Etesevimab

Mechanism of Action

Many glycosylated S proteins layer the surface of SARS-CoV-2, helping the virus bind to the host cell's ACE2 (Angiotensin-converting enzyme-2 receptor) and facilitating viral entry. The S protein has 2 subunits: S1 and S2. The S1 subunit comprises NTD (N-terminal domain) and RBD (receptor-binding domain).[7] The RBD of the S1 subunit binds to the host cell's ACE2. The RBD is a primary target for producing neutralizing monoclonal antibodies. Etesevimab, bamlanivimab, casirivimab, and imdevimab are neutralizing monoclonal antibodies available against SARS-COV-2. Etesevimab and bamlanivimab bind to the overlapping epitopes in RBD (see Figures. Mechanism of Action of Etesevimab, Bamlanivimab, Mechanism of Action of Etesevimab). Casirivimab and imdevimab bind to non-overlapping epitopes of RBD.[8]

Administration

The authorized dose in adults and pediatric patients (12 years of age and above and weighing 40 kg or more) is 700 mg of bamlanivimab and 1400 mg of etesevimab. The combination product comes in a package with the following.

1. Bamlanivimab (700 mg) - 1 vial
2. Etesevimab (700 mg) - 2 vials
3. Sterile prefilled infusion bag - 0.9% sodium chloride (50 mL, 100 mL, 150 mL, or 250 mL)

The package should be stored in the refrigerator. The vials must be warmed to room temperature for 20 minutes before preparation without exposure to direct heat. Withdraw 20 ml and 40 ml of bamlanivimab and etesevimab from vials, then inject them into a prefilled infusion bag. The preparation should not be shaken; gently invert the infusion bag 10 times to mix. The prepared solution can stay at room temperature for 7 hours, including the administration time, and be kept in the refrigerator for 24 hours. If refrigerated, the solution must be warmed to room temperature for 20 minutes before use.[9] The combination product's compatibility with other medications and IV solutions other than 0.9% sodium chloride is not known. Therefore, it is advisable not to administer the prepared solution with any other medication. After the infusion, flush the tubing with 0.9% sodium chloride to ensure the correct total dose is given. 

Adverse Effects

The BLAZE-1 trial (randomized, double-blind trial) has witnessed a significant decrease in SARS-CoV-2 viral load among the patients who took bamlanivimab plus etesevimab compared to the placebo group. The hospitalization and death rates were significantly lower with the antibody group than the placebo group.[10][11]

1. The most frequently reported adverse events were nausea and diarrhea.
2. Infusion-related reactions can be possible with combination therapy. Signs and symptoms of infusion-related reactions include fever, chills, headache, myalgia, confusion, chest pain, breathing difficulty, wheezing, hypoxia, arrhythmia, hypotension, hypertension, nausea, angioedema, throat irritation, and urticaria. If an infusion-related reaction is suspected, consider slowing or stopping the infusion. Supportive care may be given.
3. Anaphylaxis or severe hypersensitivity reactions can be possible with bamlanivimab monotherapy or combination therapy. Immediately discontinue the infusion and initiate supportive care. 
4. Clinical worsening of SARS-CoV2 symptoms like fever, hypoxia, and respiratory distress after bamlanivimab monotherapy has been reported. Some of these events required hospitalization. 

The following adverse events need to be reported within 7 days to the FDA. 

• Death
• A life-threatening adverse event
• Inpatient hospitalization 
• A significant incapacity  
• Medical or surgical intervention to prevent death
• A congenital anomaly 

Contraindications

There are no strict contraindications to using etesevimab. The following is a list of precautions or warnings while using Etesevimab and Bamlanivimab.

1. Pregnant patients:  Etesevimab and bamlanivimab can only be prescribed for pregnant patients with SARS-CoV-2 only if the benefit overbalances the risk for the duo (fetus and mother). Being an IgG antibody, both bamlanivimab and etesevimab can cross the placenta and reach the fetus. However, whether this placental transfer is beneficial or risky for the growing fetus is unclear. 
2. Lactating mother: No data has shown any potential adverse effects on the breastfed child.[12] Lactating mothers with SARS-CoV-2 should follow routine practices like wearing masks to avoid exposing the infant to SARS-CoV-2. 
3. Pediatric patients: Etesevimab and bamlanivimab are not recommended for children less than 12 years or children weighing < 40 Kg.[13] The same adult dose regimen is followed for adolescents weighing >40 kg or >12. 
4. Geriatric patients: The pharmacokinetics of etesevimab and bamlanivimab in elderly patients are similar to those of young adults, so no dose adjustment is required. 
5. Hepatic and Renal Impairment: The dose adjustment is not required for renal and mild hepatic impairment. However, more studies are required to study the safety of moderate or severe liver impairment.

Monitoring

Etesevimab and bamlanivimab infusions should be given only by a qualified healthcare professional in an outpatient facility who can manage hypersensitive reactions. The patient should be monitored for anaphylaxis for at least 1 hour after infusion completion.

Toxicity

Doses up to 7000 mg of bamlanivimab (10 times the FDA recommended dose) or 7000 mg of etesevimab (5 times the FDA recommended dose ) have been studied in clinical trials, which did not show any of the dose-limiting toxicity. If an overdose of bamlanivimab and etesevimab happens, treatment comprises supportive measures, including vitals and clinical status monitoring. As of now, there is no specific antidote available for the overdose.[9]

Enhancing Healthcare Team Outcomes

The interprofessional healthcare team must communicate with the patient, parent, or caregiver and provide a copy of the fact sheet before administering the combination therapy (bamlanivimab and etesevimab). The fact sheet includes the following information: 

• The FDA has approved etesevimab and bamlanivimab for emergency use to treat mild to moderate SARS-CoV-2. 
• It can be used in adults and pediatrics if they are 12 years old and above, weigh 40 kg or more, and are at high risk of progressing to severe COVID-19 or hospitalization. 
• The patient or parent/caregiver has the option to accept or refuse.
• The potential risks and benefits of medications are unknown. 
• Patients treated with bamlanivimab and etesevimab should follow the CDC guidelines (wear a mask, social distancing, avoid sharing personal items, and frequent handwashing).

Etesevimab and bamlanivimab infusion should be given only by a qualified healthcare professional, and the patient should be monitored for anaphylaxis for at least 1 hour after completing the infusion. The healthcare team comprising the physician, nurse practitioner, and nurse is jointly responsible for reporting medication errors and serious adverse events related to etesevimab and bamlanivimab treatment within 7 days from the onset of the event. The Secretary of the HHS (Department of Health and Human Services) has announced a public health emergency that justifies the EUA of etesevimab and bamlanivimab during the SARS-CoV-2 pandemic. This EUA can be terminated when the HHS secretary finds that the situation justifying the EUA no longer exists. When administering this novel therapy, all interprofessional team members must communicate constantly and operate as a functional unit, collaborating and coordinating their activities and information collection. This includes clinicians, specialists, nurses, and pharmacists operating as a cohesive unit to optimize patient outcomes.