Introduction

Antiviral; recombinant human IgG₁ neutralizing monoclonal antibodies specific for SARS-CoV-2 virus; used in a combination regimen.

Uses for Tixagevimab and Cilgavimab

Prevention of Coronavirus Disease 2019 (COVID-19)

Being investigated for and has been used for prevention of coronavirus disease 2019^{† [off-label]} caused by SARS-CoV-2.

Although efficacy and safety not definitely established, tixagevimab and cilgavimab is available under an FDA emergency use authorization (EUA) for preexposure prophylaxis of COVID-19 in certain individuals who are not expected to mount an adequate immune response to a complete COVID-19 vaccination series or for whom COVID-19 vaccination is not recommended.

On December 8, 2021, FDA issued the initial EUA that permits use of tixagevimab and cilgavimab for the preexposure prophylaxis of COVID-19 in adults and pediatric individuals ≥12 years of age weighing ≥40 kg who are not currently infected with SARS-CoV-2 and who have not had a known recent exposure to an individual infected with SARS-CoV-2 and who have moderate to severe immune compromise due to a medical condition or receipt of immunosuppressive medications or treatments and may not mount an adequate immune response to COVID-19 vaccination or individuals for whom vaccination with any approved or authorized COVID-19 vaccine is not recommended due to a history of severe adverse reaction (e.g., severe allergic reaction) to a COVID-19 vaccine(s) and/or COVID-19 vaccine component(s).

On January 26, 2023, FDA revised the scope of authorization of the EUA to limit use of tixagevimab and cilgavimab for pre-exposure prophylaxis of COVID-19 in the US only when, based on available information including variant susceptibility to tixagevimab and cilgavimab and national variant frequencies, the combined frequency of non-susceptible variants nationally is ≤90%. Based on this revision, tixagevimab and cilgavimab are not currently authorized for use in the US until further notice by the Agency.

Tixagevimab and cilgavimab are not authorized under the EUA for the treatment of COVID-19 or for postexposure prophylaxis in individuals who have been exposed to someone infected with SARS-CoV-2.

Preexposure prophylaxis with tixagevimab and cilgavimab is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended. Individuals for whom COVID-19 vaccination is recommended, including individuals with moderate to severe immune compromise who may derive benefit from COVID-19 vaccination, should receive COVID-19 vaccination.

Consult tixagevimab and cilgavimab EUA letter of authorization, EUA fact sheet for health care providers, and EUA fact sheet for patients, parents, and caregivers for additional information.

The National Institutes of Health (NIH) and Infectious Diseases Society of America (IDSA) have revised their guideline recommendations to address the current prevalence of SARS-CoV-2 variants that are likely to be resistant to tixagevimab and cilgavimab; consult the guidelines for additional information.

Tixagevimab and Cilgavimab Dosage and Administration

General

Pretreatment Screening

• Consider risks and benefits prior to initiating tixagevimab and cilgavimab in individuals at high risk for cardiovascular events.

  Consider consulting an allergist-immunologist prior to administration of tixagevimab and cilgavimab in patients with a history of severe hypersensitivity reaction to a COVID-19 vaccine.

Patient Monitoring

• Clinically monitor patients after injection of tixagevimab and cilgavimab and observe for at least 1 hour. Ensure that appropriate medical support is available to manage any severe hypersensitivity reactions that may occur during this time.

Dispensing and Administration Precautions

• Administer with caution to individuals with thrombocytopenia or any coagulation disorder.

• Completion of FDA MedWatch forms to report all medication errors and all serious adverse events potentially related to tixagevimab and cilgavimab is mandatory. The FDA fact sheet for health care providers that is provided with the drugs and available at the FDA website should be consulted for requirements and instructions regarding reporting of adverse reactions and medication errors.

Other General Considerations

• In individuals who have received a COVID-19 vaccine, tixagevimab and cilgavimab should be administered ≥2 weeks after vaccination.

Administration

Must be prepared and administered by a qualified health care provider with appropriate medical support to manage severe hypersensitivity reactions.

Administer tixagevimab and cilgavimab as 2 separate consecutive IM injections (1 injection of tixagevimab and 1 injection of cilgavimab) at different injection sites, preferably in each of the gluteal muscles.

IM Injection

Tixagevimab and cilgavimab are each supplied in separate single-dose vials in a kit. Do not shake vials. Discard vials if solution is cloudy, discolored or visible particles are observed.

Must prepare tixagevimab and cilgavimab in 2 separate syringes.

For IM administration of 150 mg tixagevimab, withdraw 1.5 mL of tixagevimab injection from a vial labeled as containing 150 mg/1.5 mL (100 mg/mL) of tixagevimab into a syringe. For IM administration of 300 mg tixagevimab, withdraw 3 mL of tixagevimab injection from 2 vials labeled as containing 150 mg/1.5 mL (100 mg/mL) of tixagevimab into a syringe.

For IM administration of 150 mg cilgavimab, withdraw 1.5 mL of cilgavimab injection from a vial labeled as containing 150 mg/1.5 mL (100 mg/mL) of cilgavimab into a syringe. For IM administration of 300 mg cilgavimab, withdraw 3 mL of cilgavimab injection from 2 vials labeled as containing 150 mg/1.5 mL (100 mg/mL) of cilgavimab into a syringe.

For IM administration of 300 mg tixagevimab and 300 mg cilgavimab, ensure that the administration sites are appropriate for the volume (3 mL per injection).

Following preparation of tixagevimab and cilgavimab in separate syringes, immediately administer the prepared syringes. If immediate administration is not possible, the total time from vial puncture to administration must not exceed 4 hours when stored at 2–8ºC or at room temperature up to 25ºC.

Tixagevimab and cilgavimab contain no preservatives; discard any unused solution remaining in the vial(s).

Dosage

Pediatric Patients

Prevention of Coronavirus Disease 2019† [off-label] (COVID-19)

IM

Pediatric patients ≥12 years of age weighing ≥40 kg: FDA EUA authorizes an initial dose of 300 mg of tixagevimab and 300 mg of cilgavimab, administered as 2 separate consecutive IM injections for preexposure prophylaxis of COVID-19^{† [off-label]}.

If the patient previously received an initial dose of 150 mg of tixagevimab and 150 mg cilgavimab, administer an additional dose of tixagevimab and cilgavimab as follows based on when the initial dose was given. If the initial dose was given ≤3 months ago, administer 150 mg tixagevimab and 150 mg cilgavimab. If the initial dose was given >3 months ago, administer 300 mg tixagevimab and 300 mg cilgavimab.

Repeated dosing of 300 mg of tixagevimab and 300 mg of cilgavimab is recommended every 6 months. Repeat dosing should be timed from the date of the most recent dose.

Administer ≥2 weeks after vaccination in individuals who have received a COVID-19 vaccine.

Adults

Prevention of Coronavirus Disease 2019† [off-label] (COVID-19)

IM

FDA EUA authorizes an initial dose of 300 mg of tixagevimab and 300 mg of cilgavimab, administered as 2 separate consecutive IM injections for preexposure prophylaxis of COVID-19^{† [off-label]}.

If the patient previously received an initial dose of 150 mg of tixagevimab and 150 mg cilgavimab, administer an additional dose of tixagevimab and cilgavimab as follows based on when the initial dose was given. If the initial dose was given ≤3 months ago, administer 150 mg tixagevimab and 150 mg cilgavimab. If the initial dose was given >3 months ago, administer 300 mg tixagevimab and 300 mg cilgavimab.

Repeated dosing of 300 mg of tixagevimab and 300 mg of cilgavimab is recommended every 6 months. Repeat dosing should be timed from the date of the most recent dose.

Administer ≥2 weeks after vaccination in individuals who have received a COVID-19 vaccine.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

Dosage adjustment not needed.

Geriatric Patients

Dosage adjustment not needed.

Contraindications

• Previous severe hypersensitivity reactions, including anaphylaxis, to tixagevimab, cilgavimab, or any component of the preparations.

Warnings/Precautions

Hypersensitivity Including Anaphylaxis

Serious hypersensitivity reactions, including anaphylaxis, may occur. Signs and symptoms may include dyspnea, chills, fatigue/asthenia, tachycardia, chest pain or discomfort, nausea/vomiting, angioedema, dizziness, urticaria, wheezing, pruritus, flushing, hyperhidrosis, myalgia, vasovagal reactions, or throat irritation.

Administer injections under the supervision of a healthcare provider with appropriate medical support to manage severe hypersensitivity reactions. If signs and symptoms of a clinically important hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care. Clinically monitor individuals after injections and observe for at least 1 hour.

Risk of Cross-Hypersensitivity with COVID-19 Vaccines

Tixagevimab and cilgavimab formulations contain polysorbate 80, which is in some COVID-19 vaccines. Polysorbate 80 is also structurally similar to polyethylene glycol, which is an ingredient in other COVID-19 vaccines.

For patients with a history of severe hypersensitivity reaction to a COVID-19 vaccine, consider consultation with an allergist-immunologist prior to administration of tixagevimab and cilgavimab. Administer injections under the supervision of a healthcare provider with appropriate medical support to manage severe hypersensitivity reactions. If signs and symptoms of a clinically important hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care. Clinically monitor individuals after injections and observe for at least 1 hour.

Clinically Important Bleeding Disorders

Administer with caution to individuals with thrombocytopenia or any coagulation disorder.

Cardiovascular Events

Serious cardiovascular adverse events (i.e., MI, cardiac failure, arrhythmia, cardiomyopathy, cardiomegaly, cardio-respiratory arrest) sometimes fatal, reported.

In the PROVENT and TACKLE studies, all individuals who experienced serious cardiovascular adverse events had cardiac risk factors and/or a prior history of cardiovascular disease. No clear temporal pattern identified in the PROVENT study, with events reported from several hours after administration of tixagevimab and cilgavimab through the end of the follow-up period. A causal relationship has not been established.

Consider risks and benefits prior to initiating tixagevimab and cilgavimab in individuals at high risk for cardiovascular events; advise such patients to seek immediate medical attention if they experience any signs or symptoms suggestive of a cardiovascular event.

EUA Requirements for Patient Monitoring and Mandatory FDA MedWatch Reporting

Safety and efficacy not established. FDA issued an EUA that permits use of the combination of tixagevimab and cilgavimab for the prevention of coronavirus disease 2019 (COVID-19)^† in certain adults and pediatric individuals who are not expected to mount an adequate immune response to a complete COVID-19 vaccination series or for whom COVID-19 vaccination is not recommended using the dosages recommended in the EUA.

Only limited data available to date regarding adverse effects associated with use of tixagevimab and cilgavimab. Serious and unexpected adverse events may occur that have not been previously reported with the drugs.

Completion of FDA MedWatch forms to report all medication errors and all serious adverse events potentially related to tixagevimab and cilgavimab is mandatory. Consult fact sheet for health care providers that is provided with the drugs and available at FDA website for requirements and instructions regarding reporting of adverse reactions and medication errors.

Specific Populations

Pregnancy

Data insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Estimated background risk of major birth defects and miscarriage related to COVID-19 unknown.

Use during pregnancy only if potential benefit outweighs potential risk for the woman and fetus. If used in pregnant women, dosage adjustment not recommended.

Nonclinical reproductive toxicity studies not performed. In a tissue cross-reactivity study with tixagevimab and cilgavimab using human fetal tissues, no binding of clinical concern detected. Human IgG₁ antibodies are known to cross the placenta; therefore, tixagevimab and cilgavimab have potential to be transferred from the pregnant woman to the developing fetus. Not known whether such potential placental transfer provides any treatment benefit or risk to the developing fetus.

Lactation

Not known whether tixagevimab and cilgavimab distribute into human or animal milk, have effects on breast-fed infant, or affect milk production. Maternal IgG is known to be present in human milk.

Consider the developmental and health benefits of breast-feeding along with the woman’s clinical need for tixagevimab and cilgavimab and any potential adverse effects on the breast-fed child from the drugs or from the underlying maternal condition.

Pediatric Use

The FDA EUA permits use for the prevention of COVID-19^† in certain pediatric patients ≥12 years of age weighing ≥40 kg.

Not authorized for use in pediatric patients <12 years of age or weighing <40 kg.

Pharmacokinetics not evaluated in pediatric individuals.

The EUA-recommended dosage is expected to result in plasma concentrations of the drugs in patients ≥12 years of age weighing ≥40 kg that are comparable to those observed in adults since adults with similar body weight were included in clinical trials (PROVENT and STORM CHASER trials) evaluating IM injection of tixagevimab and cilgavimab for the prevention of COVID-19.

Geriatric Use

In phase 1 and phase 3 studies, 21% of individuals were ≥65 years of age and 3% were ≥75 years of age.

Based on population pharmacokinetic analyses, no difference in pharmacokinetics of tixagevimab and cilgavimab in geriatric patients compared with younger patients.

Hepatic Impairment

Effect of hepatic impairment on pharmacokinetics of tixagevimab and cilgavimab unknown.

Renal Impairment

Not expected to affect tixagevimab and cilgavimab exposures; drugs not eliminated by renal excretion.

Dialysis not expected to impact the pharmacokinetics of tixagevimab or cilgavimab.

Common Adverse Effects

Most common treatment-emergent adverse events occurring in ≥3% of individuals receiving tixagevimab 150 mg and cilgavimab 150 mg (median duration of follow-up of 83 days): Headache (6%), fatigue (4%), and cough (3%).

Overall safety profile of tixagevimab and cilgavimab at a median duration of follow-up of 6.5 months was similar.

Insomnia and dizziness reported in 1% of individuals receiving tixagevimab 300 mg and cilgavimab 300 mg; no other adverse effects reported at higher incidence rates than placebo.

General

Pretreatment Screening

• Consider risks and benefits prior to initiating tixagevimab and cilgavimab in individuals at high risk for cardiovascular events.

  Consider consulting an allergist-immunologist prior to administration of tixagevimab and cilgavimab in patients with a history of severe hypersensitivity reaction to a COVID-19 vaccine.

Patient Monitoring

• Clinically monitor patients after injection of tixagevimab and cilgavimab and observe for at least 1 hour. Ensure that appropriate medical support is available to manage any severe hypersensitivity reactions that may occur during this time.

Dispensing and Administration Precautions

• Administer with caution to individuals with thrombocytopenia or any coagulation disorder.

• Completion of FDA MedWatch forms to report all medication errors and all serious adverse events potentially related to tixagevimab and cilgavimab is mandatory. The FDA fact sheet for health care providers that is provided with the drugs and available at the FDA website should be consulted for requirements and instructions regarding reporting of adverse reactions and medication errors.

Other General Considerations

• In individuals who have received a COVID-19 vaccine, tixagevimab and cilgavimab should be administered ≥2 weeks after vaccination.

Administration

Must be prepared and administered by a qualified health care provider with appropriate medical support to manage severe hypersensitivity reactions.

Administer tixagevimab and cilgavimab as 2 separate consecutive IM injections (1 injection of tixagevimab and 1 injection of cilgavimab) at different injection sites, preferably in each of the gluteal muscles.

IM Injection

Tixagevimab and cilgavimab are each supplied in separate single-dose vials in a kit. Do not shake vials. Discard vials if solution is cloudy, discolored or visible particles are observed.

Must prepare tixagevimab and cilgavimab in 2 separate syringes.

For IM administration of 150 mg tixagevimab, withdraw 1.5 mL of tixagevimab injection from a vial labeled as containing 150 mg/1.5 mL (100 mg/mL) of tixagevimab into a syringe. For IM administration of 300 mg tixagevimab, withdraw 3 mL of tixagevimab injection from 2 vials labeled as containing 150 mg/1.5 mL (100 mg/mL) of tixagevimab into a syringe.

For IM administration of 150 mg cilgavimab, withdraw 1.5 mL of cilgavimab injection from a vial labeled as containing 150 mg/1.5 mL (100 mg/mL) of cilgavimab into a syringe. For IM administration of 300 mg cilgavimab, withdraw 3 mL of cilgavimab injection from 2 vials labeled as containing 150 mg/1.5 mL (100 mg/mL) of cilgavimab into a syringe.

For IM administration of 300 mg tixagevimab and 300 mg cilgavimab, ensure that the administration sites are appropriate for the volume (3 mL per injection).

Following preparation of tixagevimab and cilgavimab in separate syringes, immediately administer the prepared syringes. If immediate administration is not possible, the total time from vial puncture to administration must not exceed 4 hours when stored at 2–8ºC or at room temperature up to 25ºC.

Tixagevimab and cilgavimab contain no preservatives; discard any unused solution remaining in the vial(s).

Dosage

Pediatric Patients

Prevention of Coronavirus Disease 2019† [off-label] (COVID-19)

IM

Pediatric patients ≥12 years of age weighing ≥40 kg: FDA EUA authorizes an initial dose of 300 mg of tixagevimab and 300 mg of cilgavimab, administered as 2 separate consecutive IM injections for preexposure prophylaxis of COVID-19^{† [off-label]}.

If the patient previously received an initial dose of 150 mg of tixagevimab and 150 mg cilgavimab, administer an additional dose of tixagevimab and cilgavimab as follows based on when the initial dose was given. If the initial dose was given ≤3 months ago, administer 150 mg tixagevimab and 150 mg cilgavimab. If the initial dose was given >3 months ago, administer 300 mg tixagevimab and 300 mg cilgavimab.

Repeated dosing of 300 mg of tixagevimab and 300 mg of cilgavimab is recommended every 6 months. Repeat dosing should be timed from the date of the most recent dose.

Administer ≥2 weeks after vaccination in individuals who have received a COVID-19 vaccine.

Adults

Prevention of Coronavirus Disease 2019† [off-label] (COVID-19)

IM

FDA EUA authorizes an initial dose of 300 mg of tixagevimab and 300 mg of cilgavimab, administered as 2 separate consecutive IM injections for preexposure prophylaxis of COVID-19^{† [off-label]}.

If the patient previously received an initial dose of 150 mg of tixagevimab and 150 mg cilgavimab, administer an additional dose of tixagevimab and cilgavimab as follows based on when the initial dose was given. If the initial dose was given ≤3 months ago, administer 150 mg tixagevimab and 150 mg cilgavimab. If the initial dose was given >3 months ago, administer 300 mg tixagevimab and 300 mg cilgavimab.

Repeated dosing of 300 mg of tixagevimab and 300 mg of cilgavimab is recommended every 6 months. Repeat dosing should be timed from the date of the most recent dose.

Administer ≥2 weeks after vaccination in individuals who have received a COVID-19 vaccine.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

Dosage adjustment not needed.

Geriatric Patients

Dosage adjustment not needed.

Not metabolized by CYP isoenzymes and not renally excreted; interactions unlikely if used concomitantly with drugs that are substrates, inducers, or inhibitors of CYP isoenzymes or with drugs that are renally excreted.