Casirivimab

Mechanism of Action

Casirivimab 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 the 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. Imdevimab binds to a non-overlapping portion of the spike protein RBD, similar to casirivimab, and the combination is theorized to limit the development of viral mutations. The cocktail of the 2 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

Carsirivimab is not authorized to be used alone. The authorized dosage is a combination of casirivimab 600 mg + imdevimab 600 mg (was previously casirivimab 1200 mg + imdevimab 1200 mg) administered as a single IV infusion. There is an option for SQ administration as an alternative route if awaiting IV infusion would delay treatment, 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, casirivimab 600 mg + imdevimab 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 determined appropriate and vaccinated patients not expected to mount an adequate immune response, a 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 co-formulated single vials. If individual vials are used, the drugs must be diluted and mixed by qualified healthcare professionals using an aseptic technique before infusion.[7] Once diluted, the solution should be used immediately. Storage after dilution can be done in a refrigerator or left at room temperature for up to 4 hours, including infusion time. While the infusion is ongoing and up to 1 hour after completion, patients should be monitored for hypersensitivity reactions. The infusion should only occur in settings where healthcare 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 casirivimab in the presence of hepatic impairment is still unknown.[5]

Adverse Effects

Limited data is available for adverse effects of casirivimab, but other adverse effects may come to light in the future. Adverse effects reported include:

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

Due to the possibility of hypersensitivity, including anaphylaxis and infusion-related reactions, observation in the infusion center is advised for at least 1 hour post-transfusion. Slow or stop the infusion and consider administering relevant medications or supportive care if there is a concern for an infusion-related reaction.[5][9] 

Contraindications

There are no absolute contraindications for Casirivimab. 

Casirivimab and imdevimab combination is not authorized for use in patients with any of the following:

• Age < 12 years and weight < 40 kg
• Hospitalized due to COVID-19
• Requiring oxygen support
• Patients with underlying non-COVID-19 related comorbidities already on oxygen therapy who have an increase in baseline oxygen requirement from COVID-19[5] 

Monitoring

Observation is required for infusion-related and hypersensitivity reactions, including anaphylaxis during and at least 1 hour after 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. Post-infusion, patients must be monitored for at least 7 days for any serious adverse effects. Casirivimab and imdevimab are not renally excreted or metabolized by cytochrome P450 enzymes. Therefore, interactions are unlikely when given together with renally excreted medications, inducers, substrates, or inhibitors of cytochrome P450 enzymes.[5][7]

Toxicity

The recommended dose of casirivimab is 600 mg, along with imdevimab 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 vital signs and clinical status monitoring, are recommended. There is no specific antidote for toxicity due to overdose.

 Pregnancy and Lactation [10]

• Casirivimab is a humanized monoclonal antibody (IgG1). Placental transfer of IgG depends on different factors, such as maternal serum IgG level and IgG subclass.[11] Further data are needed to classify risk or benefit to the fetus. 
• Maternal IgG is present in breast milk. Casirivimab is a large protein molecule with a molecular weight of over 145,000 Da, so the amount in milk is probably low, and it is also likely partially destroyed in the infant's gastrointestinal tract. Therefore, absorption by the infant is likely low. No information is available related to using casirivimab 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 benefits and risk of exposure to the infant.
• No dose adjustment is recommended for pregnant or lactating patients per emergency use authorization by FDA (FDA 2021).

Enhancing Healthcare Team Outcomes

Casirivimab is a monoclonal antibody authorized for emergency use by the FDA due to the ongoing COVID-19 pandemic. Initial results show a decrease in 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, the prescribing physician, nurses, and pharmacists need close safety monitoring. Providers should be vigilant of any potential drug-related adverse effects. Educating 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, abdominal pain, flushing, urticaria, and pruritus, 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 must have the necessary medications and equipment in the room to ensure safe outcomes. Proper and prompt intervention can be life-saving in cases such as anaphylaxis.[7] Pharmacists can help clinicians and nurses ensure proper dosing, monitor drug interactions, and educate patients and staff on potential side effects. Proper collaboration between interprofessional healthcare team members helps achieve optimal patient outcomes while minimizing patient risks.