Health Canada has issued a notification to inform health care providers in Canada of the potential risk of treatment failure of bamlanivimab against certain SARS-CoV-2 variants. Health care providers are advised that:
In in vitro assays, bamlanivimab exhibited reduced activity against SARS-CoV-2 variants with E484K (eg, South Africa or Brazil origin) and L452R (eg, California origin) mutations.
Local epidemiology of variants should be considered before empiric use of bamlanivimab as single monoclonal antibody therapy. Bamlanivimab should be used only in regions where there is a known or confirmed low prevalence of lineages containing E484K and/or L452R SARS-CoV-2 variants.
Patients treated with bamlanivimab should be monitored for COVID-19 signs and symptoms of infection and should be provided additional confirmation or treatment of disease where required.
The Canadian product monograph for bamlanivimab has been updated to include new information concerning SARS-CoV-2 variants.
Further information is available at https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2021/75503a-eng.php.
The FDA has revoked the Emergency Use Authorization (EUA) for the monoclonal antibody bamlanivimab, when administered alone, for the treatment of mild to moderate COVID-19 in adults and pediatric patients. Based on ongoing analysis of emerging scientific data, specifically the sustained increase of SARS-CoV-2 viral variants that are resistant to bamlanivimab alone resulting in increased risk for treatment failure, the FDA has determined that the known and potential benefits of bamlanivimab, when administered alone, no longer outweigh the known and potential risks for its authorized use. Therefore, the FDA has determined that the criteria for issuance of an authorization are no longer met and has revoked the EUA. Alternative monoclonal antibody therapies remain available under EUA, including REGEN-COV (casirivimab and imdevimab, administered together), and bamlanivimab and etesevimab, administered together, for the same uses as previously authorized for bamlanivimab alone. Based on information available at this time, the FDA believes that these alternative monoclonal antibody therapies remain appropriate to treat patients with COVID-19 when used in accordance with the authorized labeling.
Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-monoclonal-antibody-bamlanivimab.
The US government, in coordination with Eli Lilly, has stopped the distribution of bamlanivimab alone as of March 24, 2021 in response to the sustained increase in SARS-CoV-2 viral variants in the United States that are resistant to bamlanivimab administered alone, and the availability of other authorized monoclonal antibody therapies that are expected to retain activity to these variants. Health care providers should review the Antiviral Resistance information in Section 15 of the authorized Fact Sheets for each monoclonal antibody therapy available under an emergency use authorization for details regarding specific variants and resistance. Health care providers should also refer to the CDC (https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-proportions.html) and information from state and local health authorities regarding reports of viral variants of importance in their region to guide treatment decisions. All treatment delivery sites will continue to be able to order bamlanivimab and etesevimab, to be administered together, or REGEN-COV from the authorized distributer following existing ordering and reporting procedures. Additionally, sites can order etesevimab alone to pair with the current supply of bamlanivimab the site has available.
Further information may be found at https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Bamlanivimab/Pages/default.aspx.
FDA issued an emergency use authorization for the investigational monoclonal antibody bamlanivimab for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients with positive results of direct SARS-CoV-2 viral testing who are ≥12 years of age weighing ≥40 kg, and who are at high risk for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab is not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy (or an increase in baseline oxygen flow rate in those on chronic oxygen therapy because of an underlying non-COVID-19 related comorbidity) due to COVID-19. While the safety and efficacy of this investigational agent continues to be evaluated, bamlanivimab was shown in clinical trials to reduce COVID-19-related hospitalization or emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo. A benefit of bamlanivimab treatment has not been shown in patients hospitalized due to COVID-19. Monoclonal antibodies, such as bamlanivimab, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen or mechanical ventilation.
Health care provider fact sheet: https://www.fda.gov/media/143603/download
Patient fact sheet: https://www.fda.gov/media/143604/download
Frequently Asked Questions for bamlanivimab: https://www.fda.gov/media/143605/download
Further information may be found at:
ClinicalTrials.gov: https://www.clinicaltrials.gov/ct2/results?cond=bamlanivimab&term=&cntry=&state=&city=&dist=
IDSA: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
NIH: https://www.covid19treatmentguidelines.nih.gov/
In Canada, Health Canada has permitted an interim authorization for the use of bamlanivimab. Further information is available at https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2020/74573a-eng.php.
COVID-19, mild to moderate:
Note: Due to concerns of decreased susceptibility among SARS-CoV-2 variants, the FDA revoked the emergency use authorization (EUA) for bamlanivimab monotherapy in the United States effective April 16, 2021 (FDA 2021b). Circulating SARS-CoV-2 variants may be associated with resistance to bamlanivimab; there is a potential risk of treatment failure. Bamlanivimab is only for use in patients who are at high-risk of progression to severe disease or hospitalization; refer to Canadian product monograph for more information on patients at high risk for progression to severe disease. Bamlanivimab should NOT be used in patients who are hospitalized due to severe COVID-19 respiratory disease or in patients with COVID-19 requiring high flow oxygen or mechanical ventilation.
Health Canada interim order: Children ≥12 years and Adolescents weighing ≥40 kg: IV: 700 mg as a single dose; administer as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset. Note: Bamlanivimab has not been studied in pediatric patients; Health Canada's interim order for use in pediatric patients ≥12 years of age weighing ≥40 kg is based on likelihood of exposures similar to adults.
There are no dosage adjustments provided (has not been studied); however, renal impairment is not expected to affect bamlanivimab exposure.
There are no dosage adjustments provided (has not been studied).
(For additional information see "Bamlanivimab (United States: Authorization of single-ingredient product discontinued): Drug information")
COVID-19, mild to moderate (off-label use):
Note: Due to concerns of decreased susceptibility among SARS-CoV-2 variants, the FDA revoked the emergency use authorization (EUA) for bamlanivimab monotherapy in the United States effective April 16, 2021 (FDA 2021b). However, bamlanivimab may still be available in Canada. Reserve for patients with positive SARS-CoV-2 direct viral testing who are at high risk for progression to severe disease or hospitalization; refer to Canadian product monograph for more information on patients at high risk for progression to severe disease. Use is not authorized for patients who are hospitalized or require new or increased oxygen therapy due to COVID-19; outcomes may be worse if used in patients requiring high-flow oxygen or mechanical ventilation. Consider local prevalence of SARS-CoV-2 variants when evaluating treatment options.
IV: Weight ≥40 kg: 700 mg as a single dose; administer as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset.
There are no dosage adjustments provided (has not been studied); however, renal impairment is not expected to affect the exposure of bamlanivimab.
There are no dosage adjustments provided (has not been studied).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous [preservative free]:
Generic: Bamlanivimab 700 mg/20 mL (20 mL [DSC])
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Generic: Bamlanivimab 700 mg/20 mL (20 mL)
Investigational agent; approved under interim authorization by Health Canada November 2020.
The distribution of bamlanivimab alone has stopped as of March 24, 2021 in response to the sustained increase in SARS-CoV-2 viral variants in the United States that are resistant to bamlanivimab administered alone as well as the availability of other authorized monoclonal antibody therapies that are expected to retain activity to these variants. All treatment delivery sites will continue to be able to order bamlanivimab and etesevimab, to be administered together, from the authorized distributer following existing ordering and reporting procedures. Additionally, sites can order etesevimab alone to pair with the current supply of bamlanivimab the site has available. Sites of care can submit requests for etesevimab directly to AmerisourceBergen via C19 Therapies Direct Order Request (http://www.smartsheet.com); for more information visit: https://app.smartsheet.com/b/form/255d164d67834793b4ab549e160941e8.
Parenteral: IV: Must be diluted prior to administration. If diluted solution is refrigerated following preparation, allow solution to come to room temperature (~20 minutes) prior to administration. Administer as an IV infusion over ≥60 minutes. Administer through a PVC or polyethylene-lined PVC infusion set containing a 0.2 or 0.22 micron in-line or add-on polyethersulfone filter. Entire infusion solution in the bag should be administered; flush line with NS following completion of infusion to ensure entire dose is administered. Slow or interrupt infusion and treat as appropriate if the patient develops any signs of infusion-related reaction (eg, urticaria, pruritus, rash, swelling of the face, chest discomfort); if severe or life-threatening hypersensitivity reactions occur, immediately discontinue infusion and initiate appropriate medications and/or supportive care.
IV: Must be diluted prior to administration. If diluted solution is refrigerated following preparation, allow solution to come to room temperature (~20 minutes) prior to administration. Administer as an IV infusion over ≥60 minutes. Administer through a PVC or polyethylene-lined PVC infusion set containing a 0.2 or 0.22 micron in-line polyethersulfone filter. Slow or stop infusion and treat as appropriate if an infusion-related reaction occurs. Flush infusion line with NS following completion of infusion.
Store intact vials at 2°C to 8°C (36°F to 46°F); protect from light. Do not freeze, shake, or expose to direct light or heat.
Diluted infusion solution should be administered immediately. If immediate administration is not possible, store diluted bamlanivimab infusion solution for up to 48 hours refrigerated at 2°C to 8°C (36°F to 46°F) or up to 14 hours at 20°C to 25°C (68°F to 77°F) including infusion time. If refrigerated, allow infusion solution to warm to room temperature for ~20 minutes prior to administration.
Note: No longer authorized for use in the United States; due to concerns of decreased susceptibility among SARS-CoV-2 variants, the FDA revoked the emergency use authorization (EUA) for bamlanivimab monotherapy in the United States effective April 16, 2021 (FDA 2021b).
Health Canada interim order: Investigational agent for treatment of mild to moderate COVID-19 in patients who are at high risk of progressing to severe COVID-19 illness and/or hospitalization (Health Canada issued interim order for use in ages ≥12 years weighing ≥40 kg and adults).
A high-risk patient is a person with ≥1 of the following:
• BMI ≥35 (if ≥18 years of age)
• Chronic kidney disease
• Diabetes
• Immunosuppression (due to treatment or underlying disease)
• Age ≥65 years
• Age ≥55 years AND have ≥1 of the following:
- Cardiovascular disease
- Hypertension
- Chronic respiratory disease (including chronic obstructive pulmonary disease)
• Age 12 to 17 years AND have ≥1 of the following:
- BMI ≥85th percentile for age and gender
- Sickle cell disease
- Congenital or acquired heart disease
- Neurodevelopmental disorders (eg, cerebral palsy)
- Medical-related technological dependence (eg, tracheostomy, gastrostomy, positive pressure ventilation [not related to COVID-19])
- Reactive airway or other chronic respiratory disease that requires daily medication for control (eg, asthma)
Bamlanivimab should NOT be used in patients who are hospitalized due to severe COVID-19 respiratory disease or in patients with COVID-19 requiring high flow oxygen or mechanical ventilation.
Bamlanivimab may be confused with belimumab
Hypersensitivity reactions, including anaphylaxis, and infusion related reactions, have been reported with bamlanivimab. Patients may experience altered mental status, angioedema, asthenia, bronchospasm, cardiac arrhythmia (including atrial fibrillation, sinus tachycardia, bradycardia), chest pain or discomfort, chills, diaphoresis, dizziness, dyspnea, fatigue, fever, headache, hypertension, hypotension, myalgia, nausea, pruritus, rash (including urticaria), reduced oxygen saturation, and throat irritation with infusion related reactions, but most reactions were mild in severity (Ref). Slower infusion rates may be considered. All reactions were reversible; severe reactions required discontinuation and treatment (Ref).
Onset: Rapid; most infusion related reactions occurred during infusion (Ref).
The following adverse drug reactions and incidences are derived from the original FDA issued emergency use authorization (EUA) (FDA 2021a). However, the FDA revoked the EUA for bamlanivimab monotherapy in the United States effective April 16, 2021 (FDA 2021b).
1% to 10%:
Dermatologic: Pruritus (2%) (table 1)
Drug (Bamlanivimab) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Bamlanivimab) |
Number of Patients (Placebo) |
Source |
---|---|---|---|---|---|---|---|
2% |
1% |
Adults |
700 mg |
COVID-19, mild to moderate |
101 |
156 |
FDA 2021a |
Hypersensitivity: Hypersensitivity reaction (2%; including type 1 hypersensitivity reaction, flushing, and facial swelling) (table 2)
Drug (Bamlanivimab) |
Placebo |
Population |
Indication |
Number of Patients (Bamlanivimab) |
Number of Patients (Placebo) |
Source |
---|---|---|---|---|---|---|
2% |
1% |
Adults |
COVID-19, mild to moderate |
309 |
156 |
FDA 2021a |
Nervous system: Dizziness (3%) (table 3) , headache (3%) (table 4)
Drug (Bamlanivimab) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Bamlanivimab) |
Number of Patients (Placebo) |
Source |
---|---|---|---|---|---|---|---|
3% |
2% |
Adults |
700 mg |
COVID-19, mild to moderate |
101 |
156 |
FDA 2021a |
Drug (Bamlanivimab) |
Placebo |
Population |
Dose |
Indication |
Number of Patients (Bamlanivimab) |
Number of Patients (Placebo) |
Source |
---|---|---|---|---|---|---|---|
3% |
2% |
Adults |
700 mg |
COVID-19, mild to moderate |
101 |
156 |
FDA 2021a |
Frequency not defined:
Hypersensitivity: Anaphylaxis
Miscellaneous: Infusion related reaction (including severe infusion related reaction)
Hypersensitivity to bamlanivimab or any component of the formulation or container.
Other warnings/precautions:
• Antiviral resistance: Development of SARS-CoV-2 variants that are resistant to bamlanivimab may increase risk of treatment failure; use of bamlanivimab alone should only be considered if other monoclonal antibodies that retain neutralization activity against prevalent variants are not available.
• Clinical worsening: Clinical worsening of COVID-19, including signs or symptoms of altered mental status, arrhythmia (atrial fibrillation, bradycardia, tachycardia), fatigue, fever, hypoxia, or increased respiratory difficulty, has been reported in the 24 hours after administration of bamlanivimab; some of these events required hospitalization. It is not known if these events were related to bamlanivimab.
• Limitations of use: Bamlanivimab is not authorized for use in patients who are hospitalized due to COVID-19, require oxygen therapy due to COVID-19, or require an increase in baseline oxygen flow rate due to COVID-19 in those on chronic oxygen therapy due to underlying non-COVID-19 related comorbidity. Benefit of treatment has not been observed in patients hospitalized due to COVID-19 (Lundgren 2020). Monoclonal antibodies may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high-flow oxygen therapy or mechanical ventilation.
None known.
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
The emergency use authorization for bamlanivimab monotherapy has been revoked (FDA 2021b). The original bamlanivimab clinical trials required male and female patients of reproductive potential to use effective contraception during the study (Gottlieb 2021).
The emergency use authorization for bamlanivimab monotherapy has been revoked (FDA 2021b). Nonclinical reproductive toxicity studies have not been conducted (FDA 2021a).
Bamlanivimab is a humanized monoclonal antibody (IgG1). Placental transfer of human IgG is dependent upon the IgG subclass, maternal serum concentrations, newborn birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009). The potential benefits or risks of in utero exposure to bamlanivimab to the fetus are not known (FDA 2021a).
The risk of severe illness from COVID-19 infection is increased in pregnant patients, and pregnancy is one of the high-risk medical conditions defined by the CDC. An increased risk of adverse pregnancy outcomes may also occur in COVID-19 positive patients with symptomatic infection. These include preterm birth, preeclampsia, coagulopathy, and stillbirth. Pregnant patients with symptomatic COVID-19 infection are more likely to require ICU admission, mechanical ventilation and ventilatory support (ECMO) compared to nonpregnant symptomatic patients. Maternal age and comorbidities may also increase the risk of severe illness in pregnant and recently pregnant patients (ACOG 2021; NIH 2021).
In general, the treatment of COVID-19 infection during pregnancy is the same as in nonpregnant patients (NIH 2021). The original clinical trials of bamlanivimab did not include persons who were pregnant (Gottlieb 2021). 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 and the Society for Maternal-Fetal Medicine 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 COVID-19 during pregnancy is ongoing. Health care providers are encouraged to enroll patients exposed to COVID-19 during pregnancy in the Organization of Teratology Information Specialists pregnancy registry (877-311-8972; https://mothertobaby.org/join-study/).
Monitor for infusion-related reactions (eg, urticaria, pruritus, rash, swelling of the face, chest discomfort) and hypersensitivity/anaphylaxis during and after infusion.
Bamlanivimab is a recombinant neutralizing human IgG1k monoclonal antibody to the spike protein of SARS-CoV-2. Bamlanivimab binds to the spike protein, blocking attachment to the human ACE2 receptor.
Pediatric: Clinical trials have not been performed; serum exposures in patients ≥12 years of age and weighing ≥40 kg are expected to be similar to those observed in adults based on pharmacokinetic modeling.
Solution (Bamlanivimab Intravenous)
700 mg/20 mL (per mL): $0.00
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