Omalizumab - Indication, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Drug Overview:

Omalizumab injection is administered to mitigate the occurrence of asthma attacks in individuals who are afflicted with allergic asthma. This type of asthma stems from exposure to allergenic substances such as pollen, dust mites, and animal dander. This treatment is particularly relevant for those whose symptoms remain uncontrolled despite using inhaled steroids. Moreover, Omalizumab is employed for managing nasal polyps, characterized by inflammation in the nasal lining, in adults when conventional inhaled steroid treatments prove ineffective. FDA (Food and Drug Administration) approved Omalizumab for moderate-to-severe asthma on June 20, 2003.

For Patients:

What Are the Clinical Indications for Omalizumab?

Omalizumab injection is indicated for:

• For individuals aged six and above who have moderate to severe persistent asthma and show a positive skin test or in vitro reactivity to a year-round airborne allergen, along with symptoms that are not effectively managed by inhaled corticosteroids, Omalizumab is recommended.

• Omalizumab is suitable for adults and adolescents aged 12 and above dealing with chronic idiopathic urticaria (it is a form of hives with no identifiable cause). This applies to those who continue to experience symptoms despite undergoing treatment with H1 antihistamines.

What Is Allergic Asthma?

Allergic asthma is a type of asthma triggered by allergens, which are substances that the immune system reacts to. When someone with allergic asthma is exposed to these allergens (such as pollen, pet dander, dust mites, or mold), their immune system overreacts, causing inflammation and narrowing of the airways in the lungs. This leads to symptoms like wheezing, coughing, shortness of breath, and chest tightness. Treatment often involves medications to control inflammation and bronchodilators to open up the airways, as well as avoiding known allergens whenever possible.

How Is Omalizumab Used?

The Omalizumab injection is available both as a prefilled syringe and as a powder that requires mixing with water for subcutaneous administration (under the skin). In the context of treating allergic asthma or nasal polyps, the usual injection frequency is once every two or four weeks. The number of injections a patient receives depends on their weight and medical condition. When addressing chronic hives (raised, itchy welts on the skin), the injection is typically given once every four weeks. The treatment duration is determined by the doctor based on the patient's response to the medication and overall condition.

For those who will be self-administering the injection or having someone else administer it at home, the doctor will provide instructions on how to properly inject the medication. Reading the provided written instructions for use is also recommended.

Before injecting, it is important to check the expiration date on the prefilled syringe packaging. When holding the syringe with the covered needle downward, the liquid should be clear or slightly pale in color, without cloudiness, discoloration, lumps, or particles. Any issues with the package or syringe should be addressed with the pharmacist before injection.

Allowing the syringe to reach room temperature after taking it out from the refrigerator by keeping it away from direct sunlight for a duration of 15 to 30 minutes is advised. Microwaving, using hot water, or other methods should not be used to warm the medication. The injection should be administered within four hours after removing it from the refrigerator. Proper disposal of used syringes in a puncture-resistant container is crucial.

The cap on the prefilled syringe should only be removed right before injection and should not be replaced afterward. Dropping the syringe on the floor renders it unusable. Injection sites can be the front of the thighs, various areas on the stomach (excluding the navel and its 2-inch vicinity), and, if administered by another person, the outer part of the upper arms. The injection should be avoided on tender, bruised, red, hard, or damaged skin, as well as areas with scars, moles, or bruises. It is recommended to shift or change the injection spot, at least 1 inch away from previous sites, to prevent discomfort. If the full dose is not administered, medical advice should be sought.

Adjusting the dosage of other asthma, nasal polyps, or hives medications or discontinuing them should only be done under a doctor's guidance. The doctor may suggest gradual dose reductions of other medications.

It is important to note that Omalizumab injection is not meant for addressing sudden asthma attacks. A short-acting inhaler prescribed by the doctor is appropriate for such situations. Patients experiencing worsened asthma symptoms or more frequent attacks should promptly consult their doctor.

What Are the Special Precautions to Be Followed While Using Omalizumab?

• Prior to receiving the Omalizumab injection, individuals should inform their healthcare provider and pharmacist if they have allergies to Omalizumab, any other medications, or any components present in the Omalizumab injection. It is advisable to consult a pharmacist for a comprehensive list of ingredients. If opting for the prefilled syringe, patients should inform their doctor if they or the individual administering the injection are allergic to rubber or latex.

• The doctor and pharmacist should be informed about all prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products being taken or intended to be taken. Special mention should be made of allergy shots (a series of injections designed to prevent the body's development of allergic reactions to specific substances) and medications that suppress the immune system. Dosing adjustments or careful side-effect monitoring might be necessary.

• If the patient has a history of cancer or is currently dealing with it, the doctor should be informed. For individuals who are pregnant, planning to conceive, or breastfeeding, it is important to discuss this with the doctor. If pregnancy occurs during the use of Omalizumab injection, prompt communication with the doctor is essential.

• The doctor should be consulted regarding the risk of developing infections caused by worms such as hookworm, roundworm, whipworm, or threadworm. If a history of such infections exists, or if there is a heightened susceptibility to them, the use of Omalizumab injection could potentially increase the likelihood of infection. The doctor will closely monitor the patient during and after treatment in such cases.

What Are the Side Effects of Omalizumab?

The administration of Omalizumab injection may lead to the occurrence of side effects. Individuals are advised to promptly inform their healthcare provider if any of these symptoms become severe or persist:

• Pain, redness, swelling, warmth, burning, bruising, hardness, or itching at the injection site of Omalizumab.

• Pain, particularly in joints, arms, or legs.

• Tiredness.

• Ear pain.

• Headache.

• Nausea.

• Swelling within the nose, throat, or sinuses.

• Stomach pain.

• Nosebleeds.

Certain side effects warrant immediate attention. If any of the following symptoms arise, it is important to contact a doctor promptly or seek emergency medical assistance:

• Fever, muscle aches, rash, and swollen glands occur within one to five days following the administration of an Omalizumab injection.

• Shortness of breath.

• Coughing up blood.

• Skin sores.

• Intense pain, numbness, and tingling experienced in the hands and feet.

While some individuals who have received Omalizumab injections have reported chest pain, heart attacks, blood clots in the lungs or legs, temporary instances of one-sided body weakness, slurred speech, and alterations in vision, there is insufficient data to definitively attribute these symptoms to the Omalizumab injection.

It should be noted that the usage of Omalizumab injection might elevate the risk of developing specific types of cancer. However, there is not enough information to conclusively determine whether Omalizumab injection is causally related to these cancers.

What Are the Important Steps for Storage and Disposal of Omalizumab?

The medication should be stored in its original packaging, protected from light, and kept tightly closed, ensuring it is inaccessible to children. Omalizumab injection should be stored in a refrigerator; however, it should not be frozen. Any medication that has exceeded its expiration date or is no longer required should be properly discarded. Consultation with a pharmacist is recommended to understand the appropriate method of disposing of the medication.

For Doctors:

Indication:

In individuals aged six years and older with moderate to severe persistent asthma, Omalizumab is prescribed for those who exhibit a positive skin test or in vitro reactivity to an ongoing airborne allergen and whose symptoms are not effectively managed through inhaled corticosteroids. Omalizumab effectiveness has been demonstrated in reducing the frequency of asthma exacerbations in this patient group.

It is important to note that Omalizumab is not intended for addressing acute bronchospasm or status asthmaticus, and it is not suitable for treating other allergic conditions. For adults and adolescents aged 12 years and older experiencing chronic idiopathic urticaria, Omalizumab is indicated when symptoms persist despite treatment with H1 antihistamines. However, it should be emphasized that Omalizumab is not designed for the treatment of alternative forms of urticaria.

Dose:

The recommended daily dose is subcutaneous injection of doses ranging from 75 to 375 mg (milligrams) every two or four weeks.

What Are the Warnings and Precautions of Using Omalizumab?

The following precautions should be taken:

• Anaphylaxis: Instances of anaphylaxis have been documented following the administration of Omalizumab, both during premarketing clinical trials and through post marketing spontaneous reports. These occurrences have presented with symptoms such as bronchospasm, hypotension, urticaria, syncope, and angioedema of the throat or tongue, some of which have posed life-threatening risks. Within the premarketing clinical trials involving asthma patients, anaphylaxis was observed in three out of 3507 patients (0.1 percent). Notably, two of these cases occurred after the initial dose of Omalizumab, while one was linked to the fourth dose. The onset time for anaphylaxis varied, with two cases experiencing it 90 minutes after administration and one case after two hours.

A case-control study established an elevated risk of anaphylaxis associated with Omalizumab in patients with a history of anaphylaxis to foods, medications, or other triggers.

Anaphylaxis instances have been noted as early as after the first Omalizumab dose and such cases have also been reported beyond one year of initiating regular treatment.

To ensure patient safety, the administration of Omalizumab should exclusively take place within a healthcare setting under the supervision of healthcare providers who are prepared to manage potentially life-threatening anaphylactic reactions. Close monitoring of patients for an appropriate duration after Omalizumab administration is crucial, considering the observed onset times of anaphylaxis in clinical trials and post marketing reports. Patients should be educated about anaphylaxis signs and symptoms and instructed to seek immediate medical assistance if such symptoms manifest.

• Malignancy: The occurrence of malignant neoplasms was identified in 20 out of 4127 Omalizumab treated patients (0.5 percent) as opposed to 5 out of 2236 control patients (0.2 percent) during clinical studies involving adults and adolescents aged 12 years and above, with asthma and other allergic disorders. Among the Omalizumab-treated patients, the observed malignant neoplasms encompassed various types, including breast, non-melanoma skin, prostate, melanoma, and parotid, with some types recurring multiple times and five other types occurring once each. Most of the patients were under observation for less than one year. The potential impact of extended exposure to Omalizumab or its usage in patients at a higher risk for malignancy (such as the elderly or current smokers) remains unknown.

• Acute Asthma Symptoms: There is no evidence that Omalizumab helps in acute asthmatic flare-ups. Omalizumab should not be used to treat status asthmaticus or acute bronchospasm.

• Corticosteroid Reduction: When starting Omalizumab treatment for asthma, one should not abruptly stop using systemic or inhaled corticosteroids. Under the close supervision of a doctor, the intake of corticosteroids is gradually reduced. The combination of Omalizumab and corticosteroids has not been studied in CIU (chronic idiopathic urticaria) patients.

• Eosinophilic Conditions: Rarely, asthma patients on Omalizumab may develop significant systemic eosinophilia, which may occasionally accompany clinical signs of vasculitis associated with Churg-Strauss syndrome, a disease that is frequently managed with systemic corticosteroid treatment. These occurrences have typically, but not always, been linked to the cessation of oral corticosteroid medication. Eosinophilia, vasculitic rash, increasing pulmonary symptoms, cardiac problems, and neuropathy are among the indications that doctors should be on the lookout for in their patients. It has not been demonstrated that Omalizumab causes these underlying diseases.

• Rash, Fever, and Arthralgia: Following the initial or subsequent injections of Omalizumab, some patients have reported a constellation of signs and symptoms, including arthritis or arthralgia, rash, fever, and lymphadenopathy, which usually appear one to five days later. Some individuals' indications and symptoms returned after subsequent dosages. These signs and symptoms are comparable to those experienced by individuals with serum sickness, despite the absence of circulating immune complexes or a skin biopsy that is consistent with a Type III response in these situations. If a patient exhibits this combination of symptoms, doctors should discontinue the patient from using Omalizumab.

• Parasitic Infection: While using Omalizumab, keep an eye on individuals who are very susceptible to helminth infection. The period of monitoring for helminth infections after ceasing Omalizumab medication cannot be determined due to a lack of evidence.

What Are the Pharmacological Aspects of Omalizumab?

Mechanism of Action:

Asthma: Omalizumab acts by impeding the interaction between immunoglobulin E (IgE) and the high-affinity IgE receptor found on mast cells and basophils. By diminishing the presence of IgE bound to the cell's surface, the release of allergic response mediators is restricted. Omalizumab treatment also leads to a reduction in the quantity of cell receptors on basophils among atopic patients.

Pharmacokinetics:

Following subcutaneous (SC) administration, Omalizumab exhibited an average absolute bioavailability of 62 percent. In adult and adolescent patients with asthma who received a single SC dose, Omalizumab was absorbed gradually, reaching peak serum concentrations around seven to eight days on average. Similar peak serum concentrations were observed for patients with chronic idiopathic urticaria (CIU) after a single SC dose. The pharmacokinetics of Omalizumab were linear at doses greater than 0.5 mg/kg (milligrams per kilogram).

In asthma patients, following multiple doses of Omalizumab, the areas under the serum concentration-time curve from day 0 to day 14 at steady state were up to six times greater than those observed after the initial dose. In CIU patients, Omalizumab's pharmacokinetics remained linear across the dose range of 75 mg to 600 mg when administered as a single subcutaneous dose. With repeat dosing from 75 to 300 mg every four weeks, the trough serum concentrations of Omalizumab increased proportionally with the dose levels.

In vitro studies showed that Omalizumab formed complexes with IgE of limited size, and no precipitating or excessively large complexes were observed either in vitro or in vivo. Distribution studies in Cynomolgus monkeys indicated no specific uptake of 125I-labeled Omalizumab by any organ or tissue. The apparent volume of distribution of Omalizumab after SC administration in asthma patients was 78 ± 32 mL/kg (milliliters per kilogram), and the distribution profile in CIU patients resembled that of asthma patients based on population pharmacokinetics.

Omalizumab clearance involved IgG clearance mechanisms, as well as clearance facilitated by specific binding and complex formation with its target ligand, IgE. Liver elimination of IgG involved degradation within the liver's reticuloendothelial system (RES) and endothelial cells, with intact IgG also excreted in bile. Studies in mice and monkeys demonstrated that Omalizumab: IgE complexes were eliminated through interactions with Fcγ receptors within the RES at rates generally faster than IgG clearance.

In asthma patients, the serum elimination half-life of Omalizumab averaged 26 days, with an apparent clearance averaging 2.4 ± 1.1 mL/kg/day. Doubling body weight roughly doubled the apparent clearance. In CIU patients at steady state, Omalizumab's serum elimination half-life averaged 24 days, and the apparent clearance averaged 240 mL/day (equivalent to 3.0 mL/kg/day for an 80 kg patient).

What Are the Clinical Studies of Omalizumab?

Adult and Adolescent Patients 12 Years of Age and Older:

The safety and effectiveness of Omalizumab were assessed through three randomized, double-blind, placebo-controlled, multicenter trials. These trials included individuals aged 12 to 76 years with moderate to severe persistent asthma, according to NHLBI (National Heart, Lung, and Blood Institute) criteria, lasting for at least one year. Participants also had a positive skin test response to a perennial aeroallergen. In all trials, Omalizumab dosage was determined based on the individual's body weight and baseline serum total IgE concentration. Patients needed to have a baseline IgE level between 30 and 700 IU/mL (international units per milliliter) and a body weight not exceeding 330 pounds (150 kg).

The administration was guided by a dosing table, with the aim of delivering at least 0.016 mg/kg/IU (IgE/mL) of Omalizumab or an equivalent volume of placebo during each 4-week period. The highest permissible Omalizumab dose within a 4-week span was 750 mg.

Across the three trials, an exacerbation was defined as a deterioration of asthma necessitating systemic corticosteroid treatment or a doubling of the baseline inhaled corticosteroid (ICS) dose. Most exacerbations were managed in an outpatient setting, with the majority being addressed using systemic steroids. Hospitalization rates did not exhibit significant disparities between patients treated with Omalizumab and those receiving placebo. Notably, the overall hospitalization rate remained low. Among individuals encountering exacerbations, the severity distribution of these events was comparable between the treatment groups.

Use in Specific Population:

• Pregnancy: The available data concerning the use of Omalizumab in pregnant women are inadequate to provide conclusive information regarding associated drug risks. Monoclonal antibodies, such as Omalizumab, exhibit a linear transport pattern across the placenta as pregnancy advances. Consequently, the potential impact on a developing fetus is likely to be more pronounced during the second and third trimesters.

  • Reproductive studies conducted in Cynomolgus monkeys did not uncover any evidence of harm to the fetus when subjected to subcutaneous doses of Omalizumab that were approximately ten times the maximum recommended human dose (MRHD), as indicated in animal data.

  • In the general US population, the estimated background risk of major birth defects and miscarriages in pregnancies that are clinically recognized is around two to four percent and 15 to 20 percent, respectively.

• Lactation: There is no information on Omalizumab's presence in human milk, its effects on nursing infants, or its impact on milk production. IgG1 kappa is a human monoclonal antibody found in Omalizumab, and human milk contains immunoglobulin G (IgG). The developmental and health advantages of nursing should be taken into account, as well as the mother's clinical requirement for Omalizumab and any potential negative effects of Omalizumab or the underlying maternal disease on the breastfed infant before starting the medication.

• Pediatric Population: Children with asthma under the age of six have not yet been studied for the safety and effectiveness of Omalizumab. As per clinical trial results, patients on Omalizumab saw a statistically significant decrease in the risk of exacerbations for children aged six to 12 with moderate to severe persistent asthma who had a positive skin test or in vitro reactivity to a perennial aeroallergen.

• Geriatric Population: There is no sufficient data to support that patients 65 and older respond differently from younger patients while receiving treatment from Omalizumab.