Evusheld (Solution kit) Instructions for Use

Marketing Authorization Holder

AstraZeneca AB (Sweden)

Manufactured By

Samsung Biologics, Co. Ltd. (Republic of Korea)

Labeled By

SAMSUNG BIOLOGICS, Co.Ltd. (Republic of Korea)

Or

ASTRAZENECA, AB (Sweden)

Quality Control Release

ASTRAZENECA, AB (Sweden)

Contact Information

AstraZeneca Pharmaceuticals LLC (Russia)

ATC Code

J06BD03 (Tixagevimab and cilgavimab)

Active Substances

Tixagevimab (Rec.INN registered by WHO)

Cilgavimab (Rec.INN registered by WHO)

Dosage Form

Evusheld

Solution set for intramuscular administration 100 mg/1 ml and 100 mg/1 ml: fl. 1.5 ml 1 pc. and fl. 1.5 ml 1 pc.

Dosage Form, Packaging, and Composition

Solution kit for intramuscular administration.

Solution for intramuscular administration (Tixagevimab) clear or opalescent solution from colorless to light yellow.

Excipients: L-histidine – 2.4 mg, L-histidine hydrochloride monohydrate – 3 mg, sucrose – 123.2 mg, polysorbate 80 – 0.6 mg, water for injections – approximately 1312 mg¹.

Solution for intramuscular administration (Cilgavimab) clear or opalescent solution from colorless to light yellow.

Excipients: L-histidine – 2.4 mg, L-histidine hydrochloride monohydrate – 3 mg, sucrose – 123.2 mg, polysorbate 80 – 0.6 mg, water for injections – approximately 1312 mg¹.

1.5 ml (Tixagevimab) and 1.5 ml (Cilgavimab) – colorless glass vials (2*) – cardboard packs with first-opening control.

¹ The delivered dose volume of 1.5 ml is ensured by overfilling to 1.9 ml (the overfill is 0.4 ml).
* 1 vial of tixagevimab and 1 vial of cilgavimab in a cardboard insert.

Clinical-Pharmacological Group

Antiviral drug. Immunomodulator

Pharmacotherapeutic Group

Immune sera and immunoglobulins; immunoglobulins; antiviral monoclonal antibodies

Pharmacological Action

Mechanism of action

Tixagevimab and cilgavimab are recombinant human monoclonal antibodies of the IgG1k class, with amino acid substitutions in the Fc region to increase half-life and reduce antibody effector function and the potential risk of antibody-dependent enhancement of infection. Tixagevimab and cilgavimab can simultaneously bind to non-overlapping epitopes of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Tixagevimab, cilgavimab, and the combination of tixagevimab and cilgavimab bind to the spike protein with equilibrium dissociation constants K_D of 2.76 pM, 13.0 pM, and 13.7 pM, respectively, blocking its attachment to the human angiotensin-converting enzyme 2 (ACE2) receptor, leading to the prevention of entry and effective neutralization of the SARS-CoV-2 virus.

Tixagevimab, cilgavimab, and the combination of tixagevimab and cilgavimab block the binding of RBD to the human ACE2 receptor at half-maximal inhibitory concentrations (IC₅₀) of 0.32 nM (48 ng/ml), 0.53 nM (80 ng/ml), and 0.43 nM (65 ng/ml), respectively.

Antiviral activity

Analysis of SARS-CoV-2 virus neutralization using Vero E6 cells revealed that tixagevimab, cilgavimab, and the combination of tixagevimab and cilgavimab neutralize SARS-CoV-2 virus (isolate USA-WA1/2020) at half-maximal effective concentrations (EC₅₀) of 60.7 pM (9 ng/ml), 211.5 pM (32 ng/ml), and 65.9 pM (10 ng/ml), respectively. These in vitro values correlate with the clinically effective serum concentration of Evusheld obtained in vivo – 2.2 µg/ml.

Antiviral resistance

Serial passage of SARS-CoV-2 in cell culture or recombinant vesicular stomatitis virus encoding the SARS-CoV-2 spike protein (pseudovirus) was performed in the presence of cilgavimab alone and tixagevimab alone, as well as in the presence of the combination of cilgavimab and tixagevimab. Resistant virus variants were identified in the passage series in the presence of cilgavimab, but not tixagevimab or the combination of cilgavimab and tixagevimab.

In neutralization studies using recombinant SARS-CoV-2 pseudovirus containing individual substitutions in the spike protein found in circulating SARS-CoV-2, virus variants with reduced susceptibility to tixagevimab alone included strains with amino acid substitutions in the spike protein F486S (> 600-fold) and F486V (121-149-fold); virus variants with reduced susceptibility to cilgavimab alone included strains with amino acid substitutions in the spike protein R346I (> 200-fold), K444E (> 200-fold), and K444R (> 200-fold).

The combination of tixagevimab and cilgavimab demonstrated complete or nearly complete neutralizing activity against pseudotyped virus-like particles and/or live SARS-CoV-2 virus variants with strain variants containing all spike protein substitutions, namely Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Delta [+K417N] (AY.1/AY.2), Omicron (BA.2). Pseudotyped virus-like particles with the spike protein and authentic reduced susceptibility to the combination of tixagevimab and cilgavimab are presented in Table 1.

Data collection is ongoing to obtain additional information on how the small reduction in activity observed in authentic SARS-CoV-2 virus or pseudotyped virus-like particle assays may correlate with clinical outcomes.

Table 1. Neutralization data for SARS-CoV-2 pseudovirus and authentic virus variants by the combination of tixagevimab and cilgavimab

¹Range of reduced in vitro activity across multiple groups of co-occurring amino acid substitutions and/or in testing laboratories using research-grade assays; mean fold change in the half-maximal inhibitory concentration (IC₅₀) of the monoclonal antibody required to reduce infection by 50% compared to the wild-type reference strain.

²Pseudoviruses expressing the full-length variant SARS-CoV-2 virus spike protein and individual characteristic spike protein substitutions were analyzed, except for L452Q, including Alpha (+L455F, E484K, F490S, Q493R and/or S494P) and Delta (+K417N), containing additional specified RBD substitutions that are no longer detected or are detected at very low levels in these lineages.

³Authentic SARS-CoV-2 viruses expressing the full-length variant spike protein were analyzed, including Alpha (+E484K or S494P), containing additional specified RBD substitutions that are no longer detected or are detected at very low levels in these lineages.

N/d – not determined; RBD – receptor-binding domain.

It is unknown how SARS-CoV-2 pseudovirus or authentic virus neutralization susceptibility data correlate with clinical outcome.

During the PROVENT clinical trial, virus sequencing results were obtained from the clinic visit for 21 patients infected with COVID-19 (6 patients received Tixagevimab and cilgavimab, 15 patients received placebo). At an allele fraction of ≥25%, 14 patients were infected with Variants of Concern or Interest, including 8 patients with the Alpha strain (B.1.1.7) (8 from the placebo group), 1 patient with the Beta strain (B.1.351) (1 patient receiving Tixagevimab and cilgavimab), 3 patients with the Delta strain (B.1.617.2) (3 from the placebo group), and 2 patients with the Epsilon strain (B.1.429) (2 patients receiving the combination of tixagevimab and cilgavimab). Additionally, an RBD spike protein substitution, V503F, with an allele fraction of ≥3%, was detected in the tixagevimab and cilgavimab group.

It is possible that variants resistant to tixagevimab and cilgavimab may collectively exhibit cross-resistance to other monoclonal antibodies targeting the SARS-CoV-2 virus RBD. Tixagevimab and cilgavimab in combination retained activity against pseudoviruses carrying individual SARS-CoV-2 virus spike protein substitutions (E484D/K/Q, F490S, Q493R, S494P, K417E/N, D420N, K444Q, V445A, Y453F, L455F, N460K/S/T, F486V, and Q493K), isolated in variants resistant to other monoclonal antibodies directed against the SARS-CoV-2 virus spike protein RBD.

During the TACKLE clinical trial, virus sequencing results were obtained from the clinic visit for 834 patients (413 patients receiving Tixagevimab and cilgavimab, and 421 patients receiving placebo). At an allele fraction of ≥25%, proportional representation was observed in the groups of patients infected with Variants of Concern or Interest, including patients with the Alpha strain (139 patients receiving Tixagevimab and cilgavimab and 119 patients receiving placebo), Beta (only 1 patient in the placebo group), Gamma (37 patients receiving Tixagevimab and cilgavimab and 46 patients receiving placebo), Delta (33 patients receiving Tixagevimab and cilgavimab and 33 patients receiving placebo), Lambda (11 patients receiving Tixagevimab and cilgavimab and 9 patients receiving placebo), and Mu (only 2 patients in the placebo group).

Pharmacodynamic properties

According to the PROVENT study, after a single intramuscular administration of 150 mg tixagevimab and 150 mg cilgavimab, the geometric mean titers (GMT) of neutralizing antibodies at 7 (n=891), 28 (n=954), 57 (n=43) days post-administration were similar to the GMT observed in the phase 1 study in healthy volunteers and were 16, 22, 17 times higher, respectively, than the GMT obtained from the analysis of plasma from patients recovered from COVID-19 (GMT=30.8).

Immunogenicity

According to the PROVENT study, after a single administration of Evusheld (150 mg tixagevimab and 150 mg cilgavimab) on day 183, 0.8% of patients (6 out of 716) had antibodies to tixagevimab, 1.1% of patients (7 out of 644) had antibodies to cilgavimab, and 1.3% (10 out of 743) had antibodies to Evusheld. There were no data on the relationship between the presence of anti-drug antibodies and efficacy and safety.

According to the TACKLE study, on day 169 after administration of the Evusheld dose (300 mg tixagevimab and 300 mg cilgavimab), 5.2% (14 out of 271) of patients evaluated for anti-drug antibodies had antibodies to tixagevimab, 10.7% (33 out of 307) had antibodies to cilgavimab, and 10.7% (37 out of 346) had antibodies to Evusheld.

Pharmacokinetics

The pharmacokinetics of tixagevimab and cilgavimab are comparable, linear, and dose-proportional over the range from 150 mg tixagevimab, 150 mg cilgavimab to 1500 mg tixagevimab, 1500 mg cilgavimab upon single intravenous administration. Dose proportionality was confirmed by population analysis of pharmacokinetic parameter values in healthy volunteers and in patients included in the TACKLE clinical trial after intramuscular administration of cilgavimab and tixagevimab.

Absorption

After intramuscular administration of a single dose of 150 mg tixagevimab and 150 mg cilgavimab to healthy volunteers, the mean (coefficient of variation, %) C_max was 16.5 µg/ml (35.6%) for tixagevimab and 15.3 µg/ml (38.5%) for cilgavimab with a median T_max of 14 days. According to calculations, the absolute bioavailability after intramuscular administration of a single dose of 150 mg tixagevimab and 150 mg cilgavimab was 68.5% for tixagevimab and 65.8% for cilgavimab.

After intramuscular administration of 300 mg tixagevimab and 300 mg cilgavimab to patients with mild to moderate COVID-19 participating in the TACKLE study, the mean (coefficient of variation, %) C_max of tixagevimab was 21.9 µg/ml (61.7%), and the C_max of cilgavimab was 20.3 µg/ml (63.6%), which were achieved at a median T_max of 15 days.

Distribution

Based on pharmacokinetic modeling data, the central V_d of tixagevimab was 2.72 L, and that of cilgavimab was 2.48 L. The peripheral V_d of tixagevimab was 2.64 L, and that of cilgavimab was 2.57 L.

Metabolism

Tixagevimab and cilgavimab are expected to be broken down into small peptides and amino acids by catabolism in the same manner as endogenous IgG antibodies.

Elimination

The clearance of tixagevimab was 0.041 L/day, the clearance of cilgavimab was 0.041 L/day, with interpatient variability of 21% and 29%, respectively. The estimated mean terminal T_1/2 in the population was 89 days for tixagevimab and 84 days for cilgavimab.

In the PROVENT study, after a single intramuscular administration of 150 mg tixagevimab and 150 mg cilgavimab, the median serum concentration of Evusheld on day 183 was 8.3 µg/ml (range 1.3 to 19.5 µg/ml).

In the TACKLE study, after a single intramuscular administration of 300 mg tixagevimab and 300 mg cilgavimab, the geometric mean serum concentration on day 29 was 37.2 µg/ml. Based on population pharmacokinetic modeling, the minimum serum concentrations 9 months after a single intramuscular administration of a 300 mg tixagevimab and 300 mg cilgavimab dose are expected to be equal to the serum concentrations 6 months after a single intramuscular administration of a 150 mg tixagevimab and 150 mg cilgavimab dose. COVID-19 infection did not affect the clearance of tixagevimab and cilgavimab. There was no clinically significant difference in the clearance of tixagevimab or cilgavimab between patients with COVID-19 included in the TACKLE study and patients included in COVID-19 prevention studies.

Pharmacokinetics in Special Patient Groups

Patients with renal impairment. Specific studies investigating the effect of renal impairment on the pharmacokinetics of tixagevimab and cilgavimab have not been conducted. Tixagevimab and cilgavimab are not excreted unchanged in the urine. Therefore, renal impairment is not expected to have a significant impact on the exposure of tixagevimab and cilgavimab. Furthermore, dialysis is also not expected to affect the pharmacokinetics of tixagevimab and cilgavimab. According to population pharmacokinetic analysis, the clearance of tixagevimab and cilgavimab in patients with mild (n=978) or moderate (n=174) renal impairment is not different from that in patients with normal renal function. The population pharmacokinetic model does not allow for any conclusions regarding severe renal impairment due to an insufficient number of patients (n=21).

Patients with hepatic impairment. Specific studies investigating the effect of hepatic impairment on the pharmacokinetics of tixagevimab and cilgavimab have not been conducted. The effect of hepatic impairment on the pharmacokinetics of tixagevimab and cilgavimab is expected to be insignificant. Tixagevimab and cilgavimab are expected to undergo catabolism in various tissues via proteolytic degradation to amino acids and conversion into other proteins; therefore, hepatic impairment is not expected to affect the exposure of tixagevimab and cilgavimab.

Elderly patients. Among the 2560 patients included in the pooled pharmacokinetic analysis, 21% (n=534) were 65 years of age and older, and 4.2% (n=107) were 75 years of age and older. There are no clinically significant differences in the pharmacokinetics of tixagevimab and cilgavimab between elderly (≥ 65 years) and younger patients.

Pediatric population. Evaluation of the pharmacokinetics of tixagevimab and cilgavimab in individuals under 18 years of age has not been conducted. Based on the results of population pharmacokinetic modeling and simulation, when the drug is used according to the recommended dosing regimen, the serum concentration of tixagevimab and cilgavimab in children aged 12 years and older and weighing at least 40 kg is expected to be comparable to the serum concentration in adult patients, as clinical studies for the prevention and treatment of COVID-19 involved adult patients with similar body weight.

Patients with overweight. According to the results of population pharmacokinetic modeling, a decrease in the serum concentration of tixagevimab and cilgavimab was observed in patients with overweight. The mean predicted serum concentration in adult patients with a body weight > 95 kg after a single intramuscular dose of tixagevimab 150 mg and cilgavimab 150 mg was approximately 37% lower than in adult patients with a body weight of 65 kg.

Other special patient groups. According to population pharmacokinetic analysis, sex, age, race, ethnicity, presence of cardiovascular diseases, diabetes, and immune system deficiency do not have a clinically significant impact on the pharmacokinetic profile of tixagevimab and cilgavimab.

Indications

The drug is indicated for use in adult patients aged 18 years and older for the purpose of

• Pre-exposure prophylaxis of the novel coronavirus infection COVID-19 in patients:
  • Who are currently not infected with SARS-CoV-2 and, to the best of their knowledge, have not been in contact with a person infected with SARS-CoV-2, and have moderate or severe immune compromise due to a medical condition or the use of immunosuppressive medications or therapy, and who lack an adequate immune response to COVID-19 vaccination,
  • Or for whom vaccination with an available COVID-19 vaccine according to an approved or authorized schedule is not recommended due to a history of severe adverse reaction (e.g., severe allergic reaction) to COVID-19 vaccine(s) and/or component(s) of the COVID-19 vaccine (see the “Special Precautions” section);
• Treatment of mild to moderate novel coronavirus infection COVID-19 with an increased risk of progression to severe disease (see the “Special Precautions” section).

ICD codes

Dosage Regimen

Intramuscularly.

The use of Evusheld is possible only as prescribed by a doctor and under the supervision of qualified medical personnel.

Pre-exposure prophylaxis of COVID-19

The dose for adult patients aged 18 years and older is 150 mg of tixagevimab and 150 mg of cilgavimab. This dose should be administered intramuscularly as two separate consecutive injections.

Depending on the predominant circulating SARS-CoV-2 virus strains, administration of a dose of 300 mg tixagevimab and 300 mg cilgavimab as two separate consecutive intramuscular injections may be possible.

For patients who require re-administration of Evusheld for COVID-19 prophylaxis, the next dose of 300 mg tixagevimab and 300 mg cilgavimab is administered once every 6 months.

Treatment of COVID-19

The recommended dose is 300 mg tixagevimab and 300 mg cilgavimab (see Table 2). This dose should be administered intramuscularly as two separate consecutive injections.

Evusheld should be administered as soon as possible after a positive test for SARS-CoV-2 infection and within 7 days of the onset of symptoms of the novel coronavirus infection COVID-19.

Table 2

¹ Depending on the predominant circulating SARS-CoV-2 virus strains, administration of a dose of 300 mg tixagevimab and 300 mg cilgavimab as two separate consecutive intramuscular injections may be possible.

Children

The safety and efficacy of Evusheld in children under 18 years of age have not been established. No data available.

Method of administration

Administration of the medicinal product Evusheld must be performed only by qualified medical personnel, following aseptic rules to ensure the sterility of each administered dose.

Inspect the vials for particulate matter and discoloration. Tixagevimab is a clear or opalescent solution, colorless to light yellow. Cilgavimab is a clear or opalescent solution, colorless to light yellow. Discard the vials if the solution is cloudy, discolored, or contains particulate matter. Do not shake the vials.

Draw one dose of tixagevimab and one dose of cilgavimab into separate syringes, administer intramuscularly into different body sites, preferably the gluteal muscle.

Disposal

The medicinal product Evusheld does not contain preservatives. Any unused medicinal product should be discarded.

Shelf life of the drug drawn into a syringe for injection

4 hours at a temperature of 2°C (35.6°F) to 8°C (46.4°F) or not exceeding 25°C (77°F).

Adverse Reactions

In total, within the framework of Phase 3 studies investigating the prophylactic effect, 4210 adult patients received 150 mg tixagevimab and 150 mg cilgavimab intramuscularly. The most frequent adverse reactions (≥1%) were administration site reactions (1.3%) and hypersensitivity (1.0%).

In the Phase 3 study investigating the use of Evusheld for the treatment of COVID-19, 452 non-hospitalized adult patients with mild or moderate COVID-19 who received 300 mg tixagevimab and 300 mg cilgavimab intramuscularly participated. The overall safety profile in patients who received 300 mg tixagevimab and 300 mg cilgavimab for the treatment of mild or moderate COVID-19 was generally comparable to the overall safety profile of patients who received the drug at 150 mg tixagevimab and 150 mg cilgavimab for the prevention of COVID-19.

The most frequent adverse reaction (≥1%) was administration site reaction (2.4%).

Adverse reactions are grouped by system organ class of the Medical Dictionary for Regulatory Activities (MedDRA) and are presented in Table 3. Within each class, adverse reactions are listed in descending order of frequency, and within the same frequency category, in descending order of severity. The frequency of occurrence of adverse reactions is presented in the following gradation: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency not known (frequency cannot be estimated from the available data).

Table 3. Adverse Reactions

¹Frequency is based on pooled data from clinical studies using the 150 mg tixagevimab and 150 mg cilgavimab dose for COVID-19 prevention.

²Frequency of adverse reactions for the 300 mg tixagevimab and 300 mg cilgavimab dose based on data from the TACKLE clinical study: hypersensitivity – uncommon; administration site reaction – no data; injection site reaction – common.

³Adverse reactions reported as administration related reaction included headache, chills, and redness, discomfort, or pain at the injection site.

Re-administration

In an open-label supplemental study, 305 patients who received the first dose of 150 mg tixagevimab and 150 mg cilgavimab in the PROVENT study received a second dose of 150 mg tixagevimab and 150 mg cilgavimab 10-14 months after the first dose administration. The median follow-up period after the second dose administration was 17 days. The overall safety profile in patients who received the second dose of Evusheld was comparable to that after the first dose administration.

Children

There are no data on the use of the drug in children under 18 years of age.

Contraindications

• Hypersensitivity to tixagevimab, cilgavimab or to any of the excipients of the drug;
• Children under 18 years of age;
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of tixagevimab and cilgavimab in pregnant women are limited. Preclinical studies on the reproductive toxicity of tixagevimab and cilgavimab have not been conducted. In a cross-reactivity study of tixagevimab and cilgavimab on human fetal tissues, no binding was detected.

It is known that human immunoglobulin G1 (IgG1) antibodies cross the placental barrier; therefore, Tixagevimab and cilgavimab may be transferred from the mother to the developing fetus. It is not known whether the potential transfer of tixagevimab and cilgavimab provides benefit or poses a risk to the developing fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

Evusheld is contraindicated during pregnancy.

Women of childbearing potential should use effective methods of contraception during the use of Evusheld and for at least 30 days after the administration of the last dose.

Breastfeeding

It is not known whether Tixagevimab and cilgavimab are excreted in human and animal milk. There are no data on the effects of tixagevimab and cilgavimab on milk production. It is known that maternal immunoglobulins are present in breast milk. A risk to the breastfed child cannot be excluded.

Evusheld is contraindicated during breastfeeding. If the drug is used, breastfeeding should be discontinued.

Fertility

Data on the effects of tixagevimab and cilgavimab on human fertility are not available.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

The use of Evusheld is possible only as prescribed by a doctor and under the supervision of qualified medical personnel. In case of adverse effects, they should be reported in the established manner for pharmacovigilance activities.

Hypersensitivity reactions, including anaphylaxis

With the use of other IgG1 monoclonal antibodies, serious hypersensitivity reactions, including anaphylaxis, have been rarely observed. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, administration of the drug should be discontinued immediately, and appropriate medications and/or supportive therapy should be initiated.

Clinically significant bleeding disorders

As with any drug administered via intramuscular injection, Evusheld should be administered with caution to patients with thrombocytopenia or any coagulation disorders.

Cardiovascular, thromboembolic complications

In the PROVENT clinical trial, serious cardiovascular adverse events were more frequently reported in the group of patients who received Evusheld compared to the placebo group (0.7% compared to 0.3%), in particular, coronary events (e.g., myocardial infarction). A smaller difference was observed for serious thromboembolic events (0.5% compared to 0.2%). Most patients had cardiovascular risk factors and/or a history of cardiovascular disease that could explain the occurrence of these events. A causal relationship between the use of Evusheld and these events has not been established.

In individuals at high risk of cardiovascular or thromboembolic events, the risk-benefit ratio should be considered before initiating Evusheld. Patients should be informed about signs or symptoms indicative of cardiovascular events (in particular, chest pain, shortness of breath, weakness, dizziness, or fainting) and the need to seek immediate medical attention if such symptoms occur.

Antiviral resistance

Clinical studies of Evusheld were conducted when the Alpha, Beta, Gamma, and Delta strains of the SARS-CoV-2 virus were predominant. The efficacy of tixagevimab and cilgavimab against some circulating SARS-CoV-2 variants with reduced in vitro susceptibility has not been established.

Based on clinical data from the PROVENT study, the expected duration of protective effect after a single administration of Evusheld (150 mg tixagevimab and 150 mg cilgavimab) is at least 6 months. Due to the observed decrease in in vitro neutralizing activity against the Omicron strain subvariants BA.1, BA.1.1 (BA.1+R346K), BA.4, and BA.5, the duration of the protective effect of Evusheld against these subvariants is currently unknown.

Infection after pre-exposure prophylaxis or lack of treatment efficacy due to antiviral resistance

Circulating SARS-CoV-2 variants may be resistant to monoclonal antibodies, including tixagevimab and cilgavimab. Information on the neutralizing activity of Evusheld against SARS-CoV-2 in vitro is provided in the “Pharmacological Properties” section (Table 1).

Patients prescribed Evusheld for prophylaxis should be informed about the possible development of infection despite drug administration. Patients should be informed of the need to seek immediate medical attention if signs or symptoms of COVID-19 appear (the most common symptoms are fever, cough, fatigue, loss of taste or smell; the most severe symptoms are difficulty breathing or shortness of breath, loss of speech or mobility, or confusion and chest pain).

The decision to use Evusheld for the treatment of COVID-19 should be made taking into account available information on the characteristics of circulating SARS-CoV-2 variants, including their geographical distribution.

Vaccination against the novel coronavirus infection COVID-19

Pre-exposure prophylaxis with Evusheld is not a substitute for vaccination in people for whom COVID-19 vaccination is recommended. Individuals for whom COVID-19 vaccination is recommended, including those with moderate and severe immune compromise who may be eligible for COVID-19 vaccination, should receive COVID-19 vaccination. In people who have been vaccinated against COVID-19, Evusheld should be administered no less than 2 weeks after vaccination.

Medical conditions or therapies that may lead to moderate or severe immune compromise or an inadequate immune response to COVID-19 vaccination include, but are not limited to, the following:

• Active treatment for solid tumor and hematological malignancies;
• Solid organ transplantation and use of immunosuppressive therapy;
• Immunotherapy with chimeric antigen receptor (CAR) T-cells or hematopoietic stem cell transplantation (within 2 years after transplantation or immunosuppressive therapy);
• Moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome);
• Advanced or untreated HIV infection (individuals with HIV and CD4 cell count <200/mm³, history of AIDS without immune reconstitution, or clinical manifestations of symptomatic HIV);
• Active therapy with high doses of glucocorticosteroids (i.e., ≥20 mg of prednisone or an equivalent drug per day for ≥ 2 weeks), alkylating agents, antimetabolites, transplant-associated immunosuppressive drugs, anticancer chemotherapeutic agents classified as severely immunosuppressive drugs, TNF blockers, and other biological agents that are immunosuppressive or immunomodulatory (e.g., anti-B-cell agents).

Criteria for Risk of Disease Progression to Severe Form

Groups at risk for progression of COVID-19 to a severe form consist of patients meeting any of the following criteria:

• Age 65 years and older;
• Age under 65 years and at least one of the following comorbid diseases/conditions:
  • Oncological disease;
  • Chronic lung disease or moderate or severe asthma;
  • Obesity (body mass index >30);
  • Arterial hypertension;
  • Cardiovascular diseases (including history of stroke);
  • Diabetes mellitus;
  • Chronic kidney disease;
  • Chronic liver disease;
  • Immunosuppression associated with solid organ or bone marrow transplantation, immunodeficiency, HIV infection, use of glucocorticosteroids or immunosuppressive drugs;
  • Sickle cell anemia;
  • Patient was or is a smoker.

Effect on Ability to Drive and Operate Machinery

Evusheld has no or negligible influence on the ability to drive and operate machinery.

Overdose

In clinical studies, no dose-limiting toxicity was observed with intramuscular administration of doses of 300 mg tixagevimab and 300 mg cilgavimab and intravenous administration of doses of 1500 mg tixagevimab and 1500 mg cilgavimab.

Treatment There is no specific treatment for Evusheld overdose. In case of overdose, general medical care should be provided, including monitoring of vital signs and observation of the patient’s general condition.

Drug Interactions

Studies of drug interactions between Evusheld and other medicinal products have not been conducted.

Tixagevimab and cilgavimab are not excreted by the kidneys and are not metabolized by liver enzymes; therefore, interaction with concomitant medicinal products that are excreted in the urine or are substrates, inducers, or inhibitors of cytochrome P450 enzymes is unlikely.

Based on population pharmacokinetic modeling data, vaccination after administration of Evusheld did not have a clinically significant effect on the elimination of Evusheld.

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 2°C (35.6°F) and 8°C (46.4°F). Do not freeze.

Shelf Life

The shelf life is –
1.5 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.