Vaccine Information: EVUSHELD (Page 4 of 8)

6.4 Required Reporting for Serious Adverse Events and Medication Errors

The prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory reporting of all serious adverse events* and medication errors potentially related to EVUSHELD within 7 calendar days from the healthcare provider’s awareness of the event, using FDA Form 3500 (for information on how to access this form, see below). The FDA requires that such reports, using FDA Form 3500, include the following:

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Patient demographics and baseline characteristics (e.g., patient identifier, age or date of birth, gender, weight, ethnicity, and race)

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A statement “EVUSHELD use for COVID-19 under Emergency Use Authorization (EUA)” under the “Describe Event, Problem, or Product Use/Medication Error” heading

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Information about the serious adverse event or medication error (e.g., signs and symptoms, test/laboratory data, complications, timing of drug initiation in relation to the occurrence of the event, duration of the event, treatments required to mitigate the event, evidence of event improvement/disappearance after stopping or reducing the dosage, evidence of event reappearance after reintroduction, clinical outcomes)

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Patient’s preexisting medical conditions and use of concomitant products

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Information about the product (e.g., dosage, route of administration, NDC #)

Submit adverse event and medication error reports, using Form 3500, to FDA MedWatch using one of the following methods:

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Complete and submit the report online: www.fda.gov/medwatch/report.htm

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Complete and submit a postage-paid FDA Form 3500 (https://www.fda.gov/media/76299/download) and return by:

∘

Mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, or

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Fax to 1-800-FDA-0178, or

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Call 1-800-FDA-1088 to request a reporting form

In addition, please provide a copy of all FDA MedWatch forms to AstraZeneca:

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Fax 1-866-742-7984

and to report adverse events please:

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Visit https://contactazmedical.astrazeneca.com, or

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Call AstraZeneca at 1-800-236-9933.

The prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory responses to requests from FDA for information about adverse events and medication errors following receipt of EVUSHELD.

*Serious adverse events are defined as:

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Death

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A life-threatening adverse event;

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A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions;

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A congenital anomaly/birth defect;

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Other important medical event, which may require a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly;

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Inpatient hospitalization or prolongation of existing hospitalization.

6.5 Other Reporting Requirements

Healthcare facilities and providers will report therapeutics information and utilization data as directed by the U.S. Department of Health and Human Services.

7 DRUG INTERACTIONS

Drug-drug interaction studies have not been performed.

Tixagevimab and cilgavimab are not renally excreted or metabolized by cytochrome P450 (CYP) enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of CYP enzymes are unlikely [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. EVUSHELD should only be used during pregnancy if the potential benefit outweighs the potential risk for the mother and the fetus.

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 immunoglobulin G1 (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. It is unknown whether the potential transfer of tixagevimab and cilgavimab provides any treatment benefit or 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.2 Lactation

Risk Summary

There are no available data on the presence of tixagevimab or cilgavimab in human milk or animal milk, the effects on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EVUSHELD and any potential adverse effects on the breastfed infant from EVUSHELD.

8.4 Pediatric Use

EVUSHELD is not authorized for use in pediatric individuals under 12 years of age or weighing less than 40 kg. The safety and effectiveness of EVUSHELD have not been established in pediatric individuals. The dosing regimen is expected to result in comparable serum exposures of tixagevimab and cilgavimab in individuals 12 years of age and older and weighing at least 40 kg as observed in adults, since adults with similar body weight have been included in the trials PROVENT, STORM CHASER and TACKLE [see Adverse Reactions (6.1) and Clinical Studies (14)].

8.5 Geriatric Use

Of the 2,555 subjects in the pooled pharmacokinetics (PK) analysis (Phase I and Phase III studies), 21% (N= 533) were 65 years of age or older and 3% (N= 81) were 75 years of age or older. There is no clinically meaningful difference in the PK of tixagevimab and cilgavimab in geriatric subjects (≥65 years) compared to younger subjects.

8.6 Renal Impairment

Tixagevimab and cilgavimab are not eliminated intact in the urine, renal impairment is not expected to affect the exposure of tixagevimab and cilgavimab. Similarly, dialysis is not expected to impact the PK of tixagevimab and cilgavimab.

8.7 Hepatic Impairment

The effect of hepatic impairment on the PK of tixagevimab and cilgavimab is unknown.

8.8 Other Specific Populations

Based on a population PK analysis, the PK profile of tixagevimab and cilgavimab was not affected by sex, age, race, or ethnicity. Population PK model-based simulations suggest that body weight had no clinically relevant effect on the PK of tixagevimab and cilgavimab in healthy adults over the range of 36 kg to 177 kg.

10 OVERDOSAGE

Treatment of overdose with EVUSHELD should consist of general supportive measures including the monitoring of the clinical status of the individual. There is no specific treatment for overdose with EVUSHELD.

11 DESCRIPTION

Tixagevimab, a SARS-CoV-2 spike protein-directed attachment inhibitor, is a human immunoglobulin G1 (IgG1κ) monoclonal antibody produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. The molecular weight is approximately 149 kDa.

Tixagevimab injection is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow solution supplied in a single-dose vial for intramuscular use. The vial stoppers are not made with natural rubber latex. Each 1.5 mL contains 150 mg tixagevimab, L- histidine (2.4 mg), L- histidine hydrochloride monohydrate (3.0 mg), polysorbate 80 (0.6 mg), sucrose (123.2 mg), and Water for Injection, USP. The pH is 6.0.

Cilgavimab, a SARS-CoV-2 spike protein-directed attachment inhibitor, is a human IgG1κ monoclonal antibody produced in CHO cells by recombinant DNA technology. The molecular weight is approximately 152 kDa.

Cilgavimab injection is a sterile, preservative-free, clear to opalescent and colorless to slightly yellow solution supplied in a single-dose vial for intramuscular use. The vial stoppers are not made with natural rubber latex. Each 1.5 mL contains 150 mg cilgavimab, L- histidine (2.4 mg), L- histidine hydrochloride monohydrate (3.0 mg), polysorbate 80 (0.6 mg), sucrose (123.2 mg), and Water for Injection, USP. The pH is 6.0.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tixagevimab and cilgavimab are two recombinant human IgG1 monoclonal antibodies with amino acid substitutions to extend antibody half-life (YTE), reduce antibody effector function, and minimize the potential risk of antibody-dependent enhancement of disease (TM). Tixagevimab and cilgavimab can simultaneously bind to non-overlapping regions of the receptor binding domain (RBD) of SARS CoV 2 spike protein. Tixagevimab, cilgavimab, and their combination bind to spike protein with equilibrium dissociation constants of K_D = 2.76 pM, 13.0 pM and 13.7 pM, respectively, blocking its interaction with human ACE2, the SARS-CoV-2 receptor, which is required for virus attachment. Tixagevimab, cilgavimab, and their combination blocked RBD binding to human ACE2 with IC₅₀ values of 0.32 nM (48 ng/mL), 0.53 nM (80 ng/mL), and 0.43 nM (65 ng/mL), respectively.

12.3 Pharmacokinetics

A summary of PK parameters and properties of tixagevimab and cilgavimab following administration of a single EVUSHELD (300 mg of tixagevimab and 300 mg of cilgavimab) intramuscular dose is provided in Table 5.

Table 5 Summary of PK Parameters and Properties of Tixagevimab and Cilgavimab Following a Single EVUSHELD (300 mg Tixagevimab and 300 mg Cilgavimab) Intramuscular Dose

PK Parameters	Tixagevimab	Cilgavimab
* Geomean (geometric %CV) † Median (range) ‡ Observed geomean (geometric %CV) concentration 2 day after dosing § Observed geomean (geometric %CV) concentration 84 days after dosing ¶ Based on a single EVUSHELD (150 mg tixagevimab and 150 mg cilgavimab) # Arithmetic mean (SD)
Cmax (µg/mL)*	21.9 (61.7)	20.3 (63.6)
Tmax (day)†	14.9 (1.1 – 86)	15.0 (1.1 – 85)
C2 (µg/mL)‡	9.5 (77)	9.1 (80)
C84 (µg/mL)§	15 (48)	14 (51)
AUC0-84 (day•µg/mL)*	1408 (54)	1307 (58)
Absorption
Bioavailability *¶	68.5	65.8
Distribution
Apparent Volume of Distribution (L)*	7.7 (1.97)	8.7 (2.73)
Elimination
Half-life (days)*#	87.9 (13.9)	82.9 (12.3)
Apparent Clearance (L/day)#	0.062 (0.019)	0.074 (0.028)
Metabolism	Catabolic pathways; Same manner as endogenous IgG
Excretion	Not likely to undergo renal excretion

In the PROVENT repeat dose sub-study, following a second IM dose of EVUSHELD (150 mg of tixagevimab and 150 mg of cilgavimab) administered 10 to 14 months after the initial IM dose of EVUSHELD (150 mg of tixagevimab and 150 mg of cilgavimab) (N= 53), the geometric mean serum concentration was 26.4 µg/mL on post-administration Day 29. This serum concentration was similar to the geometric mean drug concentration on post-administration Day 29 (23.3 μg/mL) following the initial IM EVUSHELD dose (150 mg of tixagevimab and 150 mg of cilgavimab) in the PROVENT parent study.

The primary analysis in the clinical efficacy study PROVENT was conducted prior to the emergence of the Omicron variant; the dominant variants in circulation at that time were Alpha, Beta, Gamma, and Delta. Pharmacokinetic and pharmacodynamic modeling using cell-based EC₅₀ values of EVUSHELD against the currently circulating variants in the U.S. suggest in vivo activity against these variants may be retained at drug concentrations achieved following a single EVUSHELD initial dose of 300 mg tixagevimab and 300 mg cilgavimab for 6 months [see Dosage and Administration (2.1)].

Specific Populations

The PK profile of tixagevimab and cilgavimab were not affected by sex, age, race or ethnicity. Body weight had no clinically relevant effect on the PK of tixagevimab and cilgavimab in adults over the range of 36 kg to 177 kg.

Pediatric Population

The PK of tixagevimab and cilgavimab in pediatric individuals have not been evaluated.

The dosing regimen is expected to result in comparable plasma exposures of tixagevimab and cilgavimab in pediatric individuals ages 12 years of age or older who weigh at least 40 kg as observed in adult individuals [see Use in Specific Populations (8.4)].

Renal impairment

Tixagevimab and cilgavimab are not eliminated intact in the urine.

Renal impairment is not expected to impact the PK of tixagevimab and cilgavimab, since monoclonal antibodies with molecular weight >69 kDa are known not to undergo renal elimination. Similarly, dialysis is not expected to impact the PK of tixagevimab and cilgavimab.

There is no difference in the clearance of tixagevimab and cilgavimab in individuals with mild or moderate renal impairment compared to individuals with normal renal function. There were insufficient subjects with severe renal impairment to draw conclusions [see Use in Specific Populations (8.6)].

Hepatic impairment

No specific studies have been conducted to examine the effects of hepatic impairment on the PK of tixagevimab and cilgavimab. The impact of hepatic impairment on the PK of tixagevimab and cilgavimab is unknown [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Drug-drug interaction studies have not been performed. Based on key elimination pathways, tixagevimab and cilgavimab interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of CYP enzymes are unlikely [see Drug Interactions (7)].