Covifor - Remdesivir Injection

Remdesivir Injection 100mg/20ml (5mg/ml) Solution

Covifor - Remdesivir for Injection

Remdesivir for Injection 100mg/Vial Lyophilized Powder

The 2019 coronavirus disease (COVID-19) incidence and mortality are rapidly climbing and the treatment options are limited. There is a need of new therapeutic options but it is limited by a lack of evidence and time required for development. Since there is no licensed treatment that specifically acts against COVID-19, medications such as broad-spectrum antivirals are being studied as experimental adjuncts to supportive care. SARS-CoV-2 and influenza viruses show similar disease presentations and similar organ trophism.

COVIFOR (Remdesivir for Injection)

COVIFOR contains remdesivir, an nucleotide analog with broad spectrum antiviral activity is approved by Food and Drug Administration (FDA) issue an Emergency Use Authorization (EUA) for emergency use for the treatment of hospitalized 2019 coronavirus disease (COVID-19) patients.

Remdesivir may have a potential activity against COVID-19 on basis of the in vitro and in vivo activity in animal models against the viral pathogens MERS and SARS, which are also coronaviruses and are structurally similar to COVID-19.

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Formulations

Remdesivir Injection 100mg/20ml (5mg/ml) Solution,

Remdesivir for Injection 100mg/Vial Lyophilized Powder

 

Indications / Authorised Use

Remdesivir is indicated for treatment of suspected or Laboratory confirmed corona virus disease 2019 (COVID-19) in adults and children hospitalized with severe disease.

 

Dosage And Administration

General Information

  • The optimal dosing and duration of treatment is unknown. The suggested dose and duration may be updated as data from clinical trials becomes available.
  • Adult and pediatric patients (>28 days old) must have an eGFR determined and full-term neonates (≥7 days to ≤28 days old) must have serum creatinine determined before dosing of remdesivir.
  • Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir.
  • Remdesivir should be administered via intravenous (IV) infusion only. Do not administer as an intramuscular (IM) injection.

Adult Patients

Dosage in adult and pediatric patients Loading dose on Day 1 via IV infusion Maintenance dose from Day 2-5 via IV infusion
Body weight 40 kg and higher 200 mg 100 mg

Extension of administration of drug beyond 5 days to 10 days is not recommended.


Pediatric Patients

Dosing in pediatric patients is based upon physiologically based pharmacokinetic (PBPK) modeling and simulation of pharmacokinetic data from healthy adult subjects.

Body Weight Recommended dosage form Loading dose on Day 1 via IV infusion Maintenance dose from Day 2-5 via IV infusion
3.5 kg to <40 kg Remdesivir Lyophilized Powder for injection only 5 mg/kg 2.5 mg/kg
40 kg and higher Remdesivir Lyophilized Powder for Injection or Remdesivir Injection Solution 200 mg 100 mg

Extension of administration of drug beyond 5 days to 10 days is not recommended.

  • Use of the adult dose in these pediatric patients is expected to maintain exposures of both remdesivir and the nucleoside analog GS-441524 generally within the expected adult steady-state exposure range following administration of the adult therapeutic dosage regimen in healthy volunteers (N=20 Study GS-406 US-399-5505).
  • Use of this weight-based dosing regimen is expected to maintain remdesivir exposure that is comparable to that observed in adults while limiting the exposure of the nucleoside analog GS-441524 in very young children.

Pediatric patients (>28 days old) must have an eGFR determined and full-term neonates (≥7 days to ≤28 days old) must have serum creatinine determined before dosing.

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


Use in special population

Pregnancy

No adequate and well-controlled studies of remdesivir use in pregnant women have been conducted. Remdesivir should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus. In nonclinical reproductive toxicity studies, remdesivir demonstrated no adverse effect on embryofetal development when administered to pregnant animals at systemic exposures (AUC- Area Under the Curve) of the predominant circulating metabolite of remdesivir (GS-441524) that were 4 times (rats and rabbits) the exposure in humans at the recommended human dose (RHD).

Remdesivir was administered via intravenous injection to pregnant rats and rabbits (up to 20 mg/kg/day) on Gestation Days 6 through 17, and 7 through 20, respectively, and also to rats from Gestation Day 6 to Lactation/Postpartum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed in rats and rabbits at nontoxic doses in pregnant animals. During organogenesis, exposures to the predominant circulating metabolite (GS-441524) were 4 (rats and rabbits) times higher than the exposure in humans at the RHD. In a pre/postnatal development study, exposures to the predominant circulating metabolite of remdesivir (GS-441524) were similar to the human exposures at the RHD.


Nursing Mothers

There is no information regarding the presence of remdesivir in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies, remdesivir and metabolites have been detected in the nursing pups of mothers given remdesivir, likely due to the presence of remdesivir in milk. Because of the potential for viral transmission to SARS CoV-2-negative infants and adverse reactions from the drug in breastfeeding infants, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for remdesivir and any potential adverse effects on the breastfed child from remdesivir or from the underlying maternal condition.

Remdesivir and its metabolites were detected in the plasma of nursing rat pups, likely due to the presence of remdesivir and/or its metabolites in milk, following daily intravenous administration of remdesivir to pregnant mothers from Gestation Day 6 to Lactation Day 20. Exposures in nursing pups were approximately 1% that of maternal exposure on lactation day 10.


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.


Renal Impairment

Use of remdesivir 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 are reported to 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 adults and pediatric patients (>28 days old) with eGFR less than 30 mL per minute or in full-term neonates (≥7 days and ≤28 days old) with serum creatinine clearance ≥1 mg/dL unless the potential benefit outweighs the potential risk.


Pediatric population

The safety and effectiveness of remdesivir for treatment of COVID-19 have not been assessed in pediatric patients. Dosing instructions for pediatric patients were derived based on pharmacokinetic data from adult healthy volunteers and in vitro data for remdesivir and other similar compounds, as part of the PBPK modeling and simulation approach which accounts for age dependent changes in metabolism, distribution, and elimination of remdesivir. Pediatric patients (>28 days) must have creatinine clearance determined and full-term neonates (≥7 days to ≤28 days) must have serum creatinine determined before dosing. Pediatric patients should be monitored for renal function and consideration given for stopping therapy in the setting of substantial decline. The use of remdesivir is not recommended in pediatric patients (>28 days old) with eGFR < 30 mL/min and in full-term neonates (≥7 days and ≤28 days old) with serum creatinine clearance ≥1 mg/dL unless the potential benefit outweighs the potential risk. Because the excipient sulfobutylether-β-cyclodextrin sodium salt (SBECD) is renally cleared and accumulates in patients with decreased renal function, administration of drugs formulated with SBECD (such as remdesivir) is not recommended in adults and pediatric patients (>28 days old) with eGFR less than 30 mL per minute or in full-term neonates (≥7 days and ≤28 days old) with serum creatinine clearance ≥1 mg/dL unless the potential benefit outweighs the potential risk.


Geriatric Population

The pharmacokinetics of remdesivir have not been evaluated in patients >65 years of age. In general, appropriate caution should be exercised in the administration of remdesivir and monitoring of elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.


 

Dose preparation and administration

COVIFOR Remdesivir Injection 100 mg/20 mL (5 mg/mL) Solution

dilute seline_bag

Dilute with 0.9 % saline*

seline_bag

Ready to infuse

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.

*Prior to dilution, equilibrate remdesivir injection to room temperature (20°C to 25°C)


Recommended remdesivir solution dilution instructions in adults and pediatric patients weighing ≥40kg

Remdesivir Dose 0.9% saline infusion bag volume to be used Volume of saline to be withdrawn and discarded from 0.9% saline infusion bag Required volume of remdesivir injection solution
200 mg(2 vials) 250 mL 40 mL 2 x 20 mL
100 mg(1 vial) 20 mL 20 mL

Recommended rate of infusion for diluted remdesivir solution in adults and pediatric patients weighing ≥40kg

Infusion bag volume Infusion time Rate of infusion
250 mL 30 min 8.33 mL/min
60 min 4.17 mL/min
120 min 2.08 mL/min

infuse_1
Infused intravenously over 30 to 120 minutes
infuse_2


COVIFOR Remdesivir for Injection 100 mg/ Vial Lyophilized powder

lyo_powder

Remdesivir 100 mg Lyophilized Powder

lyo_powder lyo_powder arrow

Reconstitute with 19 ml sterile water for injection

shake shake

Shake the vial for 30 seconds. Allow the contents to settle for 2 to 3 minutes. A clear solution should result.*

dilute seline_bag

Dilute with 0.9 % saline*

seline_bag

Ready to infuse


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.

*If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the contents of the vial are completely dissolved.


Adults and pediatric patients weighing ≥ 40 kg

Recommended dilution instructions – Remdesivir for injection lyophilized powder in Adults and pediatric patients weighing ≥ 40 kg

Remdesivir dose 0.9% saline infusion bag volume to be used Volume of saline to be withdrawn and discarded from 0.9% saline infusion bag Required volume of reconstituted remdesivir for injection
200 mg (2 vials) 250 mL 40 mL 2 x 20 mL
100 mL 40 mL 2 x 20 mL
100 mg (1 vial) 250 mL 20 mL 20 mL
100 mL 20 mL 20 mL

Recommended rate of infusion – Diluted remdesivir for injection lyophilized powder in adults and pediatric patients weighing ≥ 40 kg

Infusion bag volume Infusion time Rate of infusion
250 mL 30 min 8.33 mL/min
60 min 4.17 mL/min
120 min 2.08 mL/min
100 mL 30 min 3.33 mL/min
60 min 1.67 mL/min
120 min 0.83 mL/min


Pediatric patients weighing 3.5 Kg to < 40 kg

Recommended rate of infusion for pediatric patients weighing 3.5 Kg to < 40 kg

Infusion bag volume Infusion time Rate of infusion*
100 mL 30 min 3.33 mL/min
60 min 1.67 mL/min
120 min 0.83 mL/min
50 mL 30 min 1.67 mL/min
60 min 0.83 mL/min
120 min 0.42 mL/min
25 mL 30 min 0.83 mL/min
60 min 0.42 mL/min
120 min 0.21 mL/min

Rate of infusion may be adjusted based on total volume to be infused


infuse_1
Infused intravenously over 30 to 120 minutes
infuse_2
 

Contraindications

Remdesivir is contraindicated in patients with known hypersensitivity to any ingredient of Remdesivir. Remdesivir is contraindicated in patients with severe renal impairment with eGFR < 30 mL/min.

 

Warnings And Precautions

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 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 COVID-19. 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 to 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
 

Drug Interactions

Drugs that should not be co-administered with remdesivir

Category COVID-19 Antivirals Antibacterials Anticonvulsants Antidepressants
Drugs Chloroquine, Hydroxychloroquine Rifampicin, Rifapentine Carbamazepine, Phenobarbital (phenobarbitone), Phenytoin, Primidone St. John's wort

There are some medications out there that will boost the Remdesivir level in bloodstream, and some that will reduce it. Some antibiotics, anticonvulsants, and even herbal products may do this, which include Clarithromycin, Rifampin, Phenytoin, Phenobarbital, St. John's Wort No in vivo interaction studies have been performed, but the ability of the parent compound remdesivir to inhibit CYP enzymes and transporters, as well it's the inducing capacity, has been tested in vitro. For remdesivir, the regulatory cut off, 50 X Cmax(unbound) is 54.6 μM based on a Cmax of 5440 ng/ml (loading dose) and 12 % fraction unbound.

CYP Inhibition/ CYP induction

The potential for remdesivir to inhibit CYP enzymes was evaluated using human hepatic microsomes and monitoring specific CYP-mediated transformations of probe substrates. Remdesivir was a weak inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Remdesivir had an IC50 for CYP3A of 1.6 μM.

The potential of induction of CYP enzymes (CYP1A2, CYP2B6, and CYP3A4) following exposure of human hepatocytes to remdesivir, and its major systemic metabolites, GS-704277 and the nucleoside analog GS-441524, was assessed by quantitating messenger RNA (mRNA) levels and CYP enzyme activities. In hepatocytes from 1 of the 3 donors, remdesivir showed induction of mRNA levels of CYP1A2 and CYP2B6 by 5.7-fold and 5.4-fold, respectively. Such induction was not observed in hepatocytes from the other 2 donors. Remdesivir showed no induction of CYP3A4 mRNA or CYP3A4/5 activity. GS-441524 and GS-704277 showed no induction of CYP enzymes tested in the study.

  • Dexamethasone and Remdesivir - Use with caution.

    Dexamethasone is a substrate of CYP3A4 and a moderate inducer of this enzyme. Due to remdesivir's rapid clearance, although remdesivir inhibits CYP3A4 it is unlikely to have a significant effect on dexamethasone. Dexamethasone can potentially reduce remdesivir concentrations due to induction of CYP3A4.

Transporter substrate/ Transporter Inhibition

Remdesivir was found to be a substrate for OATP1B1 but not for OATP1B3. Remdesivir was assessed as a substrate for the efflux transporters Pglycoprotein (P-gp) and breast cancer resistance protein (BCRP). Remdesivir was found to be a substrate for P-gp but not BCRP. In cells overexpressing human organic anion transporters (OAT) 1 and 3, no evidence for transport of remdesivir and its major systemic metabolites, GS-704277 and the nucleoside analog GS-441524, was observed.

The potential for remdesivir to inhibit drug transporters was assessed in vitro in transfected cell lines expressing OATP1B1, OATP1B3, P-gp, and BCRP. Remdesivir did not inhibit P-gp at the highest concentration tested (40 μM), but inhibited OATP1B1- and OATP1B3 with IC50 values of 2.8 and 2.1 μM, respectively. Remdesivir inhibited BSEP-, MRP4- and NTCP-mediated probe substrate transport, with calculated IC50 values of 22, 5.1, and 72 μM, respectively. No interaction of remdesivir with MRP2 was observed at up to 100 μM. The major metabolite GS-704277 showed 25% and 44% inhibition of MRP2- and NTCP-mediated transport, respectively, at the 100 μM test concentration Whereas no interaction with BSEP or MRP4 was observed. The nucleoside metabolite GS-441524 showed 24% inhibition of NTCP mediated transport at the 100 μM test concentration, but no interaction with BSEP, MRP2, or MRP4 was observed.

 

Clinical Pharmacology

Mechanism of Action

Remdesivir is a prodrug that metabolizes into its active form GS-441524. An adenosine nucleoside analog, GS-441524 interferes with the action of viral RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production. It was unknown whether it terminates RNA chains or causes mutations in them. However, it has been learned that the RNA-dependent RNA polymerase of ebola virus is inhibited for the most part by delayed chain termination. Mutations in the mouse hepatitis virus RNA replicase that cause partial resistance were identified in 2018. These mutations make the viruses less effective in nature, and the researchers believe they will likely not persist where the drug is not being used.

Pharmacodynamics

Remdesivir has been recognized as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV) infection in cultured cells, mice and nonhuman primate (NHP) models. Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination. Time-of-addition assay showed remdesivir functioned at a stage post virus entry, which is in agreement with its putative anti-viral mechanism as a nucleotide analogue. A study showed that in NHP model, intravenous administration of 10 mg/kg dose of remdesivir resulted in concomitant persistent levels of its active form in the blood (10mM) and conferred 100% protection against Ebola virus infection.

Data showed that EC90 value of remdesivir against 2019-nCoV in Vero E6 cells was 1.76mM, suggesting its working concentration is likely to be achieved in NHP. Preliminary data showed that remdesivir also inhibited virus infection efficiently in a human cell line (human liver cancer Huh-7 cells), which is sensitive to 2019-nCoV.

Pharmacokinetics

The PK of the exact proposed dosing regimen has not been evaluated, but sufficient clinical data exists to support this regimen. Following single-dose, 2-hour IV infusion of remdesivir solution formulation at doses ranging from 3 to 225 mg, remdesivir exhibited a dose-linear PK. Repeated once-daily 1-hour infusions of 150 mg remdesivir solution formulation demonstrated time-linear PK through 14 days. Following single-dose, 2-hour IV administration of remdesivir solution formulation at doses of 75 and 150 mg, remdesivir exhibited similar PK profiles as the lyophilized formulation. Even though remdesivir 75 mg administered IV over 30 minutes provided similar parent exposure as the same dose administered over 2 hours, PBMC exposure of GS443902 was higher than remdesivir 150 mg administered IV over 2 hours. This data supports the administration over the shorter time interval of 30 minutes as a more effective dosing method for maximizing the intracellular levels of the active metabolite GS-443902. A prolonged intracellular half-life of more than 35 hours was observed for GS-443902 in PBMCs, supporting the once-daily dosing of remdesivir. Furthermore, an accumulation ratio of 2.7 to 3.5-fold for intracellular metabolites suggests that a 200 mg remdesivir loading dose will better facilitate the achievement of subsequent steady-state PBMC levels of GS-443902 following repeat 100 mg daily maintenance dosing of remdesivir, which might be critical in the treatment of acutely infected patients.

 

Storage

COVIFOR Remdesivir Injection 100 mg/20 mL (5 mg/mL) Solution

Remdesivir 5mg/mL solution - Store at 2°C to 8°C until required for use. Do not use after expiration date. Dilute within the same day as administration.

Diluted Infusion Solution - Prior to dilution, equilibrate remdesivir injection to room temperature (20°C to 25°C ). Sealed vials can be stored up to 12 hours at room temperature prior to dilution. Store diluted remdesivir solution for infusion up to 4 hours at room temperature (20°C to 25°C) or 24 hours at refrigerated temperature (2°C to 8°C).

storage

COVIFOR Remdesivir for Injection 100 mg/ Vial Lyophilized powder

Lyophilized Powder - Store remdesivir for injection, 100 mg, vials below 30°C until required for use.

Reconstituted solution - After reconstitution, vials can be stored up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) prior to administration or 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Diluted Infusion Solution - 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]).

storage
 

Clinical Data For Remdesivir

Study 1: SIMPLE STUDY

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

Study design and dosage: Phase 3, open-label, trial evaluating 5-day and 10-day dosing durations of the investigational antiviral remdesivir in hospitalized patients with severe manifestations of COVID-19 disease.

The initial phase of the study randomized 397 patients in a 1:1 ratio to receive remdesivir 200 mg on the first day, followed by remdesivir 100 mg each day until day 5 or 10, administered intravenously, in addition to standard of care.

Results: As per initial study data published on April 29th demonstrates following

  • Similar clinical improvement in patients receiving a 10-day or 5-day treatment course of remdesivir (Odds Ratio: 0.75 on Day 14).
  • Key efficacy and safety results from the study are included in the table below.
5-Day Remdesivir n=200 10-Day Remdesivir n=197 Baseline adjusted p-value1
Clinical Efficacy Outcomes at Day 14
≥ 2-point improvement in ordinal scale 129 (65) 107 (54) 0.16
Clinical recovery 129 (65) 106 (54) 0.17
Discharge 120 (60) 103 (52) 0.44
Death 16 (8) 21 (11) 0.70
Safety
Any adverse event (AE) 141 (71) 145 (74) 0.86
Grade ≥3 study drug-related AE 8 (4) 10 (5) 0.65
Study drug-related serious adverse event (SAE) 3 (2) 4 (2) 0.73
AE leading to discontinuation 9 (5) 20 (10) 0.07

1 Adjusted for baseline clinical status

  • In an exploratory analysis, by day 14 remdesivir administered within 10 days of symptom onset had improved outcomes (62 %) compared to after more than 10 days of symptoms (42 %).

An expansion phase: Additional 5,600 patients, including patients on mechanical ventilation. 180 trial sites around the world, including sites in the United States, China, France, Germany, Hong Kong, Italy, Japan, Korea, the Netherlands, Singapore, Spain, Sweden, Switzerland, Taiwan and the United Kingdom.

Second SIMPLE trial: Evaluating the safety and efficacy of 5-day and 10-day dosing durations of remdesivir administered intravenously in patients with moderate manifestations of COVID-19, compared with standard of care. The results from the first 600 patients of this study are expected at the end of May.


Study 2: The Adaptive COVID-19 Treatment Trial (ACTT-1)

Remdesivir for the Treatment of Covid-19 — Preliminary Report

Methods: A double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients randomly received either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days.

Primary outcome: Time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.

Results: A total of 1063 patients underwent randomization.

  • Preliminary results from the 1059 patients (538 remdesivir and 521 placebo)
  • Median recovery time for Remdesivir of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P< 0.001).
  • The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04).
  • Serious adverse events were reported for 114 of the 541 patients in the remdesivir group (21.1%) and 141 of the 522 patients in the placebo group (27.0%).

Conclusions: Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection.


Study 3:

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Methods: A randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China.

Inclusion criteria: Adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia.

Dosage: Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for 10 days.

Patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids.

The primary endpoint: Was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first.

Results: Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo);

  • Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1.23 [95% CI 0.87–1.75]).
    • Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1.52 [0.95–2.43]).
  • Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients.
    • Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early.

Conclusion: In adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.


Study 4:

Remdesivir in Treatment of COVID-19: A Systematic Benefit-Risk Assessment

Aim: Provide a platform for a dynamic systematic benefit-risk evaluation, which starts with inevitably limited information (to meet the urgent unmet public health need worldwide), then update the benefit-risk evaluation as more data become available.

Methods: The Benefit-Risk Action Team (BRAT) framework was used to assess the overall benefit-risk of the use of remdesivir as a treatment for COVID-19 compared with standard of care, placebo or other treatments.

PubMed, Google Scholar and government agency websites were searched to identify literature reporting clinical outcomes in patients taking remdesivir for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance.

Results: Using the BRAT method, following key benefits and risks for use of remdesivir in COVID-19 compared with placebo were identified.

  • The benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR 1.23, 95% CI 0.87-1.75), although the study was underpowered.
  • A shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%).
  • Fewer serious adverse events in patients taking remdesivir (18%) compared with the placebo group (26%); however, more patients in the remdesivir group discontinued treatment as a result of an adverse event compared with those patients receiving placebo (12% vs 5%).

Conclusions: Preliminary clinical trial results suggest that there may be a favourable benefit-risk profile for remdesivir compared with placebo in severe COVID-19 infection and further data on benefits would strengthen this evaluation.


BCRP: Breast Cancer Resistance Protein; BSEP : Bile Salt Export Pump; MRP : Multidrug Resistance Protein; NTCP : Sodium Taurocholate Cotransporting Polypeptide; OAT : Organic Anion Transporters; eGFR - Estimated Glomerular Filtration Rate; LFT - Liver Function Tests; AST- Aspartate Aminotransferase; ALT – Alanine Aminotransferase


References:

1. COVIFOR, DCGI product permission, dated 20.06.2020

2. COVIFOR, package insert (accessed on 31.07.2020)

3. https://www.covid19-druginteractions.org/checker# (accessed on 24/06/2020)

4. Fact sheet for healthcare providers – Emergency Use Authorization (EUA) of remdesivir (GS-5734™) (accessed on 31/07/2020)

5. Dexamethasone in the treatment of COVID-19, From the UK CMOs and Medical Director of NHS England. Published on 16 June 2020.

6. https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19 (accessed on 30/05/2020)

7. Goldman JD, Lye DCB et al. Remdesivir for 5 or 10 Days in Patients With Severe Covid-19. N Engl J Med. 2020 May 22.

8. Beigel JH, Tomashek KM et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. May 22, 2020, at NEJM.org

9. Davies M, Osborne V, et al. Remdesivir in Treatment of COVID-19: A Systematic Benefit-Risk Assessment. Drug Saf. 2020 May 28. (accessed on 30/05/2020)

10. https://www.gilead.com/news-and-press/press-room/press-releases/2020/5/gilead-announces-approval-of-veklury-remdesivir-in-japan-for-patients-with-severe-covid19 (accessed on 30/05/2020)

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Remdesevir is used by doctors for the treatment of coronavirus disease 2019 (COVID-19). Currently, there is no approved product to treat COVID-19.

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