Tixagevimab and Cilgavimab (Monograph)

Brand name: EvusheldTM
Drug class: Monoclonal Antibodies
- SARS-CoV-2-specific Monoclonal Antibody
- SARS-CoV-2 spike protein-directed attachment inhibitor

Medically reviewed by Drugs.com on Jan 31, 2023. Written by ASHP.

Warning

As of January 26, 2023, the FDA is no longer recommending use of tixagevimab and cilgavimab in any region in the US due to the increasing circulation of COVID-19 variants that tixagevimab and cilgavimab are not effective against.

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are cautioned that a combined regimen of Tixagevimab and Cilgavimab is not an approved treatment for coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, but rather, is being investigated for and is currently available under an FDA emergency use authorization (EUA) for the preexposure prophylaxis of COVID-19 in adults and pediatric individuals. The American Society of Health-System Pharmacists, Inc. makes no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to the information contained in the accompanying monograph, and specifically disclaims all such warranties. Readers of this information are advised that ASHP is not responsible for the continued currency of the information, for any errors or omissions, and/or for any consequences arising from the use of the information contained in the monograph in any and all practice settings. Readers are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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]}.

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.

Cautions for Tixagevimab and Cilgavimab

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.

Drug Interactions

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.

Tixagevimab and Cilgavimab Pharmacokinetics

Absorption

Bioavailability

Tixagevimab: 68.5%.

Cilgavimab: 65.8%.

Duration

Time to maximum concentration: approximately 15 days.

In vivo activity against Omicron subvariants (BA.1 and BA.1.1 [BA.1+R346K]) may be retained at drug concentrations achieved following a single initial dose of 300 mg tixagevimab and 300 mg cilgavimab for 3 months.

Distribution

Not known whether tixagevimab and cilgavimab distribute into human or animal milk.

Elimination

Metabolism

Tixagevimab and cilgavimab expected to undergo catabolic pathways in a similar manner as endogenous IgG antibodies.

Tixagevimab and cilgavimab not metabolized by CYP isoenzymes.

Elimination Route

Tixagevimab and cilgavimab not eliminated by renal excretion.

Dialysis not expected to affect pharmacokinetics of either drug.

Half-life

Tixagevimab: 87.9 days.

Cilgavimab: 82.9 days.

Special Populations

Renal impairment: Not expected to affect tixagevimab and cilgavimab exposures since monoclonal antibodies with molecular mass >69 kDa do not undergo renal elimination.

Mild or moderate renal impairment: No difference in clearance compared with individuals with normal renal function.

Effects of hepatic impairment or severe renal impairment on pharmacokinetics of the drugs unknown.

Tixagevimab and cilgavimab pharmacokinetics not affected by age, sex, race, or ethnicity.

Body weight within the range of 36–177 kg had no clinically relevant effect on the pharmacokinetics of either drug in adults.

Stability

Storage

Parenteral

Injection, for IM Use

Tixagevimab and cilgavimab are each supplied as solutions in separate vials.

Store unopened vials of tixagevimab injection (150 mg/1.5 mL [100 mg/mL]) and vials of cilgavimab injection (150 mg/1.5 mL [100 mg/mL]) in a refrigerator (2–8°C) in the original carton to protect the drugs from light. Do not freeze or shake vials.

If immediate administration of prepared syringes 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.

Actions and Spectrum

Tixagevimab (IgG₁) and cilgavimab (IgG₁) are SARS-CoV-2-specific recombinant human monoclonal antibodies; produced using recombinant DNA technology in Chinese hamster ovary (CHO) cells.
The drugs bind to non-overlapping epitopes of the spike protein receptor-binding domain (RBD) of SARS-CoV-2 and block the spike protein from attaching to the human angiotensin-converting enzyme 2 (ACE2) receptor, thereby preventing the virus from entering cells and inhibiting viral replication.
Tixagevimab, cilgavimab, and the combination of tixagevimab and cilgavimab showed reduced or no antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or antibody-dependent natural killer cell activation (ADNKA) in cell culture studies.
In an in vitro SARS-CoV-2 virus neutralization assay in Vero E6 cells, tixagevimab, cilgavimab, and tixagevimab and cilgavimab together neutralized the USA/WA/1/2020 isolate of SARS-CoV-2 with estimated EC₅₀s of 0.009, 0.32, and 0.01 mcg/mL, respectively.
There is a potential risk of treatment failure due to development of viral variants with reduced susceptibility to tixagevimab and cilgavimab.

Advice to Patients

The Fact Sheet for Patients, Parents, and Caregivers: Emergency Use Authorization (EUA) of Tixagevimab and Cilgavimab for Coronavirus Disease 2019 (COVID-19) must be provided to patients or parent/caregivers prior to administration of tixagevimab and cilgavimab.
Inform patients or parent/caregivers that FDA authorized the emergency use of tixagevimab and cilgavimab, which is an investigational drug regimen that has not received FDA approval, for use in certain adults and pediatric individuals who are not expected to mount an adequate immune response to a complete COVID-19 vaccination series and for whom COVID-19 vaccination is not recommended.
Inform patients that they may need to receive additional doses of tixagevimab and cilgavimab for ongoing protection; the optimal timing of redosing is unknown at this time.
Importance of informing clinicians of any history of allergies (including history of severe allergic reaction to a COVID-19 vaccine) or serious illnesses.
Importance of informing clinicians of any low platelet counts, bleeding disorders, or anticoagulant medications.
Risk of rare serious cardiac adverse events. Importance of informing clinicians and seeking emergency medical care if symptoms of a cardiac event occurs (i.e., pain, pressure, or discomfort in the chest; discomfort in the arms, neck, back, stomach or jaw; shortness of breath; fatigue; nausea; peripheral edema).
Importance of immediately reporting any allergic reactions that occur during or after receiving tixagevimab and cilgavimab (e.g., trouble breathing/dyspnea, chills, tiredness or weakness, rapid heart rate, chest discomfort or pain, nausea/vomiting, swelling of the mouth, lips, face, or tongue, hives, wheezing, itching, skin flushing, sweating, muscle aches, lightheadedness, throat tightness) to clinicians.
Risk of pain, bruising, soreness, swelling, hemorrhage, or infection at the IM injection site.
Use of tixagevimab and cilgavimab does not replace vaccination against COVID-19.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., anticoagulants), herbal supplements, and COVID-19 vaccination.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

Additional Information

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tixagevimab and cilgavimab are not commercially available. FDA issued an emergency use authorization (EUA) for tixagevimab and cilgavimab that allows combined use of the drugs for the preexposure prophylaxis of coronavirus disease 2019^† (COVID-19). The EUA authorizes that distribution of the drugs will be controlled by the US government for use consistent with the terms and conditions of the EUA. The manufacturer will supply tixagevimab and cilgavimab to authorized distributors, who will distribute to healthcare facilities or providers as directed by the US government (in collaboration with state and local governments as needed).