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TRANSFORMAR COMO VOCÊ USA INFORMAÇÕES SOBRE DROGAS
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NOTE: Initiate treatment as soon as possible after the positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and within 7 days of symptom onset.[65314][66063][67214]
NOTE: Health care providers should choose a therapeutic option with activity against the circulating variants in their state, territory, or US jurisdiction. Current variant frequency data are available at: https://covid.cdc.gov/covid-data-tracker/#variant-proportions.
200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days.[66063]
5 mg/kg/dose (Max: 200 mg/dose) IV once on day 1, followed by 2.5 mg/kg/dose (Max: 100 mg/dose) IV once daily for 9 days.[66063]
5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 9 days.[66063]
2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 9 days.[66063]
2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 9 days.[66063]
2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 4 days was successfully used in a case report of 2 ex-premature neonates. The first neonate was born at 31 weeks, weighed 2.7 kg, and presented with SARS-CoV-2 infection at 37 weeks of life. The second neonate was born at 33 weeks (birthweight 1.5 kg) and presented with SARS-CoV-2 infection at 35 weeks of life. In both cases, the SARS-CoV-2 RNA PCR became negative only after completion of treatment with remdesivir.[66931] Another case report describes 5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 10 days successfully used in an ex-premature neonate (born at 32 weeks) weighing 2.2 kg who presented with SARS-CoV-2 infection at 37 weeks of life.[66493]
200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days.[66063]
200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days.[66063]
200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063] [65314]
5 mg/kg/dose (Max: 200 mg/dose) IV once on day 1, followed by 2.5 mg/kg/dose (Max: 100 mg/dose) IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063]
5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063]
2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063]
2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063]
2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 4 days was successfully used in a case report of 2 ex-premature neonates. The first neonate was born at 31 weeks, weighed 2.7 kg, and presented with SARS-CoV-2 infection at 37 weeks of life. The second neonate was born at 33 weeks (birthweight 1.5 kg) and presented with SARS-CoV-2 infection at 35 weeks of life. In both cases, the SARS-CoV-2 RNA PCR became negative only after completion of treatment with remdesivir.[66931] Another case report describes 5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 10 days successfully used in an ex-premature neonate (born at 32 weeks) weighing 2.2 kg who presented with SARS-CoV-2 infection at 37 weeks of life.[66493]
200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063] [65314]
200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days. May extend treatment for up to 5 additional days (i.e., 10 days total) if a patient does not demonstrate clinical improvement.[66063]
200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days.[66063] [67214] According to NIH, the optimal management of immunocompromised patients who have prolonged COVID-19 symptoms and evidence of ongoing viral replication despite receiving a course of antiviral therapy is unknown. Some members of the guideline panel suggest using longer or additional courses of remdesivir in these patients.[65314]
5 mg/kg/dose (Max: 200 mg/dose) IV once on day 1, followed by 2.5 mg/kg/dose (Max: 100 mg/dose) IV once daily for 2 days.[66063] [67214]
5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 2 days.[66063]
2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 2 days.[66063]
2.5 mg/kg/dose IV once on day 1, followed by 1.25 mg/kg/dose IV once daily for 2 days.[66063]
200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days.[66063] [67214] According to NIH, the optimal management of immunocompromised patients who have prolonged COVID-19 symptoms and evidence of ongoing viral replication despite receiving a course of antiviral therapy is unknown. Some members of the guideline panel suggest using longer or additional courses of remdesivir in these patients.[65314]
200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days.[66063] [67214]
200 mg IV on day 1, followed by 100 mg/day IV.
200 mg IV on day 1, followed by 100 mg/day IV.
5 mg/kg/dose (Max: 200 mg/dose) IV on day 1, followed by 2.5 mg/kg/day (Max: 100 mg/day) IV.
5 mg/kg/dose (Max: 200 mg/dose) IV on day 1, followed by 2.5 mg/kg/day (Max: 100 mg/day) IV.
weighing 3 kg or more: 5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/day IV.
weighing less than 3 kg: 2.5 mg/kg/dose IV on day 1, followed by 1.25 mg/kg/day IV.
Term Neonates weighing 1.5 kg or more: 2.5 mg/kg/dose IV on day 1, followed by 1.25 mg/kg/day IV.
Term Neonates weighing less than 1.5 kg: Safety and efficacy have not been established.
Premature Neonates: Safety and efficacy have not been established; however, doses of 2.5 mg/kg/dose IV on day 1, followed by 1.25 mg/kg/day IV have been used off-label.
No dosage adjustments are recommended for patients with mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C). 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]
No dosage adjustments are needed for patients with any degree of renal impairment, including patients on dialysis. Remdesivir is not efficiently removed through hemodialysis and may be administered without regard to the timing of dialysis.[66063]
† Off-label indication
Remdesivir is an intravenous antiviral medication approved to treat coronavirus disease 2019 (COVID-19) in adults and pediatric patients weighing at least 1.5 kg with positive testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is only indicated for use in patients who are hospitalized with COVID-19 or for patients with mild to moderate COVID-19 who are not hospitalized, but at high risk of progressing to severe COVID-19, including hospitalization or death.[66063]
The National Institutes of Health (NIH) COVID-19 treatment guidelines have recommendations for the use of remdesivir based on disease severity.[65314]
Adult patients
Pediatric patients
For storage information, see the specific product information within the How Supplied section.
**For pediatric patients weighing less than 40 kg, use ONLY the lyophilized powder formulation to prepare doses.**[66063]
Remdesivir Lyophilized Powder 100 mg vials
Reconstitution
Dilution
Remdesivir Solution for Injection 100 mg/20 mL vials
Preparation
Dilution
Intermittent IV Infusion
Bradycardia has been reported in patients with COVID-19, with severe cases of bradycardia tending to occur in patients who have more severe infection. Treatment with remdesivir may increase the risk of developing bradycardia. In a meta-analysis of mostly observational data, the incidence of bradycardia was 22.3% in patients treated with remdesivir compared to 9.8% in those not receiving the drug (odd ratio, 2.11; 95% CI, 1.65 to 2.71; p < 0.001). Bradycardia typically improves with resolution of the infection, and can be managed with remdesivir discontinuation or use of atropine or dopamine if necessary.[71414] Atrial fibrillation (6%) and hypotension (8%) were associated with the use of remdesivir during an open-label compassionate-use study of patients with severe COVID-19 (n = 53).[65245] In a study of patients treated for Ebola virus disease, one patient had a hypotensive episode during the administration of the loading dose of remdesivir, which led to a fatal cardiac arrest; however, the independent pharmacovigilance committee noted that the death could not be readily distinguished from underlying fulminant Ebola virus disease.[65247] Acute respiratory distress syndrome (ARDS) was reported in 4% of patients receiving remdesivir in an open-label compassionate-use study of patients with severe COVID-19 (n = 53).[65245]
Hypersensitivity reactions, including infusion-related reactions and anaphylactoid reactions, have been observed during and after treatment with remdesivir; most occurring within 1 hour. Signs and symptoms may include hypotension, hypertension, sinus tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nauseous feeling, diaphoresis, and shivering. Monitor patients during and for at least 1 hour after drug administration. Slowing the infusion rate to a maximum infusion time of up to 120 minutes can be considered to potentially prevent these reactions. If a clinically significant reaction occurs, immediately discontinue the infusion and initiate appropriate treatment. In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,476), rash was reported in less than 2% of patients treated with remdesivir.[66063] Cases of injection site reaction, including administration site extravasation, phlebitis (n = 8), and ecchymosis (n =5), have also been reported during use of remdesivir.[65247] [66063]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,476), nausea (1% to 7%), diarrhea (1%), and abdominal pain (1%) were reported in patients receiving remdesivir. Similarly, 6% of nonhospitalized patients (n = 279) who received remdesivir in a Phase 3 trial reported nausea.[66063] In an open-label compassionate-use study of remdesivir in patients with severe COVID-19 (n = 53), diarrhea was reported in 9% of patients.[65245]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,476), elevated hepatic enzymes were reported in 2% to 8% of patients receiving remdesivir. Hyperbilirubinemia, including Grade 3 or 4, has been reported in 2% or less of patients receiving remdesivir in clinical trials. In safety data from a clinical trial involving hospitalized pediatric patients with COVID-19 (n = 58), the most common hepatic adverse reaction (all grades) was increased ALT (6%). Other hepatic laboratory abnormalities (Grades 3 to 4) occurring in patients receiving remdesivir and who had at least 1 post-baseline value for the specified test were increased direct bilirubin (9%, n = 2/23) and increased ALT (4%, n = 2/51). Two patients permanently discontinued remdesivir due to increased ALT (n = 1) and increased AST and hyperbilirubinemia (n = 1). Increased direct bilirubin was also reported in 1 neonate receiving remdesivir in clinical trials.[66063] In patients with severe COVID-19, it may be difficult to attribute hepatotoxicity to remdesivir rather than the underlying disease; however, mild to moderate (Grade 1 and 2) elevated hepatic enzymes have also been associated with the use of remdesivir in healthy volunteers and patients infected with the Ebola virus.[65245] [66063] Hepatotoxicity is an identified risk with remdesivir.[65248]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,476), the most frequently reported hematologic adverse events were decreased hemoglobin or anemia (1% to 25%), decreased lymphocytes or lymphopenia (11% to 27%), increased prothrombin time (9% to 11%), increased prothrombin INR (7%), and increased thromboplastin time (5%). In a Phase 3 trial involving nonhospitalized patients (n = 279), decreased lymphocytes and increased prothrombin time were reported in 2% and 1% of remdesivir recipients, respectively. In safety data from a clinical trial involving hospitalized pediatric patients with COVID-19 (n = 58), hematologic laboratory abnormalities (Grades 3 to 4) occurring in patients receiving remdesivir and who had at least 1 post-baseline value for the specified test were decreased hemoglobin or anemia (18%, n = 9/51), increased prothrombin time (7%, n = 3/46), increased aPTT (7%, n = 3/45), decreased lymphocytes or lymphopenia (6%, n = 2/33), and decreased WBC or leukopenia (4%, n = 2/51). Increased aPTT (n = 2/5), prothrombin time (n = 1/5), and prothrombin/INR (n = 1/5) were also reported in neonates receiving remdesivir in clinical trials.[66063]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,476), the most frequently reported metabolic adverse events for remdesivir were increased blood glucose or hyperglycemia (3% to 15%), increased uric acid or hyperuricemia (11%), decreased albumin or hypoalbuminemia (12%), increased lipase (12%), increased sodium or hypernatremia (3%), and increased calcium or hypercalcemia (3%). Similarly, 6% of nonhospitalized patients (n = 279) who received remdesivir in a Phase 3 trial reported increased blood glucose. In safety data from a clinical trial involving hospitalized pediatric patients with COVID-19 (n = 58), metabolic laboratory abnormalities (Grades 3 to 4) occurring in patients receiving remdesivir and who had at least 1 post-baseline value for the specified test were increased blood glucose or hyperglycemia (4%, n = 2/52) and decreased potassium or hypokalemia (4%, n = 2/52). Increased potassium (hyperkalemia) was reported in 1 neonate receiving remdesivir in clinical trials.[66063] In an open-label compassionate-use study of remdesivir in patients with severe COVID-19 (n = 53), 6% of patients developed hypernatremia.[65245]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,476), the most frequently reported renal adverse events for remdesivir were decreased creatinine clearance and/or glomerular filtration rate (2% to 19%) and increased creatinine (5% to 15%). Acute kidney injury (renal failure) was reported in 3 patients who received remdesivir. Similarly, in a Phase 3 trial of nonhospitalized patients (n = 279) who received remdesivir, decreased creatinine clearance and increased creatinine were reported in 6% and 3% of patients, respectively. In safety data from a clinical trial involving hospitalized pediatric patients with COVID-19 (n = 58), renal laboratory abnormalities (Grades 3 to 4) occurring in patients receiving remdesivir and who had at least 1 post-baseline value for the specified test were decreased eGFR (18%, n = 7/40), increased creatinine (10%, n = 5/52), proteinuria (6%, n = 2/36), and glycosuria (4%, n = 2/46). Increased creatinine was also reported in 1 neonate receiving remdesivir in clinical trials.[66063] In an open-label compassionate-use study of remdesivir in patients with severe COVID-19 (n = 53), renal adverse events reported included acute kidney injury (6%), renal impairment (8%), and hematuria (4%).[65245]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,476), generalized seizures were reported by less than 2% of patients treated with remdesivir.[66063] In pooled data from Gilead-sponsored studies (n = 138), headache was reported in 6 patients and extremity pain (musculoskeletal pain) was reported in 5 patients.[65247] Delirium was reported in 4% of patients treated with remdesivir in a small open-label compassionate use study (n = 53).[65245]
QT prolongation has been reported with remdesivir; however, confounding factors (e.g., age, comorbid conditions, concomitant medications) make it difficult to assess the contribution of remdesivir on QT prolongation. There is no compelling evidence for risk of torsades de pointes (TdP) with use of remdesivir.[68632] [68633] [68634] [68635]
Remdesivir was associated with the development of Kounis syndrome (an allergic reaction resulting in an acute coronary syndrome) in a case report involving a 54-year-old patient hospitalized with COVID-19. Prior to initiating remdesivir, the patient was hypotensive (blood pressure 90/60 mmHg), had a creatinine concentration of 2 mg/dL, and had a normal left ventricular systolic function verified by transthoracic echocardiography. Remdesivir was started once the kidney function improved; however, after the first 1 mL was infused, the patient developed pruritic rash and acute chest pain without dyspnea. His blood pressure was 110/80 mmHg and a transthoracic echocardiography revealed hypokinesis of the septal wall and apex with an estimated ejection fraction of 30%. Remdesivir was stopped, and the patient received treatment with intravenous hydrocortisone and an antihistamine. The symptoms resolved and subsequent imaging showed normal left ventricular systolic function without myocardial edema or fibrosis.[70081]
Remdesivir is contraindicated in patients with hypersensitivity to remdesivir or any components of the product.[66063]
Hypersensitivity reactions, including infusion-related reactions and anaphylaxis, have been observed during and after treatment with remdesivir; most occurring within 1 hour. Monitor patients during and for at least 1 hour after administration for the following adverse reactions: hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering. Slowing the infusion rate to a maximum infusion time of up to 120 minutes can be considered to potentially prevent these reactions. If a clinically significant reaction occurs, immediately discontinue the infusion and initiate appropriate treatment.[66063]
Intravenous formulations of remdesivir contain betadex sulfobutyl ether sodium (SBECD) as a solubility enhancer, which is renally cleared and accumulates in patients with decreased renal function. Administration of remdesivir to pediatric patients with renal immaturity (i.e., neonates and infants) or renal impairment may result in higher exposure to SBECD. No data are available regarding the safety of remdesivir in pediatric patients with severe renal impairment.[66063]
No remdesivir dosage adjustments are recommended for patients with mild, moderate, or severe hepatic disease (Child-Pugh A, B, or C); however, treatment has been associated with an increase in hepatic enzymes. Conduct liver function testing (LFT) in all patients before and during treatment, as clinically appropriate. For elevated hepatic enzymes developing during therapy, consider treatment discontinuation if the increase in ALT is greater than 10-times the upper limit of normal. If the ALT increase is accompanied by signs or symptoms of hepatic inflammation, discontinue remdesivir.[66063]
The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend that remdesivir be offered to pregnant patients if indicated. When evaluating the risk and benefits of remdesivir, consider that COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.[65314] Data from a clinical trial, published reports, the ongoing COVID-PR pregnancy exposure registry, and compassionate use of remdesivir in pregnant patients have not identified a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes following exposure in the second and third trimester. However, there are insufficient pregnancy data available to evaluate the risk of remdesivir exposure during the first trimester. A non-randomized, open-label clinical study (IMPAACT 2032) evaluated the safety of up to 10 days of treatment with remdesivir in 25 hospitalized pregnant and 28 hospitalized non-pregnant patients of childbearing potential. Of the 25 pregnant patients, median gestational age was 28 weeks at baseline (range: 22 to 33 weeks) and approximately half of the patients were in each of the second and third trimesters of pregnancy. The adverse reactions observed were consistent with those observed in clinical trials of remdesivir in adults.[66063] A systemic review of 13 observational studies that included 113 pregnant patients found few adverse effects from the use of remdesivir during pregnancy. The most common adverse event was mild elevations in transaminase concentrations. Among 95 pregnant patients with moderate, severe, or critical COVID-19 who were included in a secondary analysis of data from a COVID-19 pregnancy registry in Texas, the composite maternal and neonatal outcomes were similar between those who received remdesivir (n = 39) and those who did not. Remdesivir was discontinued in 16.7% of patients due to elevated transaminase concentrations; however, it was not possible to determine if the elevated concentrations were due to the drug, COVID-19, or pregnancy-related conditions. In another report, remdesivir was well tolerated among 67 pregnant and 19 postpartum patients (median postpartum day = 1; range 0 to 3 days) who were hospitalized with severe COVID-19 and received remdesivir through a compassionate use program. In this study, 45 deliveries were observed. No neonatal deaths occurred during the 28-day observation period; however, 1 spontaneous miscarriage occurred at 17 weeks gestation in a mother with concurrent S. aureus bacteremia, endocarditis, and septic arthritis.[65314] [66019] In animal studies involving rats and rabbits, no adverse effects on embryo-fetal development were observed after exposure to the predominant circulating metabolite (GS-441524) that were 4-times the exposure at the recommended human dose. There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to remdesivir during pregnancy. Pregnant and recently pregnant patients can enroll at covid-pr.pregistry.com or call 1-800-616-3791 to obtain more information.[66063]
A published case report describes the presence of remdesivir and active metabolite GS-441524 in human milk. Available data (n=11) from pharmacovigilance reports do not indicate adverse effects on breast-fed infants from exposure to remdesivir and its metabolites through breast milk. There are no available data on the effects of remdesivir on milk production.[66063] The National Institutes of Health (NIH) states that concentrations of remdesivir that would reach a breast-fed infant are estimated to be low; thus, if indicated, treatment should be offered to a lactating patient and breast-feeding can continue without interruption.[65314] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, the potential for viral transmission to SARS-CoV-2-negative infants, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.[65248] [66063]
According to the National Institutes of Health (NIH), the optimal management of patients with immunosuppression who have prolonged COVID-19 symptoms and evidence of ongoing viral replication despite receiving a course of antiviral therapy is unknown. Some members of the guideline panel suggest using longer or additional courses of remdesivir in these patients.[65314]
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 (ATP) for incorporation into nascent viral RNA chains. Once incorporated at position (i), RDV-TP terminates RNA synthesis at position (i+3). Because it does not cause immediate chain termination and allows for the incorporation of 3 additional nucleotides, RDV-TP appears to evade proofreading by viral exoribonuclease (an enzyme thought to excise nucleotide analog inhibitors). This delayed chain termination disrupts viral replication.
Remdesivir displays a broad spectrum of in vitro antiviral activity against RNA viruses, including those from the 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 and 115 nM after 48 hours of treatment, respectively. Against clinical isolates of the following SARS-CoV-2 variants [Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), Epsilon (B.1.429), Gamma (P.1), Iota (B.1.526), Kappa (B.1.617.1), Lambda (C.37), Zeta (P.2), and Omicron variants (B.1.1.529/BA.1, BA.2, BA.2.12.1, BA.2.75, BA.4, BA.4.6, BA.5, BF.5, BF.7, BQ.1, BQ.1.1, CH.1.1, EG.1.2, EG.5.1, FL.22, XBB, XBB.1.5, XBB.1.16, XBB.2.3.2, and XBF)], remdesivir retains antiviral activity that is similar (i.e., 0.2- to 2.3-fold change in EC50 value) to an earlier lineage SARS-CoV-2 isolate (lineage A). Using the SARS-CoV-2 replicon system, remdesivir also retains similar antiviral activity against Omicron subvariants BA.2.86 and XBB.1.9.2 compared to the wildtype reference replicon (lineage B).
SARS-CoV-2 isolates with reduced susceptibility to remdesivir have been selected in cell culture. Viral pools expressing amino acid substitutions at V166A, N198S, S759A, V792I, C799F, and C799R in the viral RdRp (nsp12) emerged when selected with GS-441524, the parent nucleoside of remdesivir. When these substitutions were individually introduced into a wild-type recombinant virus, the susceptibility to remdesivir decreased by 1.7- to 3.5-fold. In a cell culture resistance selection experiment, the nsp12 amino acid substitution E802D emerged and resulted in a 1.4- to 2.5-fold reduction in susceptibility to remdesivir. This nsp12 E802D substitution has emerged in 1 remdesivir treated patient and resulted in a 1.4- to 2.5-fold increase in the remdesivir EC50 value. In another section study using a SARS-CoV-2 isolate containing the P323L substitution in viral polymerase, a single amino acid substitution at V166L emerged. In recombinant SARS-CoV-2 with substitutions at P323L alone and P323L + V166L in combination, the reductions in remdesivir susceptibility were 1.3- and 1.5-fold, respectively. In clinical trials, the rate of emerging nsp12 substitutions in patients treated with remdesivir was similar to those who received placebo.
Note: SARS-CoV-2 RNA shedding results from clinical trials indicate that remdesivir does not significantly reduce the amount of detectable SARS-CoV-2 RNA in oropharyngeal or nasopharyngeal swabs or in plasma samples as compared to placebo.[65120][65133][65134][65135][65136][65137][65156][65161][65247][65248][65365][66063]
Revision Date: 11/06/2024, 01:33:10 PMRemdesivir is administered via intravenous infusion. It 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. 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 (CatA, 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, CES1, CatA, OATP1B1, OATP1B3, MATE1, P-gp, UGT1A1
In vitro, remdesivir is a substrate for the enzymes CYP3A4, CES1, and CatA and the drug transporters organic anion transporting polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp); the metabolite GS-704277 is a substrate for OATP1B1 and OATP1B3. Remdesivir is an in vitro inhibitor of CYP3A4, UDP glucuronosyltransferase 1A1 (UGT1A1), OATP1B1, OATP1B3, and the multidrug and toxin extrusion protein 1 (MATE1). No inhibitory effects have been identified for GS-704277 or GS-441524. Based on a drug interaction study, no clinically significant drug interactions are expected with inducers of CYP3A4 or inhibitors of OATP1B1/1B3 and P-gp.[66063]
Remdesivir is not suitable for oral delivery due to significant first-pass clearance.[65247]
After multiple remdesivir doses to healthy adults, the maximum plasma concentrations (Cmax) and systemic exposures (AUC) were 2,700 ng/mL and 1,710 ng x hour/mL for remdesivir, 143 ng/mL and 2,410 ng x hour/mL for GS-441524, and 198 ng/mL and 392 ng x hour/mL for GS-704277, respectively. The times to reach peak concentration were 0.67 to 0.68 hours for remdesivir, 1.51 to 2 hours for GS-441524, and 0.75 hours for GS-704277.[66063]
The pharmacokinetics of remdesivir and its metabolite GS-441524 were evaluated in healthy subjects and patients with moderate and severe hepatic impairment (Child-Pugh B and C) after administration of a single 100 mg dose. Relative to patients with normal hepatic function, the mean systemic exposure (AUC) and maximum plasma concentration (Cmax) of remdesivir and GS-441524 were similar in patients with moderate hepatic impairment and higher in patients with severe hepatic impairment; however, the exposure differences in patients with severe hepatic impairment were not considered clinically significant.[66063]
The pharmacokinetics of remdesivir, its metabolites (GS-441524 and GS-704277), and the excipient betadex sulfobutyl ether sodium (SBECD) were evaluated in healthy subjects with mild (eGFR 60 to 89 mL/minute/1.73 m2), moderate (eGFR 30 to 59 mL/minute/1.73 m2), severe (eGFR 15 to 29 mL/minutes/1.73 m2) impairment and kidney failure (eGFR less than 15 mL/minute/1.73 m2) on and not on dialysis. Additionally, the drug was studied in COVID-19 patients with severely reduced kidney function (acute kidney injury defined as 50% increase in serum creatinine within a 48-hour period that was sustained for at least 6 hours despite supportive care), chronic kidney disease (eGFR less than 30 mL/minute/1.73 m2), and end stage renal disease (eGFR less than 15 mL/minute/1.73 m2) requiring dialysis. Pharmacokinetic exposures of remdesivir were not affected by renal function or timing of remdesivir administration around dialysis. Exposure of GS-441524, GS-704277, and SBECD were up to 7.9-fold, 2.8-fold, and 21-fold higher, respectively, in those with renal impairment compared to those with normal renal function; however, these changes were not considered clinically significant. Remdesivir was not efficiently removed by hemodialysis; the average hemodialysis clearance of GS-441524 and GS-704277 was 149 mL/minute and 92.6 mL/minute, respectively.[66063]
Infants, Children, and Adolescents weighing 3 kg or more
Based on population pharmacokinetic models, geometric mean estimated exposures (AUCtau, Cmax, and Ctau) in pediatric patients weighing at least 3 kg were higher for remdesivir (33% to 130%) and GS-704277 (37% to 124%) but 3% lower to 60% higher for GS-441524 as compared to those in adult patients with COVID-19; however, the increases were not considered clinically significant.[66063]
Neonates and Infants weighing less than 3 kg
Simulated population datasets for neonates (older than 37 weeks gestation weighing at least 1.5 kg) and infants weighing 1.5 kg to less than 3 kg predicted geometric mean exposures to be higher for remdesivir (10% to 96%), 15% lower to 3% higher for GS-441524, and 14% lower to 132% higher for GS-704277 compared to those in adult patients with COVID-19; however, these changes in exposure were not clinically significant.[66063]
Pregnancy
A non-randomized, open-label clinical study evaluated the pharmacokinetics of up to 10 days of remdesivir treatment in patients who were pregnant. Data from this multiple dose study showed the Cmax, AUC, and Ctau of remdesivir and its circulating metabolites (GS-441524 and GS-704277) in pregnant patients with COVID-19 (n = 21) to be similar to those observed in non-pregnant patients with COVID-19 (n = 22). No dose adjustments are recommended in patients who receive remdesivir during pregnancy.[66063]
The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend that remdesivir be offered to pregnant patients if indicated. When evaluating the risk and benefits of remdesivir, consider that COVID-19 in pregnancy is associated with adverse maternal and fetal outcomes, including preeclampsia, eclampsia, preterm birth, premature rupture of membranes, venous thromboembolic disease, and fetal death.[65314] Data from a clinical trial, published reports, the ongoing COVID-PR pregnancy exposure registry, and compassionate use of remdesivir in pregnant patients have not identified a drug-associated risk of major birth defects, miscarriages, or adverse maternal or fetal outcomes following exposure in the second and third trimester. However, there are insufficient pregnancy data available to evaluate the risk of remdesivir exposure during the first trimester. A non-randomized, open-label clinical study (IMPAACT 2032) evaluated the safety of up to 10 days of treatment with remdesivir in 25 hospitalized pregnant and 28 hospitalized non-pregnant patients of childbearing potential. Of the 25 pregnant patients, median gestational age was 28 weeks at baseline (range: 22 to 33 weeks) and approximately half of the patients were in each of the second and third trimesters of pregnancy. The adverse reactions observed were consistent with those observed in clinical trials of remdesivir in adults.[66063] A systemic review of 13 observational studies that included 113 pregnant patients found few adverse effects from the use of remdesivir during pregnancy. The most common adverse event was mild elevations in transaminase concentrations. Among 95 pregnant patients with moderate, severe, or critical COVID-19 who were included in a secondary analysis of data from a COVID-19 pregnancy registry in Texas, the composite maternal and neonatal outcomes were similar between those who received remdesivir (n = 39) and those who did not. Remdesivir was discontinued in 16.7% of patients due to elevated transaminase concentrations; however, it was not possible to determine if the elevated concentrations were due to the drug, COVID-19, or pregnancy-related conditions. In another report, remdesivir was well tolerated among 67 pregnant and 19 postpartum patients (median postpartum day = 1; range 0 to 3 days) who were hospitalized with severe COVID-19 and received remdesivir through a compassionate use program. In this study, 45 deliveries were observed. No neonatal deaths occurred during the 28-day observation period; however, 1 spontaneous miscarriage occurred at 17 weeks gestation in a mother with concurrent S. aureus bacteremia, endocarditis, and septic arthritis.[65314] [66019] In animal studies involving rats and rabbits, no adverse effects on embryo-fetal development were observed after exposure to the predominant circulating metabolite (GS-441524) that were 4-times the exposure at the recommended human dose. There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to remdesivir during pregnancy. Pregnant and recently pregnant patients can enroll at covid-pr.pregistry.com or call 1-800-616-3791 to obtain more information.[66063]
A published case report describes the presence of remdesivir and active metabolite GS-441524 in human milk. Available data (n=11) from pharmacovigilance reports do not indicate adverse effects on breast-fed infants from exposure to remdesivir and its metabolites through breast milk. There are no available data on the effects of remdesivir on milk production.[66063] The National Institutes of Health (NIH) states that concentrations of remdesivir that would reach a breast-fed infant are estimated to be low; thus, if indicated, treatment should be offered to a lactating patient and breast-feeding can continue without interruption.[65314] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, the potential for viral transmission to SARS-CoV-2-negative infants, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.[65248] [66063]
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