The Assistant Secretary for Preparedness and Response and the FDA are announcing the authorization of an extension to the shelf-life of specific lots of the unopened AstraZeneca monoclonal antibody therapy, Evusheld (tixagevimab copackaged with cilgavimab), from 18 months to 24 months when stored at 2 to 8°C (36 to 46°F) in the original carton protected from light.
Further information, including impacted lot numbers, may be found at https://aspr.hhs.gov/COVID-19/Therapeutics/updates/Pages/important-update-28June2022.aspx.
COVID-19, preexposure prophylaxis (off-label use):
Patients with moderate to severe immune compromise who cannot be vaccinated or may have an inadequate response to vaccination:
Note: For patients who have received a COVID-19 vaccination, administer tixagevimab and cilgavimab ≥2 weeks after vaccination. Development of SARS-CoV-2 variants with reduced susceptibility to tixagevimab and cilgavimab may increase risk of treatment failure; consider local prevalence of variants when evaluating therapy options (FDA 2022). Further information on variants may be found at: https://covid.cdc.gov/covid-data-tracker/#variant-proportions.
IM:
Initial dosing: Tixagevimab 300 mg and cilgavimab 300 mg as a single dose (administered in 2 separate syringes consecutively). For patients who initially received tixagevimab 150 mg and cilgavimab 150 mg (previously approved dose), administer a follow-up dose of tixagevimab 150 mg and cilgavimab 150 mg (if initial dose was ≤3 months ago) or tixagevimab 300 mg and cilgavimab 300 mg (if initial dose was >3 months ago) as soon as possible (FDA 2022).
Repeat dosing: Tixagevimab 300 mg and cilgavimab 300 mg as a single dose (administered in 2 separate syringes consecutively) every 6 months (FDA 2022).
No dosage adjustment recommended (FDA 2022).
There are no dosage adjustments provided (has not been studied) (FDA 2022).
(For additional information see "Tixagevimab and cilgavimab (United States: Authorized for use): Pediatric drug information")
Note: Tixagevimab and cilgavimab have not been studied in pediatric patients; emergency use authorization from the FDA is based on likelihood of similar exposures in patients ≥12 years of age weighing ≥40 kg to those in adults (FDA 2022).
COVID-19, preexposure prophylaxis:
Note: Tixagevimab and cilgavimab are only for use in patients who are not currently infected with SARS-CoV-2 and who have not had a known recent exposure, and either have moderate to severe immune compromise and may not mount an adequate immune response to COVID-19 vaccination, or who cannot be vaccinated due to a history of severe adverse reaction to COVID-19 vaccines or components. Development of SARS-CoV-2 variants with reduced susceptibility to tixagevimab and cilgavimab may increase risk of treatment failure; consider local prevalence of variants when evaluating options (FDA 2022). Further information on variants may be found at: https://covid.cdc.gov/covid-data-tracker/#variant-proportions.
Children ≥12 years and Adolescents, weighing ≥40 kg: IM: Tixagevimab 300 mg and cilgavimab 300 mg, administered in 2 separate syringes consecutively, every 6 months (FDA 2022).
Patients who initially received previously authorized dose of tixagevimab 150 mg and cilgavimab 150 mg (FDA 2022):
Initial dose receipt ≤3 months ago: IM: Tixagevimab 150 mg and cilgavimab 150 mg, administered in 2 separate syringes consecutively, as soon as possible. Starting 6 months after this additional dose, administer tixagevimab 300 mg and cilgavimab 300 mg, administered in 2 separate syringes consecutively, every 6 months.
Initial dose receipt >3 months ago: IM: Tixagevimab 300 mg and cilgavimab 300 mg, administered in 2 separate syringes consecutively, as soon as possible; repeat every 6 months.
Altered kidney function: Children ≥12 years and Adolescents, weighing ≥40 kg: No dosage adjustment is recommended (FDA 2022).
There are no dosage adjustments provided in the fact sheet for health care providers (has not been studied).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intramuscular [preservative free]:
Evusheld: Tixagevimab 150 mg and cilgavimab 150 mg per 1.5 mL (3 mL) [contains polysorbate 80]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intramuscular:
Evusheld: Tixagevimab 150 mg and cilgavimab 150 mg per 1.5 mL (3 mL) [contains polysorbate 80]
Investigational agent; approved for emergency use authorization by the FDA December 2021.
Tixagevimab and cilgavimab are not commercially available; they are available under an emergency use authorization (EUA) from the FDA. The US Department of Health and Human Services will determine distribution amounts for each state/territory based on total adult population within the jurisdiction. State and territorial health departments will identify which sites in their respective jurisdictions receive product.
As part of the EUA, information consistent with fact sheets pertaining to emergency use of tixagevimab and cilgavimab are required to be available for health care providers and patients/caregivers, and certain mandatory requirements for the combination's administration under the EUA must be met as outlined in the FDA EUA letter; the fact sheets and EUA letter may be accessed at https://www.evusheld.com/. Additionally, health care providers must track and report all medication errors and serious adverse events potentially associated with tixagevimab and cilgavimab use by either submitting a MedWatch form (https://www.fda.gov/medwatch/report.htm) or an FDA Form 3500 (health professional) by mail or fax (1-800-FDA-0178); a copy of all MedWatch forms should also be provided to AstraZeneca (fax 1-866-742-7984).
IM: Administer tixagevimab and cilgavimab as 2 separate consecutive IM injections. Administer at different injection sites, preferably 1 in each of the gluteal muscles (FDA 2022).
IM: Administer tixagevimab and cilgavimab as 2 separate IM injections; administer consecutively. Administer each injection at a different site, preferably 1 in each gluteal muscle; ensure that administration sites are appropriate for dose volume (FDA 2022).
See "Use: Off-Label."
COVID-19, preexposure prophylaxis
The following adverse reactions and incidences are derived from the FDA issued emergency use authorization (EUA) unless otherwise specified. Refer to EUA for information regarding reporting adverse reactions (FDA 2022). Adverse reactions reported in adults.
1% to 10%: Nervous system: Dizziness (1%), fatigue (4%), headache (6%), insomnia (1%)
<1%: Hypersensitivity: Anaphylaxis
Severe hypersensitivity reactions, including anaphylaxis, to tixagevimab, cilgavimab, or any component of the formulation.
Concerns related to adverse effects:
• Cardiovascular events: A higher rate of serious cardiovascular adverse events, including myocardial infarction and cardiac failure, was observed among recipients of tixagevimab and cilgavimab, compared to placebo. All patients who experienced cardiac events had cardiac risk factors and/or a history of cardiovascular disease, and there was no clear temporal pattern. Consider potential risk and benefit in patients with a history of cardiovascular disease and advise patients to seek immediate medical attention if they experience signs/symptoms of a cardiovascular event (FDA 2022).
• Hypersensitivity: Serious hypersensitivity reactions, including anaphylaxis, have been observed with administration of human IgG1 monoclonal antibodies like tixagevimab and cilgavimab. If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care. Monitor patients after administration for ≥1 hour. Additionally, tixagevimab and cilgavimab contain polysorbate 80, an ingredient in some COVID-19 vaccines; polysorbate 80 is also structurally similar to polyethylene glycol, an ingredient in some other COVID-19 vaccines. Consider consultation with an allergist/immunologist prior to administering tixagevimab and cilgavimab to individuals who have experienced a severe hypersensitivity reaction (eg, anaphylaxis) to a COVID-19 vaccine (FDA 2022). See also “Polysorbate 80” warning below.
Disease-related concerns:
• Bleeding disorders: Administer with caution to individuals with thrombocytopenia or any coagulation disorder (FDA 2022).
Dosage form specific issues:
• Polysorbate 80: Tixagevimab and cilgavimab contains polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• SARS-CoV-2 viral variants: Certain SARS-CoV-2 viral variants may not be neutralized by monoclonal antibodies such as tixagevimab and cilgavimab. Tixagevimab and cilgavimab may not be effective at preventing COVID-19 caused by these variants. If signs or symptoms of COVID-19 occur, advise patients to test for COVID-19 and seek medical attention, including treatment, as necessary.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
COVID-19 Vaccines: Tixagevimab and Cilgavimab may diminish the therapeutic effect of COVID-19 Vaccines. Management: Wait at least 2 weeks after receipt of a COVID-19 vaccine before administering tixagevimab and cilgavimab for pre-exposure prophylaxis. Risk D: Consider therapy modification
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Tixagevimab and cilgavimab (administered in combination) are currently available under FDA emergency use authorization for preexposure prophylaxis of COVID-19 (FDA 2022). The phase 3 trials (NCT04625725 and NCT04625972) required patients who could become pregnant to use effective contraception and the use of condoms by males.
Nonclinical reproductive toxicity studies have not been conducted.
Tixagevimab and cilgavimab are both humanized monoclonal antibodies (IgG1). Human IgG crosses the placenta. Exposure is dependent upon the IgG subclass, maternal serum concentrations, placental integrity, newborn birth weight, and GA, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis and the highest during the third trimester (Clements 2020; Palmeira 2012; Pentsuk 2009).
The risk of severe illness from COVID-19 infection is increased in symptomatic pregnant patients compared to nonpregnant patients. Pregnant and recently pregnant patients with moderate or severe infection are at increased risk of complications such as hypertensive disorders of pregnancy, postpartum hemorrhage, or other infections compared to pregnant patients without COVID-19. Pregnant patients with symptoms may require ICU admission, mechanical ventilation, or ventilatory support (ECMO) compared to symptomatic nonpregnant patients. Other adverse pregnancy outcomes include preterm birth and stillbirth. The risk of coagulopathy, cesarean delivery, and maternal death may be increased; neonates have an increased risk for NICU admission. Maternal age and comorbidities such as diabetes, hypertension, lung disease, and obesity may also increase the risk of severe illness in pregnant and recently pregnant patients (ACOG 2022; NIH 2022).
Tixagevimab and cilgavimab (administered in combination) are currently available under FDA emergency use authorization (EUA) for preexposure prophylaxis of COVID-19 (FDA 2022). In general, the treatment of COVID-19 infection during pregnancy is the same as in nonpregnant patients (NIH 2022). Pregnant patients were excluded from the phase 3 trials (NCT04625725 and NCT04625972). Pregnancy itself is not one of the medical conditions listed in the EUA eligibility criteria for use. According to the EUA, dose adjustments are not recommended for patients who are pregnant (FDA 2022). Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.
Data collection to monitor maternal and infant outcomes following exposure to COVID-19 during pregnancy is ongoing. Health care providers are encouraged to enroll patients exposed to COVID-19 during pregnancy in the Organization of Teratology Information Specialists pregnancy registry (877-311-8972; https://mothertobaby.org/join-study/).
It is not known if tixagevimab or cilgavimab are present in breast milk.
Tixagevimab and cilgavimab are both humanized monoclonal antibodies (IgG1). Human IgG is present in breast milk; concentrations are dependent upon IgG subclass and postpartum age (Anderson 2021).
Tixagevimab and cilgavimab (administered in combination) are currently available under FDA emergency use authorization (EUA) for preexposure prophylaxis of COVID-19. Breastfeeding patients were excluded from the phase 3 trials (NCT04625725 and NCT04625972). According to the EUA, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. According to the EUA, dose adjustments are not recommended for lactating patients (FDA 2022). Lactating patients may be treated with monoclonal antibodies when otherwise clinically indicated; breastfeeding does not need to be temporarily discontinued (ACOG 2022).
Interim guidance is available from the CDC for the care of lactating patients who are diagnosed with COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/care-for-breastfeeding-women.html). Information related to COVID-19 and breastfeeding is also available from the World Health Organization (https://www.who.int/news/item/28-04-2020-new-faqs-address-healthcare-workers-questions-on-breastfeeding-and-covid-19).
Monitor for ≥1 hour after injections for hypersensitivity reactions (FDA 2022).
Tixagevimab and cilgavimab are recombinant human IgG1κ monoclonal antibodies that bind to nonoverlapping epitopes of the spike protein receptor–binding domain of SARS-CoV-2, blocking attachment to the human ACE2 receptor. Tixagevimab and cilgavimab have amino acid substitutions to extend half-life, reduce antibody effector function, and minimize the potential risk of antibody-dependent disease enhancement (FDA 2022).
Distribution: Vd: Tixagevimab: 7.7 ± 1.97 L; Cilgavimab: 8.7 ± 2.73 L (FDA 2022).
Bioavailability: Tixagevimab: 68.5%; Cilgavimab: 65.8% (FDA 2022).
Half-life elimination: Tixagevimab: 87.9 ± 13.9 days; Cilgavimab: 82.9 ± 12.3 days (FDA 2022).
Time to peak: Tixagevimab: 14.9 days (range: 1.1 to 86 days); Cilgavimab: 15 days (range: 1.1 to 85 days) (FDA 2022).
Pediatric: Clinical trials have not been performed; serum exposures in patients ≥12 years of age and weighing ≥40 kg are expected to be similar to those observed in adults (FDA 2022).
Solution (Evusheld Intramuscular)
150 & 150 mg/1.5 mL (per mL): $0.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
