Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: AstraZeneca AB, SE-151 85 Södertälje, Sweden
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Serious hypersensitivity reactions, including anaphylaxis, have been observed with monoclonal antibodies. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medicinal products and/or supportive therapy.
In the PROVENT study, participants in the EVUSHELD arm experienced more serious cardiovascular adverse events compared to those in the placebo arm (0.7% versus 0.3%), notably coronary events (e.g myocardial infarction). A smaller imbalance has been observed for thrombo-embolic events (0.8% versus 0.6%), notably pulmonary embolism. The majority of subjects had cardiovascular risk factors and/or history of cardiovascular disease that could explain the occurrence of such events. A causal relationship between EVUSHELD and these events has not been established.
The risks and benefits should be considered prior to initiating EVUSHELD in individuals at high risk for cardiovascular or thrombo-embolic events. Patients should be advised of signs or symptoms suggestive of cardiovascular event (notably chest pain, dyspnoea, malaise, feeling lightheaded or faint) and to seek immediate medical attention if such symptoms occur.
As with any other intramuscular injections, EVUSHELD should be given with caution to patients with thrombocytopenia or any coagulation disorder.
The clinical trials with EVUSHELD were conducted when Alpha, Beta, Gamma and Delta variants were predominant. Efficacy of tixagevimab and cilgavimab against some circulating SARS-CoV-2 variants with decreased in-vitro susceptibility is uncertain (see section 5.1).
Based on clinical data from PROVENT, the duration of protection following administration of a single EVUSHELD dose (150 mg of tixagevimab and 150 mg of cilgavimab) is estimated to be at least 6 months. Due to the observed decrease in in-vitro neutralisation activity against the Omicron subvariants BA.1 and BA.1.1 (BA.1+R346K), the duration of protection of EVUSHELD for these subvariants is currently not known.
Pre-exposure prophylaxis with EVUSHELD is not a substitute for vaccination in individuals for whom COVID-19 vaccination is recommended.
No human interaction studies have been performed.
EVUSHELD is not expected to undergo metabolism by hepatic enzymes or renal elimination. Tixagevimab and cilgavimab are not renally excreted or metabolised by cytochrome P450 (CYP) enzymes; therefore, interactions with medicinal products that are renally excreted or that are substrates, inducers, or inhibitors of CYP enzymes are unlikely.
Based on pharmacokinetic (PK) modelling, COVID-19 vaccination following EVUSHELD administration had no clinically relevant impact on the clearance of EVUSHELD.
Based on PK modelling, immunocompromised condition had no clinically relevant impact on the clearance of EVUSHELD.
No human interaction studies have been performed.
There are no or limited data from the use of tixagevimab and cilgavimab in pregnant women.
Non-clinical reproductive toxicity studies have not been performed with tixagevimab and cilgavimab (see section 5.3). In tissue cross reactivity studies with tixagevimab and cilgavimab using human foetal tissues no binding of clinical concern was detected. Human immunoglobulin G1 (IgG1) antibodies are known to cross the placenta therefore tixagevimab and cilgavimab have the potential to be transferred from the mother to the developing foetus. The potential treatment benefit or risk of placental transfer of tixagevimab and cilgavimab to the developing foetus is not known.
EVUSHELD should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.
It is not known whether tixagevimab and cilgavimab are excreted in human milk but maternal IgG is known to be transferred to milk during the first days after birth.
As tixagevimab and cilgavimab directly target the spike protein of SARS-CoV-2, and in view of low systemic absorption after oral ingestion of antibodies, administration of EVUSHELD whilst breastfeeding can be considered when clinically indicated.
There are no data on the effects of tixagevimab and cilgavimab on human fertility. Effects on male and female fertility have not been evaluated in animal studies.
EVUSHELD has no or negligible influence on the ability to drive and use machines.
The most common adverse reactions were injection site reactions (1.3%) and hypersensitivity (1.0%).
A total of 4,210 adult participants have received 150 mg tixagevimab and 150 mg cilgavimab, via intramuscular injection, in Phase III prophylaxis studies.
The adverse reactions in Table 2 are listed by MedDRA system organ class and frequency. Frequencies are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from available data).
Table 2. Tabulated list of adverse reactions:
| MedDRA system organ class | Adverse reaction | Frequency |
|---|---|---|
| Immune system disorders | Hypersensitivitya | Common |
| General disorders and administration site conditions | Injection related reactionb | Uncommon |
| Injury, poisoning and procedural complications | Injection site reactionc | Common |
a Including the preferred terms Rash and Urticaria.
b Description of events reported under the preferred term Injection related reaction include headache, chills and redness, discomfort or soreness near where the injection was given.
c Including the preferred terms Injection site pain, Injection site erythema, Injection site pruritus, Injection site reaction and Injection site induration.
No data are available for paediatric patients <18 years old (see section 4.2 and 5.2).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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