Evusheld (tixagevimab with cilgavimab) for COVID-19 pre-exposure prophylaxis

Evusheld is the trade name given to tixagevimab and cilgavimab, two monoclonal antibodies packaged together for co-administration.¹ One vial of each medicine is included in each packet, for administration as two separate and sequential intramuscular injections, one into each gluteal muscle. In clinical trials or neutralising studies, you may see Evusheld referred to as “AZD7442”.

The medicine is intended for pre-exposure prophylaxis (PrEP):

• in severely immunocompromised people who are unlikely to mount an adequate immune response to COVID-19 vaccination or infection, OR
• in people considered at high risk of severe illness from COVID-19 infection who cannot be vaccinated due to medical contraindication (for example, a history of severe adverse reaction to a COVID-19 vaccine or its components).²

Those who may benefit from Evusheld prophylaxis and are eligible include some transplant recipients, some people having treatment for cancer and some people with HIV.² Refer to Pharmac’s Evusheld access criteria for the full eligibility criteria.

Evusheld has so far been offered by hospital-based specialists but, to improve accessibility, from 3 October 2022 it is available for community supply and primary care administration to those who meet Pharmac access criteria (estimated to be approximately 10,000 people or two per 1000 population).² This was communicated in a 30 September 2022 letter to the primary care sector from Te Whatu Ora – Health New Zealand COVID-19 Care in the Community, at the same time as an Evusheld claiming guide for primary care and a process overview flowchart were made available (both are on HealthPathways).³

Thus, it is now important to think about Evusheld when seeing immunocompromised patients in primary care, and to facilitate administration of therapy if it is requested by secondary/tertiary care clinicians.

Guidance on Evusheld and its use can be found in advice to all health professionals from the Manatū Hauora – Ministry of Health Therapeutics Technical Advisory Group (TAG) document “Update for health professionals: Use of Evusheld for the prevention and treatment of COVID-19” – a reference to support clinicians prescribing and administering Evusheld.⁴

Guidance is provided within the Community HealthPathways online resource for COVID-19 Therapeutics in Adults.⁶

Tixagevimab and cilgavimab are long-acting recombinant human IgG1κ monoclonal antibodies, which each target distinct and non-overlapping epitopes of the SARS-CoV-2 spike protein located in the receptor binding domain. The antibodies neutralise SARS-CoV-2 virions, similarly to host antibody response, by binding to the spike protein and blocking interactions between the virus and the host’s cellular receptors.⁷

Hence, Evusheld (tixagevimab co-packaged with cilgavimab) is a dual monoclonal antibody product with activity against SARS-CoV-2. It has been granted provisional approval by Medsafe⁸ and is available for use as PrEP of COVID-19 in adults and adolescents (12 years or older and weighing at least 40kg), who are severely immunocompromised and unlikely to mount an immune response to COVID-19 vaccination or infection, or in people considered at high risk of severe illness from COVID-19 infection who cannot be vaccinated due to medical contraindication.²

Evusheld access criteria were announced on 25 August 2022 as part of the Pharmac COVID-19 treatments portfolio, which includes antiviral and monoclonal antibody therapies.⁹ This is the first PrEP therapy for COVID-19 available in New Zealand.

Evusheld is available through Te Whatu Ora hospitals, and in the community subject to Pharmac access criteria. A summary of the key access criteria includes that:

• the person does not currently have SARS-CoV-2 infection AND
  • the person must have a cause for moderate to severe immune compromise listed in the full access criteria OR
  • the person is both unable to be vaccinated against COVID-19 due to a medical contraindication AND is considered at high risk of severe illness from COVID-19 infection.²

Patient eligibility for Evusheld is set out in the full Pharmac access criteria and reflects efforts towards prioritising patients who will benefit most.²

The evidence supporting Evusheld for PrEP has been assessed by Medsafe, while post-exposure treatment – to prevent infection or as treatment – is under evaluation. The Therapeutics TAG update provides a helpful summary of the supportive evidence.⁴

The purpose of the ongoing PrEP trial – PROVENT – has been to evaluate the safety and efficacy of a single dose of Evusheld at preventing symptomatic, PCR-confirmed COVID-19. This key trial shows a relative risk reduction of 76.7 per cent for infections in the treatment group (primary analysis). Extended follow-up at a median of six months showed a relative risk reduction of 82.8 per cent.¹⁰

Adverse effects were mostly mild or moderate in severity and showed little difference in frequency between the treatment and placebo groups.¹⁰

Over 75 per cent of participants in the PROVENT study were high risk for severe COVID-19 due to co-morbidities, indicating this treatment is appropriate for immunocompromised people.¹¹

The PROVENT trial data were obtained prior to the emergence of the Omicron strain, and this is one among a small number of study limitations.⁴

The available nonclinical data indicate that the neutralising activity of Evusheld decreases 33 to 65-fold against the Omicron subvariants BA.4 and BA.5 (BA.5 is prevalent in New Zealand at the time of writing). Despite this, pharmacokinetic modelling suggests sufficient activity against these subvariants may be retained for six months at drug concentrations achieved following a doubled dose of Evusheld.¹²

Use of the doubled dose of Evusheld (tixagevimab 300mg and cilgavimab 300mg) was recommended early in 2022 by the manufacturer and the US Food and Drug Administration (FDA). Repeat dosing every six months, if ongoing protection is needed, has also been recommended.¹²

In New Zealand, the Therapeutics TAG also recommends PrEP for COVID-19 using a 600mg dose of Evusheld intramuscularly (tixagevimab 300mg into one gluteal muscle and cilgavimab 300mg into the opposite gluteal muscle).⁴

Evusheld 600mg is now also the recommended dose in the New Zealand Formulary; however, it is not currently an approved dose. An application has been submitted to Medsafe for approval but, at the time of writing, prescribing the higher dose is subject to Section 25 of the Medicines Act 1981 (see later).

Repeat dosing is not currently funded in New Zealand but this may be reviewed, considering – among other factors – what COVID-19 strains may be expected to predominate in six months’ time.

From 3 October 2022, GPs, pharmacist prescribers and nurse practitioners may prescribe Evusheld. It is important for primary care staff to be aware of the community availability of this PrEP therapy for COVID-19, and who can benefit from it. The access criteria cover a wide range of immunosuppression-linked conditions, therapies and pertinent timeframes.²

Primary care should employ opportunistic patient discussions and be open to systematic searches of patient records to identify and contact those who may be eligible. Requests from specialist services may also be received for patients who would prefer to have PrEP for COVID-19 administered by their primary care provider.

The Te Whatu Ora process overview flowchart illustrates an anticipated coordinated approach between primary and secondary/tertiary care.

It is anticipated that, initially, specialist services may identify many of the patients who meet the Evusheld access criteria and offer PrEP in a specialist setting. To ensure equity and accessibility, particularly in rural and remote areas, people will now be able to access the treatment via general practice and other primary care settings.^3,13

Once a patient has given consent to treatment, a prescription can be sent to a community pharmacy and transport arranged, maintaining cold chain, for Evusheld to be delivered to the clinic. There are no restrictions on which pharmacies may order Evusheld, provided they have an account with Healthcare Logistics (HCL). Evusheld should only be ordered upon receipt of a prescription, and not in anticipation of receiving a prescription.³

Te Whatu Ora has made funding available to support access to Evusheld in the community. Notable conditions of the claiming guide and fee schedule include:³

• full funding of telephone and video translation services for COVID-19 related consultations
• pharmacy claims for prescription co-payment, dispensing, delivery (up to $25) and administration (where local delivery model allows)
• pharmacy providers will receive payment for the service through a variation to their COVID Care in the Community Pharmacy agreement with their Te Whatu Ora district.

There are very few contraindications or precautions with using Evusheld but the main considerations are listed below. A full list of contraindications and precautions for the prescribing of Evusheld can be obtained within the Medsafe data sheet for Evusheld, and the New Zealand Formulary.^1,16

According to the Medsafe data sheet, Evusheld is contraindicated in people with:

• a history of severe hypersensitivity reactions (including anaphylaxis) to its active ingredients (tixagevimab and cilgavimab) or excipients (L-histidine, L-histidine hydrochloride and polysorbate 80).¹

Additional special precautions are listed for use in the following scenarios:¹

• Clinically significant bleeding disorders – as with any intramuscular injection, caution is needed with thrombocytopenia or a coagulation disorder; intravenous infusion of Evusheld should be sought in preference where the risk of intramuscular haematoma cannot be ameliorated following discussion with a haematologist.
• High risk of cardiovascular and/or thromboembolic events – a causative relationship between Evusheld and these adverse events has not been confirmed; however, people with a significant history of, or at very high risk of, such events should receive Evusheld only after careful consideration of the six-month risk of severe COVID-19 versus that of cardiovascular or thromboembolic events.
Pregnancy and lactation – there are limited data in this group; Evusheld should only be used during pregnancy if the potential benefit outweighs the uncertain risk for the mother and the foetus. It is not known whether tixagevimab and cilgavimab are excreted in human milk.

Interaction studies have not been conducted, as Evusheld is not expected to undergo metabolism by hepatic enzymes or renal elimination. Dose adjustments for age, renal or hepatic impairment are not required.¹

The recommended COVID-19 PrEP dose of Evusheld 600mg is currently available only under Section 25 of the Medicines Act, as an “unapproved dosage regimen”.¹⁴ The prescriber must be working within their scope of practice and must meet the patient’s rights under the Code of Health and Disability Services Consumers’ Rights, particularly the “Right to make an informed choice and give informed consent” to treatment.¹⁵ As the Evusheld product itself is approved for use in New Zealand, Section 29 reporting is not required.

Prescribers should aim to outline the benefits and risks of treatment, any alternatives, side effects and administration considerations with regard to Evusheld, and provide the patient with an appropriate Evusheld patient information sheet.^17,18 The Health Navigator NZ Evusheld fact sheet for patients is available in English, te reo Māori, Samoan, Tongan, Chinese (simplified) and Cook Islands Māori. Key messages from this and other useful patient resources include:^17,18

• Evusheld is a monoclonal antibody and its use in PrEP is to protect against, not treat, disease (and it is different to vaccines).
• Medsafe has provisionally approved the 300mg course of Evusheld.
• Medsafe is reviewing an application to increase the approved Evusheld dose to 600mg.
• Both doses are funded, but the 600mg dose is expected to provide better protection against currently circulating strains of SARS-CoV-2, protection which may last up to six months.
• Evusheld should reduce the likelihood of infection and of serious outcomes from COVID-19 if infection occurs.
• The treatment involves two intramuscular injections, one to each gluteal muscle (buttock).
• Monitoring will occur after the injections to check there are no immediate adverse effects – these are generally minor (eg, headache, fatigue injection site soreness, swelling) but more unusually may relate to allergic reactions to the treatment.
Side effects are possible later – your healthcare provider will advise when you might need to contact them or Healthline on 0800 611 116 urgently (for some less-common but serious side effects). If you are at all concerned, always seek medical help and say you have had Evusheld.

The full Medical Council of New Zealand statement on obtaining informed consent is available online.¹⁹

The Evusheld carton contains co-packaged tixagevimab 150mg/1.5mL solution for injection (single-dose vial; dark grey cap) and cilgavimab 150mg/1.5mL solution for injection (single-dose vial; white cap); the vials do not require reconstitution. Evusheld storage instructions are: store at 2° to 8°C (refrigerate, do not freeze), do not shake, protect from light.¹

The solutions for injection contain no preservative; therefore, prepared syringes should be administered immediately. If this is not possible, and the prepared tixagevimab and cilgavimab syringes need to be stored, they can be done so either in a refrigerator at 2°C to 8°C or at room temperature up to 25°C. Note, the total time from vial puncture to administration should not exceed four hours.¹

Ensure the name and the batch number of the administered product is recorded in the patient’s medical record, to improve traceability if needed.

A full description of handling and administration procedures for Evusheld is provided within the Medsafe data sheet, product registration information, and consumer medicine information, and in the New Zealand Formulary and the Therapeutics TAG update “Use of Evusheld for the prevention and treatment of COVID-19”.^1,4,8,16,18 Note that some of the information may refer to the approved dose rather than the newly recommended dose.

The current New Zealand recommendation for a 600mg dose of Evusheld (tixagevimab 300mg and cilgavimab 300mg) requires the following adaptation:⁴

• two cartons of Evusheld (2 x 150mg of each antibody) need to be used
• two 150mg vials of tixagevimab should be drawn up into one syringe (ideally labelled)
• two 150mg vials of cilgavimab should be drawn up into a second syringe (ideally labelled)
• tixagevimab 300mg should be delivered intramuscularly to one gluteal muscle
• cilgavimab 300mg should be delivered intramuscularly to the contralateral gluteal muscle.

The practitioner administering Evusheld should be appropriately skilled in giving gluteal intramuscular injections. The healthcare clinic should also be equipped and staffed to handle the possibility of allergic adverse reactions.

It should be noted, there are two sites for gluteal injection (dorsogluteal and ventrogluteal), and a guide to correct technique, needle positioning and patient factors can be found in a review of success factors in the psychiatric setting.²⁰ Historically, choice of site has been based upon practitioner preference and confidence rather than evidence, and many would give the intramuscular injection in the dorsogluteal area located in the “upper outer quadrant” of the gluteal muscle. However, evidence-based literature favours the ventrogluteal area, with regard to safety, as the dorsogluteal area is close to the sciatic nerve and gluteal artery.²⁰

A refresher of good practice for intramuscular injection technique in general is available in an online continuing educational activity that summarises the anatomic landmarks, safety precautionary checklists, the recommended procedural steps and the complications to be aware of.²¹ Similar information for intramuscular injection into the dorsogluteal site is outlined in the Canterbury region “Fluid and Medication Management” manual.²²

Adverse events to Evusheld should be reported in the normal manner with CARM.