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Tixagevimab With Cilgavimab - Indication, Dosage, and Pharmacological Aspects

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Tixagevimab and Cilgavimab, under FDA emergency use, reduce COVID-19 risk in immune-compromised or unvaccinated individuals.

Medically reviewed by

Dr. Bintu Rathi

Published At June 11, 2024
Reviewed AtJune 11, 2024

Overview:

The COVID-19 challenges for blood cancer patients, particularly multiple myeloma (a type of blood cancer which begins in the bone marrow in the plasma cells, which are generally responsible for producing antibodies to fight infections in the body), include increased vulnerability and reduced vaccine efficacy. Standard preventive measures, variant-specific boosters, and antivirals are advised, but treatments like convalescent plasma offer limited benefits. Tixagevimab with Cilgavimab was issued by the FDA (Food and Drug Administration) on December 8, 2021. Tixagevimab with Cilgavimab, an authorized preventive option, faced concerns with Omicron dominance, leading to FDA withdrawal. Despite this, widespread use occurred during the authorized period. A study examined Tixagevimab with Cilgavimab's preventive effects in high-risk multiple myeloma individuals.

Available Doses and Dosage Forms:

  • Tixagevimab with Cilgavimab’s first dose consists of two separate injections into the muscles, 300 mg (milligram) each of Tixagevimab and Cilgavimab.

  • For those who received a 150 mg dosage of each of Tixagevimab and Cilgavimab in the beginning; an additional 150 mg of each again if the duration is less than three months.

  • Tixagevimab with Cilgavimab, 300 mg of each is the greater dose if it has been more than three months.

  • Tixagevimab with Cilgavimab, taken every six months, beginning on the date of the most recent dose, provides the larger dose (300 mg of each).

For Patients:

What Is COVID-19?

A virus known as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the source of COVID-19, also known as coronavirus disease 2019. It easily spreads from person to person and has claimed many lives globally, including over a million in the US alone. With symptoms resembling those of pneumonia, the flu, or a cold, COVID-19 primarily affects the respiratory system.

What Is the Dosage of Tixagevimab With Cilgavimab?

Tixagevimab with Cilgavimab is available as an injection:

  • Tixagevimab is supplied in a little vial containing 1.5 mL (milliliter) of 150 mg of medication (100 mg per milliliter).

  • A little vial containing 150 mg of Cilgavimab in 1.5 mL of liquid (100 mg per milliliter) is also available.

How Effective Is Tixagevimab With Cilgavimab?

Tixagevimab and Cilgavimab, are special antibodies that are meant to stop the virus from attaching to and entering our cells. In a big study called PROVENT, these antibodies were given to people at high risk, and it was found that they reduced the chances of getting symptomatic COVID-19 by 83 percent over six months.

What Are the Things to Inform the Doctor Before Taking Tixagevimab With Cilgavimab?

  • Inform the healthcare professional if an individual has any allergies.

  • Inform the doctor if a person has some serious health issues.

  • The healthcare professional should be notified about any bleeding problems.

  • Individuals should inform the healthcare professional if they have received a COVID-19 vaccine earlier.

  • Inform the doctor if the person is having heart disease.

  • Notify the doctor if the person has previously experienced an unusual or allergic reaction to Cilgavimab, Tixagevimab, drugs, foods, colors, or preservatives.

  • If the person is nursing a baby or trying to get pregnant or already pregnant.

How Is Tixagevimab With Cilgavimab Administered?

  • Intramuscular Preparation: The medication is given in separate single-dose vials containing Tixagevimab and Cilgavimab. It needs to be ready by a licensed medical professional. Avoid shaking vials. Visually check the vials for discoloration and particle debris; they should be clear to opalescent, and colorless to slightly yellow. If the solution appears hazy or discolored, or if there are noticeable particles, discard it. Transfer 1.5 milliliters (150 mg) of each of the Cilgavimab and Tixagevimab solutions into two different syringes. Dispose of any leftover solution. Syringes should be used right away (since they do not include any preservatives) and can be kept at room temperature or in the refrigerator for up to four hours (from the time of the vial puncture to the injection).

  • Intramuscular Administration: An authorized medical professional must administer the injection. Administer Cilgavimab and Tixagevimab as two separate doses. Inject the two syringes at different locations, ideally in each gluteal muscle consecutively. After an injection, keep a clinical eye on the subjects and stay there for at least an hour.

What Are the Side Effects of Tixagevimab With Cilgavimab?

  • Headache (six percent) and fatigue (four percent), were the most common side effects of Tixagevimab and Cilgavimab in PROVENT protocol.

  • Some might experience allergic reactions like skin rash, itching, hives, and swelling of the face, lips, tongue or throat.

  • Sometimes pain, irritation, or redness might occur at the site of injection.

  • Major adverse events and overall adverse impact rates were almost the same in the antibody-treated and placebo-treated groups.

  • A closer look at the PROVENT trial revealed that a higher percentage of individuals receiving the antibodies experienced severe cardiac problems (heart attacks, heart failure, and irregular heartbeats) than those receiving the fictitious treatment (0.6 percent vs. 0.2 percent).

  • single recipient of the antibodies unfortunately died after a heart attack. Crucially, there was no discernible temporal correlation between the antibody administration and the cardiac abnormalities, thus it is unclear if receiving the antibodies precipitated these cardiac problems.

Dietary Considerations:

Unless the physician recommends having a diet restriction the person is asked to continue with the normal diet.

Overdose:

When using Tixagevimab and Cilgavimab to treat overdose, general supporting measures such as the surveillance of the patient's clinical condition are taken into consideration. When using Tixagevimab and Cilgavimab, there is no specific treatment for overdose.

Storage:

Sealed Vials: To protect the medication from light, store the vials in their original package in the refrigerator (two to eight degrees C (Celsius) or 36 to 46 degrees F (Fahrenheit)). Any remaining medication should be thrown away. Avoid shaking or freezing the vials.

Ready to Use Syringe: If the syringes have already been prepared, keep them at room temperature (up to 25 degrees C or 77 degrees F) or in the refrigerator (two to eight degrees C or 36 to 46 degrees F) for a maximum of four hours.

For Doctors:

Indication:

Adults without a history of exposure to an infected person or an active SARS-CoV-2 infection are encouraged to receive pre-exposure prophylaxis for COVID-19 if they are not expected to mount a strong enough immune response to the vaccine or if immunization is not recommended.

Dose:

  • Tixagevimab Injection and Solution: 150 mg/1.5 mL vial for a single dosage.

  • Cilgavimab: Vial of single-dose 150 mg/1.5 mL.

  • First Dose: 300 mg of Tixagevimab and 300 mg of Cilgavimab given separately.

Dosing Considerations:

  • On February 24, 2022, the EUA (Emergency Use Authorization) was updated, recommending a higher starting dose for efficacy against Omicron subvariants.

  • Extra dosages are recommended for people who received smaller doses earlier, Tixagevimab and Cilgavimab, 150 mg each within ≤ 3 months; 300 mg each beyond that time.

  • Redoses are permitted every six months for those who meet EUA requirements.

  • Every six months, inject 300 mg of Cilgavimab and 300 mg of Tixagevimab.

  • Preexposure prophylaxis may be beneficial for up to six months after injection, according to the PROVENT trial.

  • Not approved for postexposure prophylaxis or COVID-19 treatment.

  • Not a replacement for the COVID-19 vaccine.

  • Suggested for people with particular medical disorders or therapies that impair their immune system moderately to severely.

What Are the Pharmacological Aspects of Tixagevimab With Cilgavimab?

  • Pharmacodynamics: Tixagevimab and Cilgavimab are human monoclonal antibodies engineered with modifications in their Fc regions to enhance their half-life and reduce the potential risk of antibody-dependent enhancement of disease. They target non-overlapping regions on the spike protein receptor binding domain (RBD) of SARS-CoV-2, preventing the virus from attaching to human ACE2 receptors necessary for infection. These antibodies effectively neutralize SARS-CoV-2 in vitro and protect animal models of infection. In cell culture studies, Tixagevimab and Cilgavimab, both individually and in combination, did not induce antibody-dependent cell-mediated cytotoxicity, cellular phagocytosis, natural killer cell activation, or complement deposition activity. These antibodies showed some decrease in efficacy when tested against SARS-CoV-2 variations, such as the Omicron form, but they still maintained their neutralizing activity. In animal models, prophylactic administration of Tixagevimab and Cilgavimab prevented upper and lower respiratory tract infections and reduced lung injury associated with COVID-19. Furthermore, these antibodies did not mediate antibody-dependent viral entry or enhance infection in primate models, even at sub-neutralizing doses. Overall, Tixagevimab and Cilgavimab demonstrate potent neutralizing activity against SARS-CoV-2 and exhibit favorable safety profiles in preclinical studies.

  • Mechanism: Tixagevimab with Cilgavimab, a combination therapy, comprises monoclonal antibodies derived from B-cells of individuals who recovered from SARS-CoV-2 infection. Targeting the spike protein of SARS-CoV-2, the therapy hinders the virus's ability to bind and fuse with host cell membranes. Human monoclonal antibodies were designed to selectively engage with receptor-binding regions on the spike protein. This resulted in the virus being neutralized and a reduction in the binding of the Fc receptor and C1q protein complex. Minimizing Fc receptor binding aims to prevent antibody-dependent enhancement of illness, a condition where virus-specific antibodies inadvertently promote infection rather than preventing it. The monoclonal antibodies' half-life is extended using YTE half-life extension technology, enhancing their duration in the body for prolonged protection. Tixagevimab with Cilgavimab has demonstrated efficacy against various SARS-CoV-2 variants, including Delta, Mu, and Omicron, as confirmed by an independent FDA study.

  • Pharmacokinetics: The pharmacokinetic (PK) parameters and characteristics of Tixagevimab with Cilgavimab after a single dose of Tixagevimab with Cilgavimab (300 mg of each) given by intramuscular injection. After administration, the highest drug concentration (Cmax) in the bloodstream is reached at around 14.9 to 15 days for both Tixagevimab with Cilgavimab. The drugs remain at detectable levels in the bloodstream for up to 84 days (C84). The total exposure to the drugs in the body (AUC0-84) is around 1408 and 1307 day•µg/mL (microgram per milliliter) for Tixagevimab with Cilgavimab, respectively. Both drugs are absorbed well by the body with a bioavailability of approximately 68.5 percent for Tixagevimab and 65.8 percent for Cilgavimab. They are distributed throughout the body with an apparent volume of distribution of 7.7 and 8.7 liters for Tixagevimab and Cilgavimab, respectively. The drugs have a long elimination half-life of about 87.9 and 82.9 days for Tixagevimab with Cilgavimab, respectively. They are metabolized in the body through catabolic pathways similar to naturally occurring IgG (immunoglobulin G) antibodies and are not likely to be excreted through the kidneys. In a follow-up study where a second dose was given 10 to 14 months later, the serum concentrations of the drugs remained similar to those observed after the initial dose. The pharmacokinetic properties suggest that a single dose of Tixagevimab and Cilgavimab may protect against certain COVID-19 variants for up to six months.

Toxicity:

  • Carcinogenicity, genotoxicity, and reproductive toxicity studies have not been conducted for Tixagevimab and Cilgavimab.

  • In a study using cynomolgus monkeys, no adverse effects were observed when Tixagevimab and Cilgavimab were given via intramuscular injection.

  • Studies on tissue cross-reactivity utilizing adult and fetal human tissues revealed that Tixagevimab and Cilgavimab did not bind in an unsettling way.

  • Tixagevimab and Cilgavimab were evaluated in rhesus macaque and cynomolgus macaque models of SARS-CoV-2 infection.

  • When administered prophylactically, these antibodies prevented SARS-CoV-2 infection in the upper and lower respiratory tracts in a dose-dependent manner.

  • They also considerably lessened lung injury linked to SARS-CoV-2 infection and viral RNA (ribonucleic acid) levels in nasopharyngeal swabs and lung samples.

Clinical Studies:

  • Based on the outcomes of the Phase III randomized, double-blind, placebo-controlled PROVENT trial, the FDA approved Tixagevimab in combination with Cilgavimab with an EUA.

  • 197 adult participants were enrolled to assess Tixagevimab with Cilgavimab's safety and efficacy against COVID-19 compared to a placebo.

  • Intramuscular injections of either saline placebo or 300 mg of Tixagevimab plus Cilgavimab were administered to participants in a 2:1 randomization.

  • The primary endpoint is the first occurrence of symptomatic COVID-19 confirmed by SARS-CoV-2 RT-PCR positive results within 183 days post-dose.

  • Results showed a 77 percent lower risk of developing symptomatic COVID-19 with Tixagevimab with Cilgavimab than placebo.

  • A six-month evaluation showed that the group receiving Tixagevimab plus Cilgavimab had an 83 percent decreased probability of symptomatic COVID-19.

  • Possible adverse effects include hypersensitivity reactions, injection site hemorrhage, headache, fatigue, and cough.

  • TACKLE Phase III trial demonstrated a significant 50 percent reduction in the relative risk of progressing to severe COVID-19 or death with a single 600mg dose of Tixagevimab with Cilgavimab for outpatient treatment of mild-to-moderate COVID-19.

What Are the Contraindications of Tixagevimab With Cilgavimab?

A person should avoid using Tixagevimab with Cilgavimab again if they have previously experienced a severe allergic reaction, such as anaphylaxis.

Warnings and Precautions:

  • Hypersensitivity and Anaphylaxis: Tixagevimab with Cilgavimab may cause serious hypersensitivity reactions, including anaphylaxis. If severe hypersensitivity symptoms appear, cease treatment right once and offer suitable medicine or supportive therapy. Monitor individuals clinically post-injections and observe for at least one hour.

  • Cross-Hypersensitivity Risk With COVID-19 Vaccines: Tixagevimab with Cilgavimab has polysorbate 80, found in some COVID-19 vaccines, structurally similar to polyethylene glycol (PEG) in other vaccines. Individuals with a severe hypersensitivity history to a COVID-19 vaccine should consult an allergist-immunologist before Tixagevimab with Cilgavimab administration.

  • Risk for COVID-19 Due to Viral Variants: Certain SARS-CoV-2 variants may not be neutralized by Tixagevimab with Cilgavimab. Inform individuals of increased COVID-19 risk from non-neutralized variants. If COVID-19 signs occur, advise testing and seek appropriate medical attention.

  • Bleeding Disorders Caution: Administer Tixagevimab with Cilgavimab cautiously to individuals with thrombocytopenia or coagulation disorders due to the risk of bleeding.

  • Cardiovascular Events: Subjects receiving Tixagevimab with Cilgavimab reported higher myocardial infarction and cardiac failure events compared to placebo. Subjects with events had cardiac risk factors or prior cardiovascular disease, and no clear causal relationship between Tixagevimab with Cilgavimab was established. Consider risks and benefits before initiating Tixagevimab with Cilgavimab in high-risk individuals for cardiovascular events. Advise immediate medical attention for signs suggestive of cardiovascular events.

What Are the Drug Interactions of Tixagevimab With Cilgavimab?

  • Anticoagulants (such as Warfarin and Acenocoumarol) and statins (like Atorvastatin and Rosuvastatin) may interact with Tixagevimab and Cilgavimab.

  • Ethanol and Tixagevimab with Cilgavimab may interact.

  • Patients with known hypersensitivity disorders, HIV, asthma, cancer, liver illness, renal issues, heart disease, epilepsy, or venous diseases should use Tixagevimab and Cilgavimab with caution.

Specific Considerations:

  • Pregnancy: Inadequate information is available to evaluate the risk of serious birth abnormalities, miscarriages, or unfavorable outcomes when using Cilgavimab and Tixagevimab. There have been no investigations on reproductive toxicity, and a tissue cross-reactivity analysis revealed no alarming binding to human fetal tissues. Although the likelihood of human IgG1 antibodies reaching the fetus is uncertain, they can pass the placental barrier.

  • Lactation: Absence of information regarding the presence of animal or human milk, its impact on milk production, and its effects on breastfed infants. IgG from mothers is found in human milk. The developmental benefits of breastfeeding should be weighed against the mother's need for medical attention and any potential repercussions on the child.

  • Pediatrics: It has not been determined whether Tixagevimab is safe or effective for use with Cilgavimabin in pediatric patients, and it is not recommended for use in those under the age of 12 or 40 kg in weight. It is anticipated that the dosage schedule for those aged 12 and above will produce serum exposures that are similar to those seen in adults.

  • Elderly: Age did not significantly alter the pharmacokinetics (PK) of Cilgavimab and Tixagevimab in participants 65 years of age or older, according to a pooled investigation.

  • Renal: Tixagevimab and Cilgavimab are not removed intact in the urine, therefore renal impairment is not anticipated to affect their exposure.

  • Liver: It is uncertain how hepatic impairment affects the PK of Cilgavimab and Tixagevimab.

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Dr. Bintu Rathi

General Practitioner

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