COVID-19, hospitalized patients; treatment: Note: Initiate as soon as possible after diagnosis of symptomatic COVID-19.
Neonates weighing <3.5 kg: Note: Very limited data available; optimal dose not defined; contacting Gilead before use is highly recommended (1-833-445-3230 or via email at [email protected]). Population not included in former FDA emergency use authorization or product labeling (Ref). Dosing provided is based on 4 reported cases.
Lyophilized powder: IV: Loading dose: 2.5 to 5 mg/kg on day 1, followed by 1.25 mg/kg/dose once daily. Dosing based on 5 reported cases (GA: 31 to 34 weeks; PNA: 8 days to 6 weeks) in which patients received remdesivir for 4 to 11 days. All patients were extubated and discharged from the hospital after receiving remdesivir; no adverse effects were noted (Ref).
Neonates weighing ≥3.5 kg: Limited data available: Lyophilized powder: IV: Loading dose: 5 mg/kg on day 1; followed by 2.5 mg/kg/dose once daily. Based on recommendations for older populations, duration is generally 5 days or until hospital discharge, whichever is first, but may be extended up to 10 days if patient does not clinically improve or requires extracorporeal membrane oxygenation or mechanical ventilation (Ref). Note: Dosing is based on previous emergency use authorization recommendations; population not included in current product labeling (Ref).
COVID-19, hospitalized patients; treatment: Note: Initiate as soon as possible after diagnosis of symptomatic COVID-19. Duration is generally 5 days or until hospital discharge, whichever is first, but may be extended up to 10 days if patient does not clinically improve or requires extracorporeal membrane oxygenation or mechanical ventilation (Ref).
Infants ≥3 kg, Children, and Adolescents:
3 to <40 kg: Lyophilized powder only: IV: Loading dose: 5 mg/kg/dose on day 1, followed by 2.5 mg/kg/dose once daily (Ref).
≥40 kg: Injection solution or lyophilized powder: IV: Loading dose: 200 mg on day 1, followed by 100 mg once daily (Ref).
COVID-19, nonhospitalized patients; treatment: Note: Reserve for the treatment of mild to moderate COVID-19 in patients at high risk for progression to severe disease, including hospitalization or death; refer to the CDC for more information on patients at high risk for progression to severe disease. Initiate as soon as possible after diagnosis of symptomatic COVID-19 and within 7 days of symptom onset (Ref).
Infants ≥3 kg, Children, and Adolescents:
3 to <40 kg: Lyophilized powder only: IV: Loading dose: 5 mg/kg/dose on day 1, followed by 2.5 mg/kg/dose once daily on days 2 and 3 (Ref).
≥40 kg: Injection solution or lyophilized powder: IV: Loading dose: 200 mg on day 1, followed by 100 mg once daily on days 2 and 3 (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function: Infants ≥3 kg, Children, and Adolescents: No dosage adjustment recommended for any degree of kidney impairment.
Hemodialysis: Infants, Children, and Adolescents: No dosage adjustment recommended; may be administered without regard to timing of dialysis sessions. Not significantly dialyzable.
Infants ≥3 kg, Children, and Adolescents (Ref):
Baseline hepatic impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Hepatotoxicity during therapy:
ALT >10 times the ULN and asymptomatic: Consider discontinuing remdesivir.
ALT elevation AND signs or symptoms of liver inflammation: Discontinue remdesivir.
(For additional information see "Remdesivir: Drug information")
COVID-19, treatment:
Hospitalized patients:
Note: In general, guidelines recommend use in conjunction with dexamethasone (Ref); may be used as monotherapy in select patients (eg, requiring minimal conventional oxygen, not requiring oxygen supplementation but at high risk of severe COVID-19) (Ref).
IV: 200 mg as a single dose on day 1, followed by 100 mg once daily. Duration is generally 5 days or until hospital discharge, whichever is first, but may extend to up to 10 days based on clinical response (Ref). Initiate as soon as possible after the diagnosis of symptomatic COVID-19 (Ref).
Nonhospitalized patients with high risk of progression to severe illness:
IV: 200 mg as a single dose on day 1, followed by 100 mg once daily on days 2 and 3. Initiate as soon as possible after COVID-19 diagnosis and within 7 days of symptom onset (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (Ref).
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable: No supplemental dose or dosage adjustment necessary; may be administered without regard to timing of dialysis sessions (Ref).
Peritoneal dialysis: Unlikely to be significantly dialyzable: No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
The hepatic dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Matt Harris, PharmD, MHS, BCPS, FAST; Jeong Park, PharmD, MS, BCTXP, FCCP, FAST; Arun Jesudian, MD; Sasan Sakiani, MD.
Note: Although randomized, controlled trials excluded patients with baseline ALT/AST ≥5 times ULN (Ref), remdesivir has been successfully used in a limited number of patients with baseline AST/ALT >5 times ULN (Ref). While AST/ALT elevations have been observed in patients treated with remdesivir (Ref) (requiring discontinuation in ~3% of patients (Ref)) an exploratory analysis to determine the risk of remdesivir-induced liver injury (defined as one of the following: total bilirubin, ALT or AST >2 times ULN, or INR >1.7) did not find an increased risk of remdesivir-induced liver injury following exposure (Ref). Additionally, elevated transaminases are a known clinical feature of COVID-19 infection, and therefore, use of remdesivir should not be avoided solely based on the presence of elevated liver chemistries (Ref).
Hepatic impairment prior to treatment initiation:
Initial or dose titration in patients with preexisting liver cirrhosis: Note: Baseline liver chemistries should be obtained prior to initiation in hospitalized patients and periodically (eg, every 1 to 2 days) during treatment and as needed in outpatients if clinically indicated (Ref).
Child-Turcotte-Pugh class A to C: No dosage adjustment necessary (Ref).
Dosage adjustment in patients with chronic, worsening hepatic function during treatment (eg, progression from Child-Turcotte-Pugh class A to B):
Progression from baseline to Child-Turcotte-Pugh class A to C:
ALT ≤10 times ULN: No dosage adjustment necessary (Ref).
ALT >10 times ULN: Consider discontinuation of remdesivir. If therapy is continued, no dosage adjustment necessary; however, in patients also experiencing signs/symptoms of liver inflammation, remdesivir therapy should be discontinued.
Acute hepatotoxicity during treatment (eg, requiring hospitalization) : Note: Baseline liver chemistries should be obtained prior to initiation in hospitalized patients and periodically (eg, every 1 to 2 days) during treatment and as needed in outpatient if clinically indicated (Ref).
ALT ≤10 times ULN: No dosage adjustment necessary; however, in patients also experiencing signs/symptoms of liver inflammation, must weigh risks/benefits of continuation of remdesivir therapy (Ref).
ALT >10 times ULN: Consider discontinuation of remdesivir. If therapy is continued, no dosage adjustment necessary; however, in patients also experiencing signs/symptoms of liver inflammation, remdesivir therapy should be discontinued.
Postmarketing reports of bradycardia, including severe bradycardia (some fatal) and sinus bradycardia, have been reported in patients receiving remdesivir for COVID-19. An observational study using data from the WHO pharmacovigilance database found that bradycardia was more likely to be reported with remdesivir treatment than with hydroxychloroquine, lopinavir/ritonavir, tocilizumab, or glucocorticoid treatment, and reports included mostly males in the United States over a wide spectrum of ages (43 to 79 years of age). Most of these patients were not receiving concurrent cardiovascular medications. Other cardiac effects were observed, most notably hypotension (Ref).
Mechanism: Unknown; it has been suggested that the active metabolite of remdesivir, a nucleotide triphosphate derivative, may slow sinoatrial node automaticity due to its similarity with adenosine triphosphate (Ref).
Onset: Bradycardia: Varied; a median onset of 2.4 days (range: 1 to 6 days) was observed in an observational study (Ref). Other reports have noted onset of bradycardia within 24 hours of administration of first dose (Ref).
In clinical trials, mild to moderate (grades 1 to 2) reversible transaminase elevations, including increased serum alanine aminotransferase, increased serum aspartate aminotransferase, and increased serum bilirubin, were observed in healthy volunteers and adult and pediatric patients with COVID-19. Hepatitis (including ischemic) and acute hepatic failure with significant increases in transaminases, coagulopathy, and encephalopathy have been reported (Ref). It is unclear if these effects are drug-related or related to COVID-19 (Ref). Most aminotransferase elevations during treatment for COVID-19 were reversible (Ref).
Onset: Varied; range of 1 to 16 days has been reported (Ref).
Hypersensitivity reactions, including anaphylaxis and infusion related reactions, have been reported during and following remdesivir administration. Patients may experience angioedema, bradycardia, diaphoresis, dyspnea, fever, hypertension, hypotension, hypoxia, nausea, shivering, skin rash, tachycardia, and wheezing. Slower infusion rates (maximum infusion time of up to 120 minutes) may be considered in patients to potentially prevent hypersensitivity or infusion related reactions.
Onset: Rapid; most commonly occurs within 1 hour.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adolescents and adults.
>10%:
Endocrine & metabolic: Increased serum glucose (grades 3/4: 3% to 11%)
Renal: Decreased creatinine clearance (grades 3/4: 2% to 19%), increased serum creatinine (grades 3/4: 3% to 15%)
1% to 10%:
Dermatologic: Skin rash (<2%)
Gastrointestinal: Nausea (3% to 7%)
Hematologic & oncologic: Decreased hemoglobin (grades 3/4: 1% to 8%), lymphocytopenia (grades 3/4: 2%), prolonged prothrombin time (grades 3/4: 9%) (table 1)
Drug (Remdesivir) |
Placebo |
Dose |
Indication |
Number of Patients (Remdesivir) |
Number of Patients (Placebo) |
---|---|---|---|---|---|
Grades 3/4: 9% |
4% |
200 mg on Day 1 and 100 mg once daily on subsequent days, for 10 days of treatment |
SARS-CoV-2 infection |
532 |
516 |
Hepatic: Increased serum alanine aminotransferase (2% to 7%), increased serum aspartate aminotransferase (3% to 6%)
Hypersensitivity: Hypersensitivity reaction (<2%)
Nervous system: Seizure (<2%)
Frequency not defined:
Hepatic: Increased serum alkaline phosphatase
Hypersensitivity: Angioedema, infusion-related reaction
Local: Erythema at injection site
Postmarketing:
Cardiovascular: Bradycardia (including severe bradycardia and sinus bradycardia) (Gubitosa 2020, Jacinto 2021, Touafchia 2021), heart failure (Wang 2020), hypotension (Touafchia 2021)
Hepatic: Acute hepatic failure (Carothers 2020), hepatitis (including ischemic) (Kim 2021, Montastruc 2020), increased serum bilirubin (Kim 2021)
Hypersensitivity: Anaphylaxis (Hopkins 2021)
Hypersensitivity to remdesivir or any component of the formulation.
Disease-related concerns:
• Renal impairment: Use caution in patients with eGFR <30 mL/minute and assess risk versus benefit based upon dosing information in renal impairment.
Dosage form specific issues:
• Injection: Contains the excipient cyclodextrin (sulfobutylether-beta-cyclodextrin [SBECD]; 6 g per 100 mg remdesivir [injection solution] or 3 g per 100 mg remdesivir [lyophilized powder]), which may accumulate in patients with renal impairment.
Sulfobutylether-beta-cyclodextrin sodium salt (SBECD) is an excipient in remdesivir; SBECD is renally cleared and accumulates in patients with decreased renal function. The lyophilized powder formulation contains 3 g of SBECD per 100 mg remdesivir, while the injection solution 5 mg/mL contains 6 g of SBECD per 100 mg remdesivir. In pediatric patients weighing <40 kg, the manufacturer recommends use of the lyophilized powder only.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous [preservative free]:
Veklury: 100 mg/20 mL (20 mL [DSC])
Solution Reconstituted, Intravenous:
Generic: 100 mg (1 ea [DSC]); 150 mg (1 ea [DSC])
Solution Reconstituted, Intravenous [preservative free]:
Veklury: 100 mg (1 ea)
Generic: 100 mg (1 ea [DSC])
May be product dependent
Solution (reconstituted) (Veklury Intravenous)
100 mg (per each): $719.38
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous:
Veklury: 100 mg/20 mL ([DSC])
Solution Reconstituted, Intravenous:
Veklury: 100 mg (1 ea)
Remdesivir is available to hospitals directly from the distributor AmerisourceBergen (1-800-746-6273 or [email protected]); more information is available at https://www.vekluryhcp.com/product-access/. Additionally, health care providers must track and report all medication errors and serious adverse events potentially associated with remdesivir use by either submitting a MedWatch form (https://www.fda.gov/medwatch/report.htm) or FDA Form 3500 (health professional) by fax (1-800-FDA-0178); a copy of all MedWatch forms should also be provided to Gilead ([email protected]).
Parenteral: IV: Administer as an IV infusion over 30 to 120 minutes in a setting where it is possible to appropriately manage severe hypersensitivity reactions (such as anaphylaxis). Do not administer simultaneously with any other medication or IV solutions other than NS (Ref). May be an irritant; avoid extravasation (Ref).
IV: Administer as an IV infusion over 30 to 120 minutes. May be an irritant; avoid extravasation (Ref).
Injection solution concentrate (5 mg/mL): Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Prior to dilution, allow vial to warm to room temperature; intact vials can be stored up to 12 hours at room temperature prior to dilution. Once diluted for infusion, may store at 20°C to 25°C (68°F to 77°F) for 24 hours or refrigerated at 2°C to 8°C (36°F to 46°F) for 48 hours. Discard unused portion of the injection solution vial.
Lyophilized powder: Store intact vials at <30°C (<86°F). After reconstitution, use vials immediately to prepare diluted solution. Once diluted for infusion, may store at 20°C to 25°C (68°F to 77°F) for 24 hours or refrigerated at 2°C to 8°C (36°F to 46°F) for 48 hours. Discard unused portion of the reconstituted vial.
Treatment of COVID-19 in patients who are hospitalized or who are not hospitalized and have mild to moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death (FDA approved in ages ≥28 days weighing ≥3 kg and adults).
Remdesivir (Veklury) is available in two formulations for IV administration, a concentrated solution and a lyophilized powder. Each product has different recommendations for storage, preparation for administration, and administration. In addition, the concentrated solution should only be used in adults and pediatric patients weighing ≥40 kg, while the lyophilized powder can be used in adults and pediatric patients weighing ≥3 kg. The Institute for Safe Medication Practices (ISMP) reports that there have been numerous medication errors related to the two formulations available; use caution with product selection and follow appropriate recommendations for the formulation (FDA 2022; ISMP 2020).
Substrate of CYP2C8 (minor), CYP2D6 (minor), CYP3A4 (minor), OATP1B1/1B3 (SLCO1B1/1B3), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Chloroquine: May diminish the therapeutic effect of Remdesivir. Risk X: Avoid combination
Hydroxychloroquine: May diminish the therapeutic effect of Remdesivir. Risk X: Avoid combination
Tacrolimus (Systemic): Remdesivir may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Warfarin: Remdesivir may enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Outcome data following use of remdesivir in pregnant patients are available from small studies and case reports (Budi 2022; Burwick 2021; Eid 2022; Gutierrez 2022; Jorgensen 2021; Marzban-Rad 2022; Nasrallah 2021; Tavakoli 2023). Based on preliminary data, maternal treatment of COVID-19 infection with remdesivir may decrease vertical transmission to the newborn and decrease NICU admissions of infants of mothers with mild or moderate disease (Tavakoli 2023). In addition, pregnant patients who received early remdesivir treatment (<7 days of symptoms) were less likely to be admitted to the ICU, progress to critical disease, and had shorter hospital stays (Eid 2022). Adverse effects in the mother were similar to those of nonpregnant patients (Burwick 2021).
The risk of severe illness from COVID-19 infection is increased in symptomatic pregnant patients compared to nonpregnant patients. Pregnant and recently pregnant patients with moderate or severe infection are at increased risk of complications such as hypertensive disorders of pregnancy, postpartum hemorrhage, or other infections compared to pregnant patients without COVID-19. Symptomatic pregnant patients may require ICU admission, mechanical ventilation, or ventilatory support (ECMO) compared to symptomatic nonpregnant patients. Other adverse pregnancy outcomes include preterm birth and stillbirth. The risk of coagulopathy, cesarean delivery, and maternal death may be increased; neonates have an increased risk for NICU admission. Maternal age and comorbidities such as diabetes, hypertension, lung disease, and obesity may also increase the risk of severe illness in pregnant and recently pregnant patients (ACOG 2023; NIH 2023).
In general, the treatment of COVID-19 infection during pregnancy is the same as in nonpregnant patients. However, because data for most therapeutic agents in pregnant patients are limited, treatment options should be evaluated as part of a shared decision-making process. Use of remdesivir is recommended if indicated (NIH 2023). Pregnancy-induced physiologic changes do not alter the pharmacokinetic properties of remdesivir in a clinically significant way; dose adjustments are not recommended. Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.
Data collection to monitor maternal and infant outcomes following exposure to remdesivir during pregnancy is ongoing.
- Pregnant and recently pregnant patients exposed to remdesivir are encouraged to enroll in the registry (800-616-3791 or http://covidpr.pregistry.com)
- Health care providers are encouraged to enroll patients exposed to COVID-19 during pregnancy in the Organization of Teratology Information Specialists (OTIS) pregnancy registry (877-311-8972; https://mothertobaby.org/join-study/).
Baseline and as clinically appropriate: Heart rate (Chow 2021; Rau 2021; Touafchia 2021); hepatic function tests (ALT, AST, bilirubin, alkaline phosphatase), prothrombin time, renal function tests (SCr, eGFR). Monitor for infusion reaction during infusion; monitor for hypersensitivity during and for ≥1 hour following infusion (manufacturer's labeling).
Remdesivir is an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication. Remdesivir is an adenosine nucleotide prodrug that is metabolized to the pharmacologically active nucleoside triphosphate metabolite after being distributed into cells. Remdesivir triphosphate (GS-443902) acts as an adenosine triphosphate analog and competes for incorporation into RNA chains by the SARS-CoV-2 RdRp, resulting in delayed chain termination during viral RNA replication. Remdesivir triphosphate can also inhibit viral RNA synthesis due to incorporation into the viral RNA template.
Protein binding: Remdesivir: 88% to 93.6%; GS-441524: 2%; GS-704277: 1%.
Metabolism: Hepatically, primarily by carboxylesterase 1 (Humeniuk 2021).
Half-life elimination: Remdesivir: ~1 hour; GS-441524: 27 hours; GS-704277: 1.3 hours.
Excretion:
Urine: Remdesivir: 10%; GS-441524: 49%; GS-704277: 2.9%
Feces: Remdesivir: Not detected; GS-441524: 0.5%; GS-704277: Not detected.
Altered kidney function:
AUCinf of remdesivir is not significantly affected by kidney function. AUCinf of GS-441524, GS-704277, and SBECD were up to 7.9-fold, 2.8-fold, and 21-fold higher, respectively, in patients with eGFR <15 mL/minute/1.73 m2 compared to patients with normal kidney function. Per the manufacturer, these changes are not considered clinically significant.
Expected drug exposure in adults with normal renal function:
Cmax (peak): IV: 100 mg once daily, steady state: Remdesivir: 2,229 ng/mL; GS-441524: 145 ng/mL; GS-704277: 246 ng/mL.
Cmin (trough): IV: 100 mg once daily, steady state: Remdesivir: Not detected; GS-441524: 69.2 ng/mL; GS-704277: Not detected.
AUC: IV: 100 mg once daily, steady state: Remdesivir: 1,585 ng • hour/mL; GS-441524: 2,229 ng • hour/mL; GS-704277: 462 ng • hour/mL.
Pediatric: In a pharmacokinetic modeling study, exposure to remdesivir and metabolites (Cmax, AUC) was higher in pediatric patients ≥28 days of age weighing ≥3 kg receiving recommended dosing regimens as compared to adults. The difference in exposure is not expected to be clinically significant.
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