Indications

As of January 24, 2022, according to the United States Food and Drug Association (FDA) fact-sheet for imdevimab, "due to the high frequency of the Omicron variant, imdevimab is not currently authorized for use in any U.S. region because of markedly reduced activity against the omicron variant. This drug may not be administered for treatment or post-exposure prevention of COVID-19 under the Emergency Use Authorization until further notice by the Agency." This article is to be used only for a historical review of the development and use of this drug.

Imdevimab is a monoclonal antibody (mAb) against spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19). It is one of the SARS-CoV-2 neutralizing antibodies proposed for use in the clinical management of COVID-19.[1] On 21st November 2020, imdevimab and casirivimab cocktail was authorized for emergency use by the United States Food and Drug Administration (FDA). These are investigational drugs not approved for any specific indication. FDA allowed these drugs only to be administered together. Imdevimab (REGN10987), and casirivimab (REGN10933) is also known as REGN-COV2 or Regeneron. The combination drug has been shown to decrease viral load and decrease the risk of hospitalization and emergency visits. It has also been shown to prevent virus-induced pathological sequelae when administered prophylactically or therapeutically in non-human primates.[1][2]

FDA authorized the drug cocktail to be used only in nonhospitalized patients who meet all three following criteria:

1. Age ≥12 years and weight ≥40 kg 
2. Lab confirmed SARS-COV-2 infection
3. Mild to moderate symptoms, which were at higher risk of progression to severe disease and/or hospitalization.[3][4]

High-risk patients include:

• Age ≥ 65 years
• Body mass index (BMI) ≥ 25 (If 12-17 years old - BMI ≥ 85th percentile for their age and gender)
• Pregnancy
• Chronic kidney disease
• Diabetes
• Immunosuppressive disease, currently on immunosuppressive treatment
• Cardiovascular disease (including congenital heart disease) or hypertension
• Chronic obstructive pulmonary disease (COPD), asthma or other chronic respiratory diseases
• Sickle cell disease
• Neurodevelopmental disorders (e.g., cerebral palsy)
• Medical device dependency (e.g., tracheostomy, gastrostomy, positive pressure ventilation [not related to COVID-19])

On June 3, 2021, the FDA updated the emergency use authorization (EUA) lowering the dosage of casirivimab and imdevimab to 600 mg each and option for subcutaneous (SQ) administration. There was another update on November 17, 2021, authorizing casirivimab and imdevimab (subcutaneously) for emergency use as post-exposure prophylaxis for COVID-19 in adults. It was recommended to be used for patients who are vaccinated but not expected to mount adequate immune response or who are not fully vaccinated.[5]

It is recommended to start the medication as soon as possible after a positive SARS-CoV-2 test and within 10 days of symptom onset. This is because active viral replication occurs between days 1 to 10 of symptoms, and these medications are unlikely to be beneficial later. Monoclonal antibodies are likely associated with worse clinical outcomes when administered to hospitalized COVID-19 patients requiring high flow oxygen or ventilator support. The imdevimab and casirivimab combination is not authorized in use for patients hospitalized or who require oxygen therapy for COVID-19. Viral load reductions with intravenous (IV) and SQ appear similar but data with SQ administration is limited.[5][6]

This being said, it is still reasonable to consider this drug combination in patients who test positive for SAR-COV-2 infection but are hospitalized due to some other indication. Patients or parents/caregivers have the option to accept or refuse this combination drug treatment. If treated with the drug cocktail, patients should continue to self-isolate and use infection control measures such as wear masks, social distance, disinfect surfaces, and maintain hand hygiene. Monoclonal antibodies provide rapid protection against infection, and protection can last for weeks to months. For patients receiving passive antibody therapy (e.g., mAbs), the recommendation is to defer COVID-19 vaccination for at least 90 days to avoid potential interference with the immune response to the vaccine.[7]

Please review the latest recommendations from the Centers for Disease Control and Prevention (CDC) and FDA on these medications as the indications and conditions for use are likely to be changed with the new variants of the virus emerging.

Mechanism of Action

Imdevimab is a recombinant neutralizing human immunoglobulin G1 (IgG1) monoclonal antibody to the spike protein of SARS-CoV-2. It binds to the S1 subunit of spike protein receptor-binding domain (RBD), blocking the attachment of SARS-CoV-2 to the human ACE2 receptor. This prevents viral binding to the host cell, thereby preventing entry and replication of the virus, thus decreasing the viral load. Casirivimab binds to a non-overlapping portion of the spike protein RBD similar to imdevimab, and the combination is theorized to limit the development of viral mutations. The cocktail of the two drugs was also found to have retained activity against the Alpha (B.1.1.7; UK), Beta (B.1.351; South Africa), Gamma (P.1; Brazil), Delta (B.1.617.2; India), Epsilon (B.1.427/429; California), Iota (B.1.526; New York), and Kappa (B.1.617.1; India) variants of SARS-CoV-2. The combination drug has no activity to the Omicron variant.[5][7][8]

Administration

Imdevimab is not authorized to be used alone. The authorized dosage is a combination of imdevimab 600 mg + casirivimab 600 mg (was previously imdevimab 1200 mg + casirivimab 1200 mg) administered as a single intravenous (IV) infusion. There is an option for SQ administration as an alternative route if awaiting IV infusion would result in treatment delay though IV infusion is still preferred. The pediatric dose of the drug combination for age ≥ 12 years and weight ≥ 40 kg is the same as the adult dose.

For post-exposure prophylaxis, imdevimab 600 mg + casirivimab 600 mg is administered together as a single IV infusion (or SQ) as soon as possible following exposure to SARS-CoV-2. In case of ongoing exposure to SARS-CoV-2 for >4 weeks who are determinted appropriate and vaccinated patient not expected to mount an adequate immune response, subsequent dose of casirivimab 300 mg + imdevimab 300 mg once every 4 weeks can be repeated for the duration of ongoing exposure.

Casirivimab and imdevimab each come in individual single-use vials or a co-formulated single vial. If individual vials are used, the drugs need to be diluted and mixed prior to infusion by qualified healthcare professionals using an aseptic technique.[7] Once diluted, the solution should be used immediately. Storage after dilution can be in a refrigerator for up to 36 hours and at room temperature for up to 4 hours, including infusion time. While the infusion is ongoing and up to 1 hour after completing the infusion, patients should be monitored for hypersensitivity reactions.

The infusion should only take place in settings where health care providers have immediate access to medication to treat infusion-related reactions, such as anaphylaxis. In cases of renal impairment, no dose adjustment is needed. Casirivimab and imdevimab are not eliminated intact in the urine, so renal impairment should not affect the exposure to the drugs. The effect on the pharmacokinetics of imdevimab in the presence of hepatic impairment is still unknown.[5] 

Adverse Effects

There is limited data available for adverse effects of imdevimab, but other adverse effects may come to light in the future. Adverse effects reported include:[9]

• Hypersensitivity including anaphylaxis (8,000 mg dose)
• Infusion-related reactions included pyrexia, chills, urticaria, pruritus, abdominal pain, and flushing (8,000 mg dose)
• Nausea and Vomiting (2,400 mg dose)

Due to the possibility of hypersensitivity, including anaphylaxis and infusion-related reaction, observation in the infusion center is advised for at least an hour post-transfusion. If there is a concern for an infusion-related reaction, slow or stop the infusion and administer appropriate medications and/or supportive care.[5]

Contraindications

No absolute contraindication.

Imdevimab and casirivimab combination is not authorized for use in patients with any of the following:[5]

• Age < 12 years and weight < 40 kg
• Hospitalized due to COVID-19
• Requiring oxygen support
• Requiring increase in baseline oxygen flow due to COVID-19 in patients on chronic oxygen therapy due to underlying non-COVID-19 related comorbidities

Monitoring

Observation is required for infusion-related reactions and hypersensitivity reactions, including anaphylaxis during and at least up to one hour following infusion completion.[5] On arrival at the infusion center, clinical stability must be assessed as the patient's symptoms may have worsened since the initial plan for infusion was made. In cases where the patient's symptoms have worsened, the decision should be made if patients need to be evaluated further for the possible need for hospitalization. Patients need to be monitored for at least 7 days for any serious adverse effects following the infusion.

Imdevimab and casirivimab are mAbs that are not renally excreted or metabolized by cytochrome P450 enzymes. Therefore, interactions with concomitant medications that are renally excreted or substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.[5][7]

Toxicity

The recommended dose of imdevimab is 600 mg along with casirivimab 600 mg. In studies, doses up to 8 g (4000 mg of each drug) have been administered without dose-limiting toxicity. In overdose situations, general supportive measures, including vitals signs and clinical status monitoring, are recommended. There is no specific antidote for toxicity due to overdose.

Pregnancy and lactation:[10]

• Imdevimab is a humanized monoclonal antibody (IgG1). Placental transfer of IgG depends on different factors such as maternal serum level of IgG and IgG subclass.[11] Further data is needed to classify risk or benefit to the fetus.
• Maternal IgG is present in breast milk. Imdevimab is a large protein molecule with a molecular weight of about 144,000 Da, so the amount in milk is probably low. It is also likely partially destroyed in the infant's gastrointestinal tract. Therefore, absorption by the infant is likely low. No information is available regarding the use of imdevimab during breastfeeding. According to the emergency use authorization, the decision to breastfeed during therapy should depend on the benefit of treatment of the mother and the benefit and risk of exposure to the infant.
• No dose adjustment is recommended for pregnant or lactating patients per emergency use authorization by the FDA (FDA 2021).

Enhancing Healthcare Team Outcomes

Imdevimab is a new monoclonal antibody that has been authorized for emergency use by FDA due to the ongoing COVID-19 pandemic. As a novel agent, all interprofessional healthcare team members involved in patient care need to be up to speed on the latest information regarding the use of this drug. Initial results show a decreasing viral load and clinical benefit if the drug is initiated early in high-risk patients with mild to moderate disease.[9] More adverse effects related to the drug might be reported in the future. Therefore, when the drug is being used, close monitoring for safety is needed not only by the prescribing clinician but also by the nurses and pharmacists. Providers should be vigilant of any potential drug-related adverse effects. Education of the patient regarding the drug is crucial. 

The drug combination is administered via IV infusion or SQ, and there is the possibility of infusion and injection-related side effects including pyrexia, chills, urticaria, pruritis, abdominal pain, and flushing, along with hypersensitivity and anaphylaxis. Observation in the infusion center after transfusion for at least 60 minutes is recommended. The interprofessional team of healthcare professionals needs to have the necessary medications and equipment in the room to ensure safe outcomes. In cases of something as serious as anaphylaxis, proper and prompt intervention can be life-saving.[7] 

Pharmacists can help clinicians and nurses to ensure proper dosing, monitor drug interactions, and educate patients and staff on potential side effects. Proper collaboration between all interprofessional healthcare team members, including clinicians, infectious disease specialists, mid-level practitioners, nurses, and pharmacists, will help achieve optimal patient outcomes while minimizing patient risks. [Level 5]