Dosing & Uses
Dosage Forms & Strengths
injection, solution
- Tixagevimab 150mg/1.5mL single-dose vial
- Cilgavimab 150mg/1.5mL single-dose vial
COVID-19 (EUA)
January 26, 2023: Not currently authorized in any U.S. region owing to high frequency of circulating SARS-CoV-2 variants that are non-susceptible
December 8, 2021: Emergency use authorization (EUA) issued by the FDA for preexposure prophylaxis of individuals who are moderately-to-severely immunocompromised owing to a medical condition or medications/treatment and may not mount an adequate immune response to COVID-19 vaccination, or have a history of severe adverse reactions to a COVID-19 vaccine and/or component(s)
Additionally, eligible patients are not currently infected with SARS-CoV-2 virus and have not recently been exposed to an individual infected with SARS-CoV-2
Initial dose: Tixagevimab 300 mg IM and cilgavimab 300 mg IM administered as separate, consecutive IM injections
November 10, 2022 NIH statement on omicron subvariants
- Subvariants BA.4.6, BA.2.75.2, BA.5.2.6, BF.7, BQ.1, and BQ.1.1 are likely to be resistant to tixagevimab/cilgavimab
- NIH Guidelines Panel recommends that in the absence of an alternative option for PrEP, clinicians should continue to recommend tixagevimab/cilgavimab as PrEP for eligible individuals
Dosing for individuals who initially received tixagevimab 150 mg and cilgavimab 150 mg
- February 24, 2022: EUA revised to change initial dose for authorized use because available data indicate that a higher dose may be more likely to prevent infection by the COVID-19 Omicron subvariants BA.1 and BA.1.1 than the originally authorized dose; also expected to have greater neutralizing effect against BA.2
- Patients who have already received the previously authorized dose (150 mg of tixagevimab and 150 mg of cilgavimab) should receive an additional dose as soon as possible to raise their monoclonal antibody levels
- ≤3 months since receiving lower dose: Administer additional 150 mg tixagevimab and 150 mg cilgavimab
- >3 months since receiving lower dose: Administer 300 mg tixagevimab and 300 mg cilgavimab
Repeat dosing
- While SARS-CoV-2 remains in circulation, individuals who qualify for tixagevimab and cilgavimab, per the conditions of the EUA, may be redosed every 6 months from the date of the most recent dose
- 300 mg tixagevimab and 300 mg cilgavimab IM q6months
- Longer-term data from PROVENT clinical trial indicate that tixagevimab and cilgavimab may be effective for preexposure prophylaxis for 6 months after administration
Dosage Modifications
Renal impairment
- Not eliminated intact in urine; neither renal impairment nor dialysis expected to affect systemic exposure
Hepatic impairment
- Effect unknown
Dosing Considerations
Limitations of use
- Not authorized for treatment of COVID-19 or for postexposure prophylaxis of COVID-19 in individuals who have been exposed to someone infected with SARS-CoV-2
- Preexposure prophylaxis is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended; individuals for whom COVID-19 vaccination is recommended, including those who are moderately to severely immunocompromised who may benefit from COVID-19 vaccination, should receive COVID-19 vaccination
- Administer at least 2 weeks after vaccination in individuals who have received a COVID-19 vaccine
Medical conditions or treatment examples resulting in moderate-to-severe immunocompromise
- Active treatment for solid tumor and hematologic malignancies
- Receipt of solid-organ transplant and taking immunosuppressive therapy
- Receipt of chimeric antigen receptor (CAR) T-cell or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy)
- Moderate or severe primary immunodeficiency (eg, DiGeorge syndrome, Wiskott-Aldrich syndrome)
- Advanced or untreated HIV infection (HIV with CD4 cell counts <200/mm3, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV)
- Active treatment with high-dose corticosteroids (ie, ≥20 mg prednisone or equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor-necrosis factor (TNF) blockers, and other biologic agents that are immunosuppressive or immunomodulatory (eg, B-cell–depleting agents)
Dosage Forms & Strengths
injection, solution
- Tixagevimab 150mg/1.5mL single-dose vial
- Cilgavimab 150mg/1.5mL single-dose vial
COVID-19 (EUA)
January 26, 2023: Not currently authorized in any U.S. region owing to high frequency of circulating SARS-CoV-2 variants that are non-susceptible
December 8, 2021: Emergency use authorization (EUA) issued by the FDA for preexposure prophylaxis of individuals aged ≥12 years (weighing at least 40 kg) who are moderately-to-severely immunocompromised owing to a medical condition or medications/treatment and may not mount an adequate immune response to COVID-19 vaccination, or have a history of severe adverse reactions to a COVID-19 vaccine and/or component(s)
Additionally, eligible patients are not currently infected with SARS-CoV-2 virus and have not recently been exposed to an individual infected with SARS-CoV-2
Initial dose: Tixagevimab 300 mg IM and cilgavimab 300 mg IM administered as separate, consecutive IM injections
November 10, 2022 NIH statement on omicron subvariants
- Subvariants BA.4.6, BA.2.75.2, BA.5.2.6, BF.7, BQ.1, and BQ.1.1 are likely to be resistant to tixagevimab/cilgavimab
- NIH Guidelines Panel recommends that in the absence of an alternative option for PrEP, clinicians should continue to recommend tixagevimab/cilgavimab as PrEP for eligible individuals
Dosing for individuals who initially received tixagevimab 150 mg and cilgavimab 150 mg
- February 24, 2022: EUA revised to change initial dose for authorized use because available data indicate that a higher dose may be more likely to prevent infection by the COVID-19 Omicron subvariants BA.1 and BA.1.1 than the originally authorized dose; also expected to have greater neutralizing effect against BA.2
- Patients who have already received the previously authorized dose (150 mg of tixagevimab and 150 mg of cilgavimab) should receive an additional dose as soon as possible to raise their monoclonal antibody levels
- ≤3 months since receiving lower dose: Administer additional 150 mg tixagevimab and 150 mg cilgavimab
- >3 months since receiving lower dose: Administer 300 mg tixagevimab and 300 mg cilgavimab
Repeat dosing
- While SARS-CoV-2 remains in circulation, individuals who qualify for tixagevimab and cilgavimab, per the conditions of the EUA, may be redosed every 6 months from the date of the most recent dose
- 300 mg tixagevimab and 300 mg cilgavimab IM q6months
- Longer-term data from PROVENT clinical trial indicate that tixagevimab and cilgavimab may be effective for preexposure prophylaxis for 6 months after administration
Dosage Modifications
Renal impairment
- Not eliminated intact in urine; neither renal impairment nor dialysis expected to affect systemic exposure
Hepatic impairment
- Effect unknown
Dosing Considerations
Limitations of use
- Not authorized for treatment of COVID-19 or for postexposure prophylaxis of COVID-19 in individuals who have been exposed to someone infected with SARS-CoV-2
- Preexposure prophylaxis is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended; individuals for whom COVID-19 vaccination is recommended, including those who are moderately to severely immunocompromised who may benefit from COVID-19 vaccination, should receive COVID-19 vaccination
- Administer at least 2 weeks after vaccination in individuals who have received a COVID-19 vaccine
Medical conditions or treatment examples resulting in moderate-to-severe immunocompromise
- Active treatment for solid tumor and hematologic malignancies
- Receipt of solid-organ transplant and taking immunosuppressive therapy
- Receipt of chimeric antigen receptor (CAR) T-cell or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy)
- Moderate or severe primary immunodeficiency (eg, DiGeorge syndrome, Wiskott-Aldrich syndrome)
- Advanced or untreated HIV infection (HIV with CD4 cell counts <200/mm3, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV)
- Active treatment with high-dose corticosteroids (ie, ≥20 mg prednisone or equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor-necrosis factor (TNF) blockers, and other biologic agents that are immunosuppressive or immunomodulatory (eg, B-cell–depleting agents)
Adverse Effects
1-10%
Headache (6%)
Fatigue (4%)
Cough (3%)
<1%
Cardiovascular serious adverse events (SAEs)
- SAEs related to coronary artery disease or myocardial ischemia (0.3%)
- Myocardial infarctions (0.2%)
- SAEs related to cardiac failure (0.2%)
- SAEs related to arrhythmias (0.1%)
- Cardiomegaly, cardiomyopathy, cardiorespiratory arrest (0.1%)
Warnings
Contraindications
Severe hypersensitivity reactions, including anaphylaxis, to tixagevimab, cilgavimab, or any of their components
Cautions
Serious hypersensitivity reactions, including anaphylaxis, reported with human immunoglobulin G1 (IgG1) monoclonal antibodies; if observed, immediately discontinue administration, and initiate appropriate medications and/or supportive care
Caution when administering IM injections to individuals with thrombocytopenia or any coagulation disorder
Cross-hypersensitivity with COVID-19 vaccines
- Contains polysorbate 80, which is in some COVID-19 vaccines and is structurally like polyethylene glycol (PEG), an ingredient in other COVID-19 vaccines
- Consider consulting an allergist/immunologist before administering to individuals with a history of severe hypersensitivity reactions to a COVID-19 vaccine
- Administer under supervision of healthcare provider with appropriate medical support to manage severe hypersensitivity reactions
- Immediately discontinue administration if signs and symptoms of clinically significant hypersensitivity reaction or anaphylaxis occur and initiate appropriate medications and/or supportive care
- Clinically monitor and observe for at least 1 hr
Cardiovascular events
- In the clinical trial, there was a higher rate of cardiovascular serious adverse events (SAEs), including myocardial infarction (1 fatal SAE) and cardiac failure, in patients who received tixagevimab and cilgavimab
- All who experienced cardiac SAEs had cardiac risk factors and/or history of cardiovascular disease, and there was no clear temporal pattern
- Causal relationship between tixagevimab and cilgavimab and these events has not been established
- There was no signal for cardiac toxicity or thrombotic events identified in the nonclinical studies
Viral variants
- Circulating SARS-CoV-2 viral variants may be associated with resistance to monoclonal antibodies
- Prescribing clinicians should consider prevalence of resistant variants in their area
- Health care providers should review antiviral resistance information provided by state and local health departments
- October 3, 2022: Tixagevimab/cilgavimab showed no significant reduction in susceptibility to the alpha, beta, gamma, delta, epsilon, or iota, kappa, lambda, mu, or zeta variants
-
November 10, 2022 NIH statement on omicron subvariants
- Subvariants BA.4.6, BA.2.75.2, BA.5.2.6, BF.7, BQ.1, and BQ.1.1 are likely to be resistant to tixagevimab/cilgavimab
- NIH Guidelines Panel recommends that in the absence of an alternative option for PrEP, clinicians should continue to recommend tixagevimab/cilgavimab as PrEP for eligible individuals
-
Omicron and omicron subvariants
- October 3, 2022: omicron and omicron subvariants showed varying degrees of reduced susceptibility
- BA.1: 132- to 183-fold reduction (pseudotyped VLPs); 12- to 30-fold reduction (authentic virus)
- BA.1.1: 424-fold reduction (pseudotyped VLPs); 176-fold reduction (authentic virus)
- BA.2: No change (pseudotyped VLPs); 5.4-fold reduction (authentic virus)
- BA.2.12.1: 5-fold reduction (pseudotyped VLPs)
- BA.2.7.5: 2.4- to 15-fold reduction (pseudotyped VLPs); - to -fold reduction (authentic virus)
- BA.3: 16-fold reduction (pseudotyped VLPs)
- BA.4: 33- to 65-fold reduction (pseudotyped VLPs)
- BA.4.6: >1,000-fold reduction (pseudotyped VLPs)
- BA.5: 33- to 65-fold reduction (pseudotyped VLPs); 2.8- to 16-fold reduction (authentic virus)
- Variant proportions circulating in the US can be monitored at the CDC website
Pregnancy & Lactation
Pregnancy
Data are insufficient to evaluate drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
Nonclinical reproductive toxicity studies have not been conducted with tixagevimab and cilgavimab; in a tissue cross-reactivity study assessing off-target binding of tixagevimab and cilgavimab to human fetal tissues, no binding of clinical concern was observed
Human IgG1 antibodies are known to cross the placental barrier; therefore, tixagevimab and cilgavimab have the potential to be transferred from the mother to the developing fetus; unknown whether the potential transfer of tixagevimab and cilgavimab provides any treatment benefit or risk to the developing fetus
Lactation
Data are unavailable regarding presence in human milk or animal milk, effects on breastfed infants, or effects on milk production
Maternal IgG is known to be present in human milk
Consider developmental and health benefits of breastfeeding, along with the mother’s clinical need for treatment and any potential adverse effects on the breastfed infant
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Long-acting recombinant human IgG1kappa monoclonal antibodies derived from B cells donated by convalescent patients after SARS-CoV-2 virus
Tixagevimab and cilgavimab can simultaneously bind to non-overlapping regions of the receptor binding domain (RBD) of SARS-CoV-2 spike protein, thereby blocking its interaction with human ACE2, the SARS-CoV-2 receptor, which is required for virus attachment
Absorption
Bioavailability
- Tixagevimab: 68.5%
- Cilgavimab: 65.8%
Peak plasma time
- Tixagevimab: 14 days
- Cilgavimab: 14 days
Peak plasma concentration
- Tixagevimab: 16.5 mcg/mL
- Cilgavimab: 15.3 mcg/mL
AUC
- Tixagevimab: 2529 day⋅mcg/mL
- Cilgavimab: 2133 day⋅mcg/mL
Distribution
Vd
- Tixagevimab: 7.7 L
- Cilgavimab: 8.7 L
Metabolism
Catabolic pathways; same manner as endogenous IgG
Elimination
Excretion: Not likely to undergo renal excretion
Half-life
- Tixagevimab: 87.9 days
- Cilgavimab: 82.9 days
Clearance
- Tixagevimab: 0.062 L/day
- Cilgavimab: 0.074 L/day
Administration
IM Preparation
Tixagevimab and cilgavimab are each supplied in individual single-dose vials
Must be prepared by a qualified healthcare provider
Do not shake vials
Visually inspect vials for particulate matter and discoloration; should appear clear to opalescent, colorless to slightly yellow; discard if the solution is cloudy or discolored or if visible particles are observed
Withdraw 1.5 mL (150 mg) of tixagevimab solution and 1.5 mL (150 mg) of cilgavimab solution into TWO separate syringes; discard any unused solution
Administer immediately (contains no preservatives); if unable to administer immediately, syringes may be refrigerated or stored at room temperature for up to 4 hours (vial puncture time to IM administration)
IM Administration
Must be administered by a qualified healthcare provider
Administer tixagevimab and cilgavimab as 2 consecutive IM injections
Administer at different injection sites, preferably 1 injection in each of the gluteal muscles, 1 after the other
Clinically monitor individuals after injections and observe for at least 1 hr
Storage
Unopened vials
- Refrigerate at 2-8ºC (36-46ºF) in the original carton to protect from light
- Discard any unused portion
- Do not freeze
- Do not shake
Prepared syringes
- Refrigerate at 2-8ºC (36-46ºF) or store at room temperature up to 25ºC (77ºF) for up to 4 hr
