Health Canada's review of available information has found a possible link between the risk of sinus bradycardia and the use of Veklury (remdesivir). Veklury is authorized in Canada to treat COVID-19 in adults and adolescents with pneumonia and requiring oxygen. Health Canada will work with the manufacturer to update the Canadian product safety information to inform health care providers and patients about the potential risk of sinus bradycardia and will continue to monitor safety information.
Further information is available at https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00271.
COVID-19 (hospitalized patients); treatment:
Note: While remdesivir efficacy has been demonstrated in adults being treated for COVID-19, data in pediatric patients are limited (Chiotos 2021; Goldman 2021). The role of remdesivir in the treatment of COVID-19 in pediatric patients (including neonates) is still evolving; use in the context of a clinical trial is recommended if possible. For study information, contact Gilead at 1-833-445-3230 or via email at [email protected]. Use outside of a clinical trial could be considered in hospitalized pediatric patients with an emergent or increasing need for supplemental oxygen, in consultation with a pediatric infectious diseases specialist (Chiotos 2021; NIH 2022).
Neonates weighing <3.5 kg: Very limited data available: Optimal dose not defined; contacting Gilead before use is highly recommended:
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 4 reported cases from the United Kingdom (GA: 31 to 33 weeks; PNA: 2.5 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 (Frauenfelder 2020; Saikia 2021a; Saikia 2021b).
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. Duration is generally 5 days or until hospital discharge, whichever is first, but may extend up to 10 days in certain hospitalized patients (eg, no substantial clinical improvement by day 5, on mechanical ventilation or extracorporeal membrane oxygenation) (Chiotos 2021; FDA 2022; Goldman 2020; manufacturer's labeling).
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 (FDA 2022).
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 on days 2 and 3. Initiate as soon as possible after diagnosis of symptomatic COVID-19 and within 7 days of symptom onset (FDA 2022).
Dosing adjustment in renal impairment: Note: The remdesivir formulation contains the excipient sulfobutylether-beta-cyclodextrin (SBECD), which accumulates in patients with kidney dysfunction, although the clinical significance of this accumulation is not certain (Hoover 2018; Luke 2010). SBECD is dialyzable (46% removed by an ~4-hour dialysis session) (Luke 2012).
Full-term neonates ≥7 days weighing ≥3.5 kg:
SCr <1 mg/dL: No dosage adjustment recommended.
SCr ≥1 mg/dL: Use is not recommended per the manufacturer (FDA 2022); however, the potential benefit may outweigh the potential risk in some cases.
COVID-19, hospitalized patients; treatment:
Note: While remdesivir efficacy has been demonstrated in adults being treated for COVID-19, data in pediatric patients are limited; use in context of a clinical trial is recommended if possible (Chiotos 2021; Goldman 2021). For study information, contact Gilead at 1-833-445-3230 or via email at [email protected]. For hospitalized pediatric patients who have an emergent or increasing need for supplemental oxygen, remdesivir is recommended in some ages and may be considered in consultation with a pediatric infectious diseases specialist in others; see "Use" for specific recommendations (NIH 2022).
Infants and Children <12 years: Limited data available: Lyophilized powder only:
3.5 to <40 kg: IV: Loading dose: 5 mg/kg/dose on day 1, followed by 2.5 mg/kg/dose once daily (Chiotos 2021; FDA 2022).
≥40 kg: IV: Loading dose: 200 mg on day 1, followed by 100 mg once daily (Chiotos 2021; FDA 2022).
Children ≥12 years and Adolescents:
<40 kg: Lyophilized powder only: IV: Loading dose: 5 mg/kg/dose on day 1, followed by 2.5 mg/kg/dose once daily (Chiotos 2021; FDA 2022).
≥40 kg: Injection solution or lyophilized powder: IV: Loading dose: 200 mg on day 1, followed by 100 mg once daily (Chiotos 2021; manufacturer's labeling).
Duration: Duration is generally 5 days or until hospital discharge, whichever is first, but may extend up to 10 days in certain hospitalized patients (eg, no substantial clinical improvement by day 5, on mechanical ventilation or extracorporeal membrane oxygenation) (Chiotos 2021; FDA 2022; Goldman 2020; manufacturer's labeling).
COVID-19, nonhospitalized patients; treatment: Note: Initiate as soon as possible after diagnosis of symptomatic COVID-19 and within 7 days of symptom onset. Reserve for the treatment of mild to moderate COVID-19 in patients at high risk for progression to severe disease, including hospitalization or death (FDA 2022; NIH 2022).
Infants and Children <12 years: Limited data available: Lyophilized powder only:
3.5 to <40 kg: IV: Loading dose: 5 mg/kg/dose on day 1, followed by 2.5 mg/kg/dose once daily on days 2 and 3 (FDA 2022).
≥40 kg: IV: Loading dose: 200 mg on day 1, followed by 100 mg once daily on days 2 and 3 (FDA 2022).
Children ≥12 years and Adolescents:
<40 kg: Lyophilized powder only: Loading dose: 5 mg/kg/dose on day 1, followed by 2.5 mg/kg/dose once daily on days 2 and 3 (FDA 2022).
≥40 kg: Injection solution or lyophilized powder: IV: 200 mg as a single dose on day 1, followed by 100 mg once daily on days 2 and 3 (Gottlieb 2021; NIH 2022; manufacturer's labeling).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: The remdesivir formulation contains the excipient sulfobutylether-beta-cyclodextrin (SBECD), which accumulates in patients with kidney dysfunction, although the clinical significance of this accumulation is not certain (Hoover 2018; Luke 2010). The injection solution contains 6 g of SBECD per 100 mg remdesivir; the lyophilized powder contains 3 g of SBECD per 100 mg remdesivir. SBECD is dialyzable (46% removed by an ~4-hour dialysis session) (Luke 2012).
Infants, Children, and Adolescents weighing ≥3.5 kg (FDA 2022; manufacturer's labeling):
eGFR ≥30 mL/minute: No dosage adjustment recommended.
eGFR <30 mL/minute: No formal safety or pharmacokinetic data are available for patients with kidney impairment or who are receiving renal replacement therapies (Barlow 2020; manufacturer's labeling). Use is not recommended by the manufacturer. However, significant toxicity with a short duration of therapy (eg, 5 to 10 days) is unlikely; benefits may outweigh the risks in select patients (Adamsick 2020). In retrospective studies in adult patients with acute or chronic kidney impairment, remdesivir administered at the recommended dose has not been shown to routinely increase serum creatinine or cause severe hepatic toxicity (ALT >5 times the normal limit) (Ackley 2020; Estiverne 2020; Pettit 2020; Thakare 2020).
In a pharmacokinetic observation of a single adult patient receiving intermittent hemodialysis and a 5-day course of remdesivir, remdesivir's predominant metabolite, GS-441524, reached high but stable concentrations, with dialysis reducing concentrations by ~50%, thus preventing accumulation (Sörgel 2020). Another observational study of 3 adult patients with end-stage kidney disease receiving hemodialysis who received 5-day courses of remdesivir reported similarly elevated concentrations of GS-441524; hemodialysis reduced concentrations by 45% to 49% (Davis 2021).
Infants ≥3.5 kg, Children, and Adolescents (FDA 2022; manufacturer's labeling):
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:
Hospitalized patients:
Note: US guideline recommendations on the role of remdesivir for hospitalized patients vary. In general, guidelines recommend use in conjunction with dexamethasone (IDSA [Bhimraj 2021]; NIH 2022; SCCM [Alhazzani 2021]); if a corticosteroid cannot be used, may use remdesivir in combination with baricitinib (NIH 2022). However, the World Health Organization recommends against the use of remdesivir in hospitalized patients, regardless of disease severity (WHO 2020).
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 in certain patients (eg, no substantial clinical improvement by day 5, on mechanical ventilation or extracorporeal membrane oxygenation) (IDSA [Bhimraj 2021]; NIH 2022). Initiate as soon as possible after the diagnosis of symptomatic COVID-19 (manufacturer’s labeling), ideally within 72 hours of a positive SARS-CoV-2 test (SCCM [Alhazzani 2021]).
Nonhospitalized patients:
Note: Reserve use for the treatment of mild to moderate COVID-19 in nonhospitalized patients at high risk for progression to severe COVID-19, including hospitalization or death.
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 and within 7 days of symptom onset (Gottlieb 2021; NIH 2022).
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 Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: The remdesivir formulations contain the excipient sulfobutylether-beta-cyclodextrin (SBECD), with the injection solution containing 6 g per 100 mg remdesivir and the lyophilized powder containing 3 g per 100 mg remdesivir. SBECD accumulates in patients with kidney dysfunction, although the clinical significance of this accumulation is not certain (Luke 2010; Hoover 2018). SBECD is dialyzable (46% removed by an ~4-hour dialysis session) (Luke 2012).
eGFR ≥30 mL/minute: No dosage adjustment necessary.
eGFR <30 mL/minute: No formal safety or pharmacokinetic data are available for patients with kidney impairment or who are receiving renal replacement therapies (Barlow 2020). Manufacturer’s labeling does not recommend use; however, significant toxicity with a short duration of therapy (eg, 5 to 10 days) is unlikely (Adamsick 2020). Benefits may outweigh the risks in select patients (Adamsick 2020). In 4 small retrospective reviews of patients with chronic or acute kidney impairment (3 that included patients receiving dialysis), remdesivir, given at the recommended dose, did not routinely increase serum creatinine or cause severe hepatic toxicity (ALT >5 times the normal limit) (Ackley 2020; Estiverne 2020; Pettit 2020; Thakare 2020).
In a pharmacokinetic observation of a single patient receiving intermittent hemodialysis and a 5-day course of remdesivir, remdesivir’s predominant metabolite, GS-441524, reached high but stable concentrations, with dialysis reducing concentrations by ~50%, thus preventing accumulation (Sörgel 2020). Another observational study of 3 patients with end-stage kidney disease receiving hemodialysis who received 5-day courses of remdesivir reported similarly elevated concentrations of GS-441524; hemodialysis reduced concentrations by 45% to 49% (Davis 2021).
Baseline hepatic impairment: There are no dosage adjustments provided in the manufacturers labeling (has not been studied).
Hepatoxicity during therapy:
ALT >10 times the ULN: Consider remdesivir discontinuation.
ALT elevation AND signs or symptoms of liver inflammation: Discontinue remdesivir.
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)
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)
May be product dependent
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 (FDA 2022; manufacturer's labeling). May be an irritant; avoid extravasation (van Merendonk 2021).
IV: Administer as an IV infusion over 30 to 120 minutes. May be an irritant; avoid extravasation (van Merendonk 2021).
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 with positive SARS-CoV-2 direct viral testing 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 ≥12 years weighing ≥40 kg and adults).
Recommended for use in the following patient populations (Chiotos 2021; NIH 2022):
• Neonates, Infants, and Children <12 years weighing ≥3.5 kg or ≥12 years weighing <40 kg: Use in the context of clinical trial is preferred, but could be considered in hospitalized pediatric patients who have an emergent or increasing need for supplemental oxygen, in consultation with a pediatric infectious diseases specialist.
• Children ≥12 years and Adolescents <16 years: Use recommended in hospitalized patients who have risk factors for severe disease in addition to an emergent or increasing need for supplemental oxygen.
• Adolescents ≥16 years: Use recommended in patients who have an emergent or increasing need for supplemental oxygen.
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 ≥3.5 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 (ISMP 2020).
Postmarketing reports of bradycardia, including severe bradycardia (some fatal) and sinus bradycardia, have been reported in patients receiving remdesivir for SARS-CoV-2. 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).
Mild to moderate (grades 1 to 2), reversible transaminase elevations, including increased serum alanine aminotransferase and increased serum aspartate aminotransferase, have been observed in healthy volunteers and patients with SARS-CoV-2. It is unclear if these effects are drug-related or related to SARS-CoV-2.
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, rash, shivering, 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: Anaphylaxis, angioedema
Local: Erythema at injection site
Miscellaneous: Infusion related reaction
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)
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; 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-β-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. The manufacturer recommends use of only the lyophilized powder in pediatric patients <12 years of age or weighing <40 kg (FDA 2022).
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
Chloroquine: May diminish the therapeutic effect of Remdesivir. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Remdesivir. Risk C: Monitor therapy
Hydroxychloroquine: May diminish the therapeutic effect of Remdesivir. Risk X: Avoid combination
Information related to use of remdesivir in pregnant patients is available from small studies and case reports (Budi 2022; Burwick 2021; Eid 2022; Jorgensen 2021; Nasrallah 2021). Based on available data, use is well tolerated (NIH 2022) and early administration improves clinical outcomes in pregnant patients (Eid 2022).
• Outcome data are available from pregnant (n = 67) and postpartum (n = 19) patients who received remdesivir through the compassionate use program:
- COVID-19 was confirmed in all cases, and all patients had an oxygen saturation ≤94% on room air or required oxygen support. Dosing was the same as nonpregnant adults. Exposure occurred <24 weeks' gestation (n = 12), 24 to 32 weeks' gestation (n = 44), >32 weeks' gestation (n = 11), or within 3 days postpartum (delivery between 24 and 32 weeks' gestation [n = 13]; delivery >32 weeks' gestation [n = 5]). Sixty-four percent of women had a comorbid medical condition that classified their pregnancy as high risk (obesity 17%, asthma 12%, gestational diabetes 10%, chronic hypertension 8%, diabetes mellitus 8%).
- In patients given remdesivir, 93% treated during pregnancy and 89% treated postpartum recovered within 28 days. Recovery was defined as discharge from hospital if on room air at baseline, return to room air or discharge if oxygen previously needed, or extubation if previously ventilated. Women not requiring ventilation had a median time to recovery of 5 days.
- Adverse effects were similar to those in nonpregnant patients; remdesivir was discontinued in 7 pregnant patients (10%) due to adverse events, most commonly due to an increase in liver enzymes (n = 5). Based on this preliminary data, maternal treatment with remdesivir during pregnancy had a high rate of recovery (Burwick 2021).
• A smaller study demonstrated the benefits of remdesivir treatment for pregnant patients hospitalized with moderate COVID-19:
- The study included 35 women (median gestation age 29.2 weeks) with moderate infection, defined as lower respiratory disease diagnosed by imaging or clinical assessment (abnormal blood gas, dyspnea, fever ≥39.0°C (102.2°F) not relieved with acetaminophen, pneumonia) and oxygen saturation on ambient air ≥94%. All patients in the study were managed with oral or IV corticosteroids and antibiotics when appropriate.
- Clinical recovery was defined as breathing on ambient air and/or hospital discharge on hospital day 7. A 5-day course of remdesivir led to clinical recovery in all patients (n = 17) when treatment was started within 48 hours of admission and in no patients when remdesivir was initiated >48 hours from admission (n = 7). Eleven pregnant patients were not treated with remdesivir; 3 progressed to severe disease and 8 required supplemental oxygen on hospital day 7.
- Oligohydramnios was diagnosed in 3 women within 5 days of their last remdesivir dose and in none of the women who did not receive remdesivir. Patients diagnosed with oligohydramnios did not have known risk factors and it is unclear if this finding was related to treatment, COVID-19 infection, or idiopathic. Amniotic fluid monitoring is recommended (Nasrallah 2021).
• A retrospective cohort study evaluated use of remdesivir to prevent ICU admission in hospitalized pregnant patients diagnosed with COVID-19 infection. Patients who received remdesivir within 7 days of symptoms (n = 24) were compared to those who received treatment ≥7 days from symptom onset (n = 17). None of the patients in this study had previously received a COVID-19 vaccine. Patients who received early remdesivir treatment were less likely to be admitted to the ICU, progress to critical disease, and had shorter hospital stays (Eid 2022).
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. Pregnant patients with symptoms 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 2022; NIH 2022).
In general, the treatment of COVID-19 infection during pregnancy is the same as in nonpregnant patients. Use of remdesivir should not be withheld if otherwise needed (NIH 2022). Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.
The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have developed an algorithm to aid practitioners in assessing and managing pregnant patients with suspected or confirmed COVID-19 (https://www.acog.org/covid-19; https://www.smfm.org/covid19). Interim guidance is also available from the CDC for pregnant patients who are diagnosed with COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/inpatient-obstetric-healthcare-guidance.html).
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 (NIH 2022).
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%.
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.
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: Pharmacokinetics have not been evaluated. Pharmacokinetic models predict that use of adult dosing in pediatric patients ≥40 kg and the recommended weight-based dosing regimen in pediatric patients <40 kg will result in remdesivir and metabolite exposure that is comparable to adult exposure (FDA 2022; manufacturer's labeling).
Solution (Veklury Intravenous)
100 mg/20 mL (per mL): $31.20
Solution (reconstituted) (Remdesivir Intravenous)
100 mg (per each): $624.00
Solution (reconstituted) (Veklury Intravenous)
100 mg (per each): $624.00
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