INTRODUCTION:

Remdesivir is used to treat people with coronavirus disease 2019 (COVID-19) who are in a hospital. Remdesivir is approved for use in adults and children at least 12 years old who weigh at least 88 pounds (40 kilograms). The US Food and Drug Administration (FDA) has authorized emergency use of remdesivir in children younger than 12 years old who weigh at least 8 pounds (3.5 kg) and are hospitalized with COVID-19. Remdesivir has not been FDA-approved to Remdesivir may also be used for purposes not listed in this medication guide treat COVID-19 in these younger patients, especially outside of a hospital. But there are some adverse effects are present their just like, Considering that remdesivir is currently considered an investigational drug, its safety profile has not yet been fully characterized. A randomized, blinded, placebo-controlled, phase I study evaluating the tolerability, and safety profile of single-dose and multiple-dose of remdesivir compared to placebo in healthy subjects reported that remdesivir was well tolerated in both study groups with no serious adverse effects or associated mortality Based on a review of available literature from randomized clinical trials, the following are the potential organ-based adverse effects reported with the use of remdesivir.Cardiovascular: Hypotension, arrhythmias, and cardiac arrestPulmonary: Dyspnea, Acute respiratory failure, acute respiratory distress, pneumothorax, pulmonary embolism Hematological: Anemia, lymphopenia Endocrine: Hyperglycemia Infectious: Pneumonia, septic shock Gastrointestinal: elevated lipase, nausea, vomiting, diarrhea, constipation, poor appetite, gastroparesis, and lower GI bleeding Hepatic: Hepatic manifestation characterized by Grade 1-4 increase in serum transaminases (ALT and/or AST) are the most common adverse effects seen in patients treated with remdesivir. Other abnormalities include hyperbilirubinemia Renal and Metabolic: Acute kidney injury or worsening of underlying chronic kidney disease, hypernatremia, hypokalemia Neurological: Headache, lightheadedness Skin: Rash, contact dermatitis, pruritus Psychiatric: Delirium Other adverse effects: Pyrexia, insomnia, multi-organ dysfunction, DVT, and hypersensitivity/anaphylactic reactions related to the infusion

Objective of Remdesivir:

Review the indication of remdesivir alone or in combination with other drugs. Outlines the recommended doses for remdesivir in both pediatric and adult patient populations.

Describe the importance of close monitoring of renal and hepatic function before, during, and after the use of remdesivir.

Describe the importance of interprofessional team approach especially given the limited published literature available on the clinical efficacy and safety profile of this drug^1,2

Mechanism of Action of Remdesivir:

Remdesivir (GS-5734) is a phosphoramidite prodrug of a monophosphate nucleoside analog (GS-441524) and acts as a viral RNA-dependent RNA polymerase (RdRp) inhibitor, targeting the viral genome replication process. Theoretically, nucleoside analogs do not permeate through the cell wall easily. Upon their subsequent entry into the host cell, they require phosphorylation to produce nucleoside triphosphate (NTP), which resembles adenosine triphosphate (ATP) and can be used by the RdRp enzymes or complexes for genome replication. Once remdesivir is metabolized by the host cells into its pharmacologic active analog adenosine triphosphate (GS-443902), it competes with ATP for integration by the RdRp complex into the nascent RNA strand and, upon subsequent incorporation of a few more nucleotides, results in termination of RNA synthesis limiting viral replication. Remdesivir demonstrated potent antiviral activity against SARS-CoV-2 in vitro in primary human airway epithelial cultures and human lung cells. Remdesivir also had a dose-dependent inhibitory effect on SARS-CoV-2 replication with a half-maximal effective concentration. Data regarding the pharmacokinetics of remdesivir is limited. A randomized, blinded, placebo-controlled, phase I study evaluating the pharmacokinetics of single-dose and multiple-dose of remdesivir compared to placebo in healthy subjects reported that, following single-dose IV administration of remdesivir over 2 hours, remdesivir and its metabolites exhibited a linear profile across the study doses that ranged from 3–225 mg with both solution and lyophilized formulations also exhibiting similar pharmacokinetic parameters¹⁷. Remdesivir is a substrate of, organic anion transporting polypeptide OATP1B1, OATP1B3, and P-glycoprotein (P-gp) transporters and many cytochrome P450 (CYP450) that include CYP2C8, CYP2D6, and CYP3A4 and is considered to be an inhibitor of CYP enzymes in vitro, however, there has been no evidence of CYP induction by remdesivir and its metabolites in vivo. However, based on its route of administration, and rapid elimination, it's potential to cause clinically significant drug–drug interactions (DDIs) may be limited. Nevertheless, further clinical studies are required to evaluate its interaction with the cytochrome P450 system which would determine the potential drug-drug interactions with remdesivir.^3,4,5,6

Adverse Effects:

Considering that remdesivir is currently considered an investigational drug, its safety profile has not yet been fully characterized. A randomized, blinded, placebo-controlled, phase I study evaluating the tolerability, and safety profile of single-dose and multiple-dose of remdesivir compared to placebo in healthy subjects reported that remdesivir was well tolerated in both study groups with no serious adverse effects or associated mortality Based on a review of available literature from randomized clinical trials, the following are the potential organ-based adverse effects reported with the use of remdesivir.^7,8

Cardiovascular	Hypotension, arrhythmias, and cardiac arrest
Pulmonary	Dyspnea, Acute respiratory failure, acute respiratory distress, pneumothorax, pulmonary embolism
Hematological	Anemia, lymphopenia
Endocrine	Hyperglycemia
Infectious	Pneumonia, septic shock
Gastrointestinal	elevated lipase, nausea, vomiting, diarrhea, constipation, poor appetite, gastroparesis, and lower GI bleeding
Hepatic	Hepatic manifestation characterized by Grade 1-4 increase in serum transaminases (ALT and/or AST) are the most common adverse effects seen in patients treated with remdesivir. Other abnormalities include hyperbilirubinemia
Renal and Metabolic	Acute kidney injury or worsening of underlying chronic kidney disease, hypernatremia, hypokalemia
Neurological	Headache, lightheadedness
Skin	Rash, contact dermatitis, pruritus
Psychiatric	Delirium
Other adverse effects	Pyrexia, insomnia, multi-organ dysfunction, DVT, and hypersensitivity/anaphylactic reactions related to the infusion

Side effects include:

Adverse effects reported in ≥5% of patients receiving remdesivir include nausea and increased ALT and AST concentrations.

Phase 3, adaptive, randomized, placebo-controlled trial in hospitalized adults with mild/moderate or severe COVID-19 (NCT04280705; ACTT-1): Serious adverse events reported in 51% of patients in remdesivir group and 57% in placebo group. Adverse events leading to discontinuance of treatment reportedly occurred in 2% of patients receiving remdesivir (seizure, infusion-related reactions, increased aminotransferase concentrations, decreased GFR, acute kidney injury) and 3% of those receiving placebo.Phase 3, randomized, open-label trial in hospitalized adults with severe COVID-19 (NCT04292899; GS-US-540-5773; SIMPLE-Severe): Adverse events reported in 70 or 74% of patients who received a 5- or 10-day remdesivir regimen, respectively; serious adverse events (e.g., respiratory distress or failure, septic shock) reported in 21 or 35%, respectively, and grade 3 or greater adverse events reported in 30 or 43%, respectively. Drug discontinued because of adverse events in 4% of patients in 5-day group and 10% of patients in 10-day group. Most common adverse events overall were nausea (10 or 9%), acute respiratory failure (6 or 11%), increased ALT concentrations (6 or 8%), and constipation (7% in both groups), ^9,10

Phase 3, randomized, open-label trial in hospitalized adults with moderate COVID-19 (NCT04292730; GS-US-540-5774; SIMPLE-Moderate): Adverse events reported in 51 or 59% of patients who received a 5- or 10-day remdesivir regimen, respectively; serious adverse events reported in 5% of patients in both treatment groups, and grade 3 or greater adverse events reported in 11 or 12% of patients receiving 5- or 10-day regimen, respectively. Most common adverse events in patients receiving these respective regimens were nausea (10 or 9%), diarrhea (6 or 5%), hypokalemia (5 or7%), and headache (5% in both treatment groups). Four patients (2%) in 5-day group and 8 patients (4%) in 10-day group discontinued remdesivir due to an adverse event.

General:

The most common side effect in healthy subjects was increased transaminases. The most common side effects in patients with coronavirus disease 2019 (COVID-19) were nausea, increased AST, and increased ALT.[Ref]^7,8

Hepatic:

In studies in healthy subjects, increases in ALT, AST, or both in those who received this drug were grade 1 (10%) or grade 2 (4%). In a clinical study of patients with COVID-19, the incidence of at least grade 3 nonserious side effects of increased aminotransferase levels (including ALT, AST, or both) was 4% with this drug compared to 6% with placebo. In a clinical trial in hospitalized patients with severe COVID-19 receiving this drug for 5 or 10 days, any grade (at least 1.25 times the upper limit of normal [1.25 x ULN]) laboratory abnormalities of increased AST and increased ALT were reported in 40% and 42% of patients, respectively; at least grade 3 (at least 5 x ULN) laboratory abnormalities of increased AST and increased ALT were both reported in 7% of patients. In a clinical trial in hospitalized patients with moderate COVID-19 receiving this drug for 5 or 10 days compared to standard of care, any grade laboratory abnormalities of increased AST and increased ALT occurred in 32% and 33% of patients, respectively, receiving this drug and 33% and 39% of patients, respectively, receiving standard of care; at least grade 3 laboratory abnormalities of increased AST and increased ALT occurred in 2% and 3% of patients, respectively, receiving this drug and 6% and 7%, respectively, receiving standard of care.[Ref] ^11,12,13

Very common (10% or more): Increased transaminases, increased ALT, increased AST Common (1% to 10%): Increased aminotransferase levels (including ALT, AST, or both), increased bilirubin Uncommon (0.1% to 1%): Increased hepatic enzyme, hypertransaminasemia, increased liver function tests[Ref]

Renal:

Very common (10% or more): Decreased CrCl (based on Cockcroft-Gault formula; up to 19%), decreased estimated glomerular filtration rate (eGFR; up to 18%), increased creatinine (up to 15%) Uncommon (0.1% to 1%): Decreased GFR, acute kidney injury[Ref]

Hematologic:

Very common (10% or more): Decreased hemoglobin (up to 15%), decreased lymphocytes (up to 11%)

Some of the common side effects of remdesivir are:

· Yellow eyes

· Dark Urine

· Pain in the upper stomach

· Some of the serious adverse effects of remdesivir are:

· Nausea

· Pain

· Bleeding

· Soreness

· Swelling near the place where Remdesivir is injected

If you have any of these serious symptoms immediately contact your doctor for further assistance. In any case, due to Remdesivir if you get any kind of reactions in your body try avoiding it.

A doctor advised you to take the medicines by seeing your problems and the benefits of this medicine are greater than the side effects. Majority of the people who use this medicine.

Mucormycosis it is the most difficult and dangerous disease comes from the treatment of COVID-19 with Remdisivir:

Mucormycosis (previously called zygomycosis) is a serious but rare fungal infection caused by a group of molds called mucormycetes. These molds live throughout the environment. Mucormycosis mainly affects people who have health problems or take medicines that lower the body’s ability to fight germs and sickness. It most commonly affects the sinuses or the lungs after inhaling fungal spores from the air. It can also occur on the skin after a cut, burn, or other type of skin injury. They live in soil and in decaying organic matter, such as leaves, compost piles, or rotten wood. People get mucormycosis by coming in contact with the fungal spores in the environment. For example, infections involving the lung or sinus can occur after someone breathes in spores. These forms of mucormycosis usually occur in people who have health problems or take medicines that lower the body’s ability to fight germs and sickness.2,3 Fungal infections, including mucormycosis, aspergillosis and invasive candidiasis, have been reported in patients with severe COVID-19 or those recovering from the disease and have been associated with severe illness and death. India has reported a recent surge in mucormycosis cases. Prevention of COVID-19 associated mucormycosis needs to focus on aiming for better glycaemic control in COVID-19 patients and monitoring the use of systemic corticosteroids in treating severe cases. Outpatient use of systemic corticosteroids/other immunomodulating drugs for mild or moderate patients with COVID-19 should be avoided. Health care facilities need to strengthen their infection prevention and control (IPC) programmes to prevent healthcare-associated outbreaks.^14,15,16

CONCLUSION:

There is both in vitro and limited clinical evidence that supports the use of remdesivir to treat SARS-CoV-2. However, Phase 3 clinical trials have not yet been completed and partial data has not yet been reported. The side-effects profile of remdesivir remains similarly not well defined. Until high-quality studies report significant improvements with administration of IV remdesivir, the use of this experimental drug should be limited to randomized controlled trials. Therefore, the potential of remdesivir as a standard of care therapy for COVID-19 remains to be determined. 3 There are some side effects or adverse effects are present their in use of remdisivir such side effects are mentioned in that particular review paper so that’s why the use of remdisivir is harmful for people or patients.

REFERENCE:

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Received on 07.09.2021 Modified on 21.09.2021

Res. J. Pharmacology and Pharmacodynamics.2021;13(4):162-166.

DOI: 10.52711/2321-5836.2021.00030