feces. 49% of the recovered dose is in the form of the metabolite GS-441524, and 10% is recovered as the unmetabolized parent compound. A small amount (0.5%) of the GS-441524 metabolite is found in feces.

Pregnancy & Breastfeeding use

No adequate and well controlled studies of Remdesivirum use in pregnant women have been conducted. Remdesivirum should be used in pregnancy only if the potential benefit justifies the potential risk for the mother fetus. There is no information regarding the presence of Remdesivirum in human milk, the effects on the breastfeed infants, or the effects on milk production. Because of the potential for viral transmission of SARS-CoV-2 negative infants and adverse reactions from the drug in breastfeeding infants, the development and health benefits of breastfeeding should be considered along with the mother's clinical need for Remdesivirum and any potential adverse effects on the breastfed child from Remdesivirum or from the underlying maternal condition.

Contraindication

Remdesivirum is contraindicated in patients with known hypersensitivity to Remdesivirum.

Storage Condition

Please do not reuse or save unused Remdesivirum Lyophilized powder, injection solution or diluted solution for infusion for further use. This product contains no preservatives.

Lyophilized Powder: Please store Remdesivirum for injection, 100 mg, vials at temperature not exceeding 30°C in a dry place until required for use. Protect from light & moisture. Do not use after expiration date.

After reconstitution: vials can be stored up to 4 hours at room temperature (20°C-25°C) prior to administration or 24 hours at refrigerated temperature (2°C-8°C). Please dilute within the same day as administration.

Diluted Solution for Infusion: Please store diluted Remdesivirum solution for infusion up to 4 hours at room temperature (20°C-25°C) or 24 hours at refrigerated temperature (2°C-8°C).

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