ContenidosdeElseviersobremedicamentos
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: Healthcare providers should choose an authorized therapeutic option with activity against the circulating variants in their state, territory, or US jurisdiction. Current variant frequency data are available at: www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-proportions.html. Remdesivir has demonstrated activity in vitro and in animal studies against the SARS-CoV-2 Omicron variant and its subvariants.[65314]
NOTE: Logistical or supply constraints may make it impossible to offer the available therapy to all eligible patients, making patient triage necessary. Prioritize use of these therapies for patients at highest risk of clinical progression. Information on which individuals might receive the greatest benefit from anti-SARS-CoV-2 therapeutics for treatment or prevention can be obtained from www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies. Healthcare providers are advised to consider the benefit-risk for each individual patient.[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] The NIH recommends a treatment duration of 5 days or until hospital discharge. This recommendation is based on study data showing the 5-day course being comparable to 10 days of therapy in hospitalized patients with moderate to severe COVID-19.[65314]
200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days.[66063] The NIH recommends against starting remdesivir in this population; however, remdesivir may be continued, in combination with dexamethasone, to complete a treatment course in patients who progress to mechanical ventilation or ECMO.[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 9 days.[66063] The NIH recommends against starting remdesivir in this population; however, remdesivir may be continued, in combination with dexamethasone, to complete a treatment course in patients who progress to mechanical ventilation or ECMO.[65314]
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]
5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for 9 days.[66063] The NIH recommends against starting remdesivir in this population; however, remdesivir may be continued, in combination with dexamethasone, to complete a treatment course in patients who progress to mechanical ventilation or ECMO.[65314]
5 mg/kg/dose IV once on day 1, followed by 2.5 mg/kg/dose IV once daily for up to 10 days is being used in an ongoing investigational study (NCT04431453) in neonates 14 to 27 days of age, gestational age more than 37 weeks, and weight 2.5 kg or more.[66492] 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] The NIH recommends a treatment duration of 5 days or until hospital discharge. This recommendation is based on study data showing the 5-day course being comparable to 10 days of therapy in hospitalized patients with moderate to severe COVID-19.[65314]
200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days.[66063] The NIH recommends against starting remdesivir in this population; however, remdesivir may be continued, in combination with dexamethasone, to complete a treatment course in patients who progress to mechanical ventilation or ECMO.[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 9 days.[66063] The NIH recommends against starting remdesivir in this population; however, remdesivir may be continued, in combination with dexamethasone, to complete a treatment course in patients who progress to mechanical ventilation or ECMO.[65314]
200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days.[66063] [67214] [65314]
200 mg IV once on day 1, followed by 100 mg 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]
200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days.[66063] [67214] [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 IV once daily.
200 mg IV on day 1, followed by 100 mg IV once daily.
weight 40 kg or more: 200 mg IV on day 1, followed by 100 mg IV once daily.
weight less than 40 kg: 5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/dose IV once daily.
weight 40 kg or more: 200 mg IV on day 1, followed by 100 mg IV once daily.
weight less than 40 kg: 5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/dose IV once daily.
5 mg/kg/dose IV on day 1, followed by 2.5 mg/kg/dose IV once daily.
Safety and efficacy have not been established; however, investigational doses of 2.5 or 5 mg/kg/dose IV on day 1, followed by 1.25 or 2.5 mg/kg/dose IV once daily have been used.
It is unknown if dosage adjustments are needed in patients with hepatic disease. Consider discontinuing treatment if ALT increases to more than 10-times ULN. Discontinue treatment if ALT elevations are accompanied by signs or symptoms of hepatic inflammation.[66063]
eGFR 30 mL/minute or more: No dosage adjustment needed.
eGFR less than 30 mL/minute: Treatment is not recommended.[66063] However, the National Institutes of Health (NIH) COVID-19 treatment guidelines contain study data (i.e., CATCO study) that suggest remdesivir can be used in patients with an eGFR less than 30 mL/minute if the potential benefits outweigh the risks.[65314]
† Off-label indicationRemdesivir is an intravenous antiviral medication approved to treat coronavirus disease 2019 (COVID-19) in adults and pediatric patients (28 days and older and weighing at least 3 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
NOTE: Remdesivir has demonstrated activity in vitro and in animal studies against the Omicron SARS-CoV-2 variant and its subvariants.[65314]
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
In an open-label compassionate-use study of patients with severe COVID-19 (n = 53), atrial fibrillation (6%) and hypotension (8%) were reported in patients receiving remdesivir.[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 = 1,313), 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 = 1,313), nausea was reported in 3% to 7% of 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 = 1,313), 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 = 53), 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).[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 = 1,313), the most frequently reported hematologic adverse event was decreased hemoglobin or anemia which was reported in 1% to 15% of patients receiving remdesivir. In safety data from the Adaptive COVID-19 Treatment Trial (ACTT-1), decreased lymphocytes or lymphopenia (11%) and increased prothrombin time (9%) were reported in patients receiving remdesivir (n = 532). 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 = 53), 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).[66063]
In safety data from clinical trials involving hospitalized adult patients with COVID-19 (n = 1,313), the most frequently reported metabolic adverse event for remdesivir was increased blood glucose or hyperglycemia occurring in 3% to 12% of patients. 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 = 53), 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).[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 = 1,313), 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 = 53), 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).[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 = 1,313), 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 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]
All potential recipients of remdesivir must have their renal function monitored prior to and during treatment, as clinically appropriate. Treatment with remdesivir is not recommended in patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/minute, as most study protocols contraindicate the use of remdesivir in patients with severe renal impairment (eGFR less than 30 mL/minute), renal failure, and in patients receiving dialysis or continuous renal replacement therapy.[66063] However, the National Institutes of Health (NIH) COVID-19 treatment guidelines contain study data (i.e., CATCO study) that suggest remdesivir can be used in patients with an eGFR less than 30 mL/minute if the potential benefits outweigh the risks.[65314] Intravenous formulations of remdesivir contain sulfobutyl ether beta-cyclodextrin sodium (SBECD) as a solubility enhancer, which is renally cleared and accumulates in patients with decreased renal function. If available, consider preferential use of the lyophilized powder formulation in patients with renal impairment, as it contains less SBECD (3 grams per 100 mg vial) as compared to the solution formulation (6 grams per 100 mg/20 mL vial).[65247] [65248] [65314] [66063]
Caution is advised when administering remdesivir to patients with hepatic disease, as 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. Data regarding the use of remdesivir during pregnancy are insufficient to determine the drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. No adequate and well-controlled studies have been conducted. 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]
There are no data regarding the presence of remdesivir in human milk, the effects on the breast-fed infant, or the effects on milk production. 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]
Remdesivir is a monophosphoramidate prodrug of remdesivir triphosphate (RDV-TP), an adenosine analog that acts as an inhibitor of RNA-dependent RNA polymerases (RdRps). Remdesivir triphosphate competes with adenosine-triphosphate for incorporation into nascent viral RNA chains. Once incorporated into the viral RNA at position i, RDV-TP terminates RNA synthesis at position i+3. Because RDV-TP does not cause immediate chain termination (i.e., 3 additional nucleotides are incorporated after RDV-TP), the drug appears to evade proofreading by viral exoribonuclease (an enzyme thought to excise nucleotide analog inhibitors). Remdesivir causes delayed RNA chain termination during the process of viral replication.
Remdesivir has a broad spectrum of in vitro antiviral activity against RNA viruses, including viruses belonging to Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae families. The 50% effective concentration (EC50) against a clinical isolate of SARS-CoV-2 in primary human airway epithelial (HAE) cells is 9.9 nM after 48 hours of treatment. The EC50 against SARS-CoV-2 in the continuous human lung epithelial cell lines Calu-3 and A549-hACE2 is 280 nM after 72 hours of treatment and 115 nM after 48 hours of treatment. Against clinical isolates of the following SARS-CoV-2 variants [Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Epsilon (B.1.429), Kappa (B.1.617.1), Lambda (C.37), Iota (B.1.526), Zeta (P.2), and Delta (B.1.617.2)], remdesivir retains antiviral activity that is similar (i.e., less than 2.5-fold change in EC50 value) to an earlier lineage SARS-CoV-2 isolate (lineage A). Remdesivir also maintains activity (1.1-fold or less change in EC50 value) against clinical isolates of 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, BQ.1.1, and XBB).
SARS-CoV-2 isolates with the following amino acid substitutions in viral RNA-dependent RNA polymerase (nsp12) have been selected in cell culture: V166A, N198S, S759A, V792I, C799F, and C799R. 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 2.5-fold reduction in susceptibility to remdesivir. This nsp12 E802D substitution has emerged in 1 remdesivir treated patient, and resulted in a 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. Specific substitutions that emerged in remdesivir treated subjects included nsp12 V792I, C799F, and A376V. These substitutions were associated with a 2.2-, 2.5-, and 12.6-fold decrease in remdesivir susceptibility, respectively.
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: 05/02/2023, 12:43:35 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]
There are no data available on the pharmacokinetics of remdesivir in patients with hepatic impairment.[66063]
There are no data available on the pharmacokinetics of remdesivir in patients with renal impairment.[66063] Both IV formulations of remdesivir contain sulfobutyl ether beta-cyclodextrin sodium (SBEDC) as a solubility enhancer. SBEDC is renally cleared and accumulates in patients with decreased renal function. The main metabolite for remdesivir, GS-441524, may theoretically increase in patients with impaired renal function.[65247]
Based on population pharmacokinetic models, geometric mean estimated exposures (AUCtau, Cmax, and Ctau) in pediatric patients 28 days to 17 years and weighing at least 3 kg were higher for remdesivir (33% to 129%), GS-441524 (0% to 60%), and GS-704277 (37% to 124%) as compared to those in adult patients with COVID-19; however, the increases were not considered clinically significant.[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. Data regarding the use of remdesivir during pregnancy are insufficient to determine the drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. No adequate and well-controlled studies have been conducted. 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]
There are no data regarding the presence of remdesivir in human milk, the effects on the breast-fed infant, or the effects on milk production. 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]