Xolair, 150 mg, lyophilisate for the preparation of solution for subcutaneous administration, complete with solvent, 1 pc.

Pharmacological properties of the drug Xolair

Omalizumab is a humanized monoclonal antibody derived from a recombinant DNA molecule that selectively binds to human immunoglobulin E (IgE). Under the influence of an allergen, a cascade of allergic reactions is triggered, which begins with the binding of IgE to high-affinity Fc RI receptors located on the surface of mast cells and basophils. This is accompanied by degranulation of the above cells and the release of histamine, leukotrienes, cytokines and other mediators. These mediators play a direct role in the pathophysiology of atopic bronchial asthma, including the development of airway edema, contraction of bronchial smooth muscles and disruption of cellular activity due to the inflammatory process. They are also involved in the formation of symptoms of allergic diseases such as bronchospasm, mucus formation, wheezing, shortness of breath, chest tightness, nasal congestion, sneezing, itching, nasal discharge and itchy nose, itchy eyes and watery eyes. . Omalizumab binds to IgE and prevents its interaction with the high-affinity Fc RI receptor, thus reducing the amount of free IgE, which is a trigger for the cascade of allergic reactions. When treating patients with atopic BA with the drug, there is a noticeable decrease in the number of Fc RI receptors on the surface of basophils. In addition, in vitro , a marked reduction (approximately 90%) in histamine release after allergen stimulation was observed in basophils isolated from patients treated with Xolair compared with data obtained before treatment. In clinical studies, serum free IgE levels decreased dose-dependently within 1 hour after the first dose of Xolair and were maintained at the same level between subsequent doses. When used at recommended doses, the mean reduction in free IgE in serum was 96%. Total serum IgE levels (bound and unbound) increased after the first dose due to the formation of the omalizumab-IgE complex, which is characterized by a slower clearance rate compared to free IgE. At 16 weeks after the first dose, the mean serum total IgE level was 5 times higher than before treatment. After discontinuation of Xolair, the increase in total IgE and decrease in free IgE caused by its action were reversible. After complete removal of the drug from the body, there was no increase in the concentration of IgE in the blood serum. The content of total IgE remained elevated for 1 year after discontinuation of Xolair. Pharmacokinetics. After subcutaneous administration, the absolute bioavailability of omalizumab averages 62%. After a single subcutaneous administration to adults and adolescents with asthma, absorption of omalizumab occurs slowly, with Cmax achieved on average after 7–8 days. When used in doses of 0.5 mg/kg, the pharmacokinetics of omalizumab are linear. After repeated administration of omalizumab over a period of 0 to 14 days at steady state, the AUC was 6 times higher than after a single dose. In vitro , omalizumab forms a complex with IgE of a certain size. The formation of precipitating complexes and complexes whose molecular weight exceeded 1 million Da was not observed in vitro or in vivo After subcutaneous administration of the drug, the apparent volume of distribution was 78±32 ml/kg. Experimental studies did not reveal specific accumulation of omalizumab in any organs or tissues. Clearance of omalizumab includes both the clearance of IgG itself and clearance by specific binding and formation of complexes with the target ligand—free serum IgE. Hepatic elimination of IgG involves degradation in the liver reticuloendothelial system and liver endothelial cells. Intact IgG is also excreted in the bile. In patients with asthma, the average half-life of omalizumab from blood serum was an average of 26 days with an average clearance of 2.4 ± 1.1 ml/kg/day. In addition, with a doubling of body weight, an approximately twofold increase in apparent clearance was observed.

Experience with the use of omalizumab in chronic spontaneous urticaria

The article discusses the pathogenesis, etiology, clinical symptoms of chronic urticaria and approaches to its treatment. Examples from clinical practice demonstrate the effectiveness and good safety profile of omalizumab in the treatment of refractory chronic idiopathic urticaria.

Table. Urticaria Activity Score (UAS7)

Introduction

Treatment of chronic urticaria (CU) still remains a significant medical and social problem, since the disease manifests itself more often in people of working age and is characterized by a pronounced decrease in the quality of life [1, 2]. Patients suffer from debilitating itching and urticarial skin rashes, which cannot but affect their psychological status [1]. In severe cases, symptoms are accompanied by an edematous component. Skin rashes occur at least three times a week and disappear without a trace within 24 hours, which makes it difficult to predict remissions and recovery. Wide prevalence (0.1–1% in the population) and complex patient population require further improvement of treatment regimens and a flexible individual approach as part of the development of personalized therapy. This is reflected in Russian and international recommendations for the treatment of CU [3].

CU can be spontaneous (CS) or idiopathic (induced) (CI).

CKS is characterized by the spontaneous appearance of blisters, angioedema, or both over a period of six weeks or more due to known or unknown causes [1].

HICs include:

• symptomatic dermographism (artificial, dermographic urticaria);
• cold urticaria (cold contact);
• delayed pressure urticaria (pressure urticaria);
• thermal urticaria (thermal contact urticaria);
• solar urticaria;
• vibration angioedema;
• cholinergic urticaria;
• contact urticaria;
• aquagenic urticaria.

In accordance with the therapeutic algorithm of CC, enshrined in the consent documents, the first stage involves the use of second-generation antihistamines (AGDs) with a two-week course in a standard dosage. In some cases, it is recommended to increase the dose fourfold, which is not always effective, but burdens the patient financially. In the future, if there is no effect, a choice of third-line medications is proposed: omalizumab, a leukotriene receptor antagonist, cyclosporine A. It should be noted that omalizumab is the only drug from this group officially registered for the treatment of CSU [4]. Prescribing the drug outside of official indications has a number of limitations due to the insufficient evidence base of effectiveness and the potential risk of developing serious adverse events. When treating CIC, it is very important to avoid exposure to trigger factors. Treatment of exacerbations is considered separately, in most cases involving the prescription of a short course of systemic glucocorticosteroids (sGCS) - three to seven days.

For an objective analysis of the severity and burden of the disease, a number of validated questionnaires and tests have been developed, recommended by leading experts as simple auxiliary tools at the stage of prescribing therapy and monitoring response to it [5, 6].

Since 2014, the official instructions for the use of omalizumab (Xolair, manufactured by Novartis) in the Russian Federation included the indication: treatment of chronic idiopathic urticaria. The drug, which is a recombinant humanized monoclonal anti-IgE antibody, has been used in domestic clinical practice for persistent atopic bronchial asthma (BA) for more than ten years. However, the criteria for selecting doses and treatment regimens for omalizumab CCK do not coincide with those for asthma. Indicators of the level of total IgE and body weight are not taken into account when prescribing the drug, and are also not criteria for effectiveness. Clinical indicators remain the key guideline.

The recommended dosing regimen was developed based on the results of multiple phase III clinical studies conducted with dose ranking and safety spectrum analysis. The dose of omalizumab for CBS is 300 mg once every four weeks. The issue of continuing treatment beyond the prescribed period is decided individually before each subsequent injection. Certain features, depending on the nosology, can be traced in the description of adverse events associated with the administration of the drug, including anaphylaxis as the most dangerous. On average, the incidence of anaphylaxis in patients with asthma was 0.14% of all those receiving omalizumab. However, no cases of anaphylaxis have been reported among patients treated with omalizumab for CBS [7, 8]. The type and total number of adverse events among patients with CKS who received omalizumab did not differ from those in the placebo group, indicating a good safety profile of the drug [7, 8]. However, since omalizumab is a biological therapy, patients should be under specialist supervision for 30 minutes after administration of the drug.

The mechanisms of pathogenesis that explain the effectiveness of omalizumab in AD and CIC/CSC do not coincide. At the moment, the exact mechanism of the drug’s effectiveness in CIC/CSC has not been established. There are various hypotheses of effectiveness based on the likely mechanisms of inflammation in the skin in CIC/CSC and the points of application of the drug.

Omalizumab isolates monoclonal IgE circulating in the blood, thereby reducing the likelihood of their interaction with mast cells.

In patients with IgG autoantibodies to IgE or FcεRI, due to the binding of IgE by omalizumab, the density of receptors on the surface of mast cells and basophils decreases, which leads to depletion of the receptor field and, as a result, reduces the likelihood of their activation.

In CU, autoreactive IgG and IgE antibodies against FcεRI or their combination, autoreactive IgE antibodies against autoallergens, which most likely form the mechanism of the inflammatory reaction in CU, can be detected [9, 10].

Thus, autoreactive IgE antibodies play an important role in the development of CC. In addition, the detection of antibodies to double- and single-stranded DNA and antibodies to thyroid peroxidase in such patients confirms the autoimmune and autoreactive theory of the development of urticaria. Omalizumab, by binding to freely circulating IgE, will isolate it from endogenous autoantigens, such as antibodies to thyroid peroxidase and antibodies to DNA [11].

The listed theories pathogenetically substantiate omalizumab therapy for CIC. In addition to these effects, the binding of omalizumab to IgE on the surface of B lymphocytes and memory cells reduces the ongoing formation of IgE-producing cells and therefore inhibits IgE synthesis [12].

Use of omalizumab in real clinical settings

From the standpoint of exchanging experience and developing new algorithms within the framework of personalized medicine, not only multicenter clinical studies are of interest, but also experience of application in real clinical conditions - a detailed analysis of the treatment of each patient.

In our department, since the registration of indications for CCI/CSC, omalizumab has been prescribed to thirteen patients. The group included ten women and three men ranging in age from 21 to 60 years. The experience of HIC/HSK varied from three months to seven years. The most widely discussed issue was the appropriateness of therapy for patients with a three-month duration of the disease due to the high probability of spontaneous remission of CU within a year in 10–30% of patients [13]. All patients had severe or moderate CIC/CSC and failed the first and second stages of therapy.

Before starting omalizumab therapy, high doses of antihypertensive drugs (fourfold increase in dose) were used in combination with H2-histamine blockers (five patients) and antileukotriene drugs (four patients). All patients had previously received courses of sGCs, including depot drugs (Diprospan, Kenalog).

Candidates for omalizumab therapy were assessed using validated questionnaires such as the urticaria calendar, quality of life assessment for patients with dermatological disease, and the UAS7 urticaria severity scale (Urticaria Activity Score 7). UAS7 involves a summary assessment of the main symptoms of the disease (number of rashes and intensity of itching) by the patient himself every 24 hours for seven consecutive days (see table) [1].

During omalizumab therapy, improvement in symptoms was observed in all patients in this group. Four (one man and three women) achieved complete remission of the disease after a four-month course of therapy. This confirms the assumption that the minimum cycle required to deplete the IgE receptor field during anti-IgE therapy is four months. The remaining patients noted a decrease in the intensity of symptoms, an improvement in the quality of life, and an increase in the effect of using antihypertensive drugs.

Clinical case 1

Patient K., 21 years old. He contacted the allergology department of City Clinical Hospital No. 52 in Moscow in November 2014 due to an exacerbation of chronic urticaria.

From the anamnesis: urticarial rashes and angioedema since the age of four. The patient was observed with a diagnosis of urticaria and Quincke's edema. From the age of 16, spontaneous remission occurred. The patient sought medical help. An allergological examination was carried out; the causes of urticaria were not established. The exacerbation began in September 2014, when swelling appeared in the upper lip. With self-administration of cetirizine, the swelling was relieved within 24 hours. Two weeks later, the swelling recurred, and the patient started taking cetirizine again. From that moment on, the patient began to notice recurrence of angioedema and the appearance of urticarial rashes on the body, mainly in the evening. Nevertheless, they were managed to stop in less than a day. The patient did not note any connection with external trigger factors. A moderate effect occurred during antihypertensive therapy. Rashes occurred daily in the amount of 30–50 elements on the body, swelling with a frequency of up to two to three times a week, predominantly localized in the face and hands. In October, the patient sought medical help. SGCs were prescribed. However, even while taking prednisolone (two tablets (10 mg) per day for a week), rashes persisted in moderate quantities (20–30 elements on the body per day). When using desloratadine at a dose of 20 mg/day, the intensity of itching decreased, but rashes on the body persisted (at least 20 elements), swelling was noted once or twice a week, more often in the area of ​​the lips and hands. Ultrasound examination of the abdominal organs and thyroid gland - without pathology. Antibodies to Helicobacter pylori

, Ascaris and Giardia were not detected. No antibodies to thyroglobulin and thyroid peroxidase were detected. The level of thyroid hormones is within acceptable values. The test with autologous serum is positive.

In the allergy department, the patient was diagnosed with chronic idiopathic urticaria of moderate severity. Recurrent angioedema." After signing the informed consent, by decision of the medical commission, the patient was started on high-dose antihypertensive therapy (fexofenadine 180 mg, four tablets per day) in combination with H2-histamine blockers and antileukotriene drugs (ranitidine 150 mg and montelukast 10 mg). However, during this therapy, skin itching persisted – 4–5 points, swelling in the face (two episodes of swelling of the eyelids and cheeks in five days). The rashes were daily. An attempt was made to replace AGP, but there was no effect from the therapy. Due to a pronounced increase in rashes during this therapy, the patient took Metypred for three days, three tablets (12 mg) per day with a moderate positive effect.

The patient was offered therapy with omalizumab. After signing the informed consent, treatment began. The initial dose of omalizumab was 300 mg subcutaneously in the upper arm. The patient was under the supervision of medical personnel for two hours. No undesirable reactions, as well as the appearance of local reactions, or changes in condition were observed. But four hours after the administration of the drug, the patient complained of a sharp increase in the number of rashes, the appearance of swelling in the face and hands, and severe itching. Upon examination, abundant urticarial rashes and swelling in the eyelids, lips, and hands were recorded. Vital indicators without features. Swelling and rashes were relieved within 24 hours due to the use of sGCs and antihypertensive drugs. Upon further observation, no recurrence of rashes or angioedema was observed and the patient was discharged with recommendations to continue taking antihypertensive drugs (loratadine at a daily dose of 40 mg). After two weeks, he independently reduced the dose to 20 mg and after two weeks stopped treatment. At a follow-up examination four weeks after the first injection of omalizumab, the skin was clean, urticarial rashes and angioedema were not a concern. A decision was made to further monitor and continue therapy with omalizumab in the event of urticarial rashes. However, to date (more than a year) the patient remains in remission of the disease.

The reason for the sharp increase in rashes four hours after the injection remains unclear. Apparently, this should be interpreted as a spontaneous exacerbation of the disease. It is unlikely that such a reaction would fit within the framework of anaphylaxis.

Clinical case 2

Patient A., 58 years old. I went to the allergy department of City Clinical Hospital No. 52 in Moscow with complaints of itchy rashes on the body. At the time of treatment, he had been ill for three months. The first rashes on the body appeared after a diet violation (use of nonspecific histamine liberators). From that moment on, the rashes became daily, worsened after eating, accompanied by intense itching (7 points). The patient sought medical help from an allergist: therapy with fexofenadine 180 mg was prescribed, with a subsequent positive effect, and a hypoallergenic diet, against the background of which the condition stabilized. According to the self-observation diary, the rashes were absent for two weeks, but due to a violation of the diet they resumed. Subsequent administration of fexofenadine had no effect. Fibrogastroduodenoscopy and a study of the level of antibodies to H. pylori

.
A diagnosis of exacerbation of H. pylori
-associated chronic gastritis was made. Eradication therapy (clarithromycin, amoxicillin, omeprazole) was started with a severe exacerbation of urticaria, which required the administration of a three-day course of corticosteroids. After eradication, urticarial rashes persisted, were daily in nature and were accompanied by intense itching. The patient was prescribed therapy with fexofenadine 180 mg (four tablets) and montelukast 10 mg/day. A positive effect was noted in the form of a reduction in the intensity of itching to 3 points and the number of rashes to 20 elements on the body per day.

According to the analysis of the self-observation diary, the therapeutic effect of the applied regimen lasted three weeks. There was a gradual increase in the number of rashes; there was no effect from a strict hypoallergenic diet. A month after the start of treatment, the number of rashes reached at least 50 elements per day, itching intensified to 3 points per day, and the overall urticaria activity index per week (UAS7) was 40 points. A collective decision was made to prescribe omalizumab at a dose of 300 mg subcutaneously. During two hours of observation of the patient after administration of the drug, a decrease in the intensity of the staining of the rash and relief of itching were noted. For three days the patient continued to have rashes ranging from 20 to 50 elements on the body per day. The number of elements was then reduced to 20. The patient continued taking fexofenadine at a quadruple dose and montelukast. After 21 days, 300 mg of omalizumab was reintroduced. Since that time, the patient noted the absence of rashes while taking fexofenadine. Montelukast was discontinued. Treatment with omalizumab at a dose of 150 mg once every 21 days lasted four months. During treatment, the dose of fexofenadine was gradually reduced to 180 mg/day. At the same time, an attempt to completely stop the antihistamine led to the resumption of rashes. In total, the patient received treatment with omalizumab for six months. The observation period from the last injection was also six months. Currently, there is a restoration of sensitivity to antihistamines. The patient remains in remission of CKS while taking fexofenadine in therapeutic doses. At the same time, the diet has been significantly expanded.

Conclusion

Our experience with the use of omalizumab as a drug of choice for the third line of treatment of refractory CIC in a small group of patients (13 people) showed effectiveness and a good safety profile. According to the results, two doses of 150 and 300 mg may be effective.

The selection of the regimen and duration of therapy, the frequency of omalizumab injections are different. However, most researchers recommend starting therapy with 300 mg once every four weeks. Subsequent doses and intervals depend on the achieved effect and tolerability of treatment. Upon achieving a pronounced but incomplete effect, it is possible to reduce the dose to 150 mg every 21st day.

Unfortunately, despite the availability of international and Russian documents on CC, the percentage of errors at the stage of diagnosis and treatment remains high. Today, therapy for CCI/CSC is more clearly defined and regulated by federal clinical guidelines. It is advisable to adhere to the drug use regimen prescribed in this consent document. This will help optimize the treatment time for patients with CIC/CKS, as well as avoid problems with the use of drugs for unregistered indications.

Future studies should focus on the mechanisms of omalizumab duration of action, optimal dosing regimens, and the creation of individualized treatment schedules required for long-term remission. To date, the maximum duration of observation is 24 months [14].

Use of the drug Xolair

The required dose and frequency of administration of Xolair is determined by the concentration of IgE (IU/ml), which is determined before the start of treatment, as well as the patient’s body weight (kg). Depending on the indicators, the recommended daily dose of Xolair is 150–375 mg. This dose can be divided into 1-3 administrations. For dose determination, see table. 1 and 2, and to determine the number of bottles for the appropriate dosage, see table. 3. To obtain a dose of 225 mg or 375 mg, you must use Xolair 150 mg in combination with Xolair 75 mg. Patients whose IgE level or body weight exceeds the level indicated in the dosage table should not be prescribed Xolair. Xolair is used only as a subcutaneous injection.

Table 1. Doses of Xolair (mg/dose) administered by subcutaneous injection every 4 weeks.

Table 2. Doses of Xolair (mg/dose) administered by subcutaneous injection every 2 weeks.

Table 3. Conversion of the dose into the number of vials, number of injections and total injection volume for each injection.

and 0.6 ml is the maximum volume taken from the vial (Xolair 75 mg); in 1.2 ml - the maximum volume of withdrawal from the bottle (Xolair 150 mg); Or use 0.6 ml from a 150 mg bottle.

Duration of treatment, monitoring and dose adjustment Xolair is intended for long-term therapy. When using Xolair during the first 16 weeks, clinical studies showed a decrease in the incidence of asthma exacerbations, a decrease in the number of cases of emergency treatment, and an improvement in symptoms of the disease. The effectiveness of Xolair therapy should be assessed after at least 12 weeks of treatment with the drug. Discontinuation of the drug usually leads to the return of elevated levels of free IgE and the development of corresponding symptoms. Total IgE levels increase during treatment and remain elevated for 1 year after cessation of therapy. Thus, the IgE level when re-determined during Xolair therapy cannot serve as a guide for selecting the required dose of the drug. To establish the dose of the drug after interruption of treatment for a period of ≤1 year, one should focus on the concentration of IgE in the blood serum established before the administration of the initial dose of the drug. If treatment with Xolair is interrupted for 1 year or more, then to establish the dose of the drug, the total concentration of IgE in the blood serum should be determined again. Xolair dosages should be adjusted if significant changes in body weight occur (see Tables 1 and 2). There is limited experience with the use of Xolair in elderly patients (over 65 years of age). However, there is no data indicating the need to adjust the dose of the drug in patients of this age. Special instructions for use The lyophilized product dissolves within 15–20 minutes, although in some cases this process may take longer. A completely dissolved drug is clear or slightly cloudy and may contain several small air bubbles or foam on the walls of the bottle. Since the solution has a viscous consistency, force is required to remove the entire prepared solution in full, which is 0.6 ml for a dose of 75 mg or 1.2 ml for a dose of 150 mg, respectively. Rules for the preparation and administration of the solution:

1. For a vial of Xolair 75 mg, withdraw 0.9 ml of water for injection from the ampoule into the syringe. For a vial of Xolair 150 mg, withdraw 1.4 ml of water for injection from the ampoule into the syringe. The syringe needle should have a wide hole (No. 18).
2. Place the bottle vertically on a smooth surface, pierce the cap with a needle and inject water for injection directly into the dry substance of the drug.
3. Keeping the bottle in an upright position, carefully rotate the bottle (without shaking) for 1 minute to evenly saturate the dry substance with water for injection.
4. To dissolve the moistened powder, carefully return the bottle in a vertical position for 5–10 s every 5 minutes. Sometimes it may take 20 minutes for the dry matter to completely dissolve. In this case, repeat step 4 until all solids are completely dissolved. When the drug is completely dissolved, there should be no visible gel-like particles in the solution; the presence of small bubbles or foam on the walls of the bottle is acceptable. The resulting solution should be transparent or slightly opalescent. If there are foreign particles in the solution, the drug cannot be used. After dissolution, a few small air bubbles or foam on the walls of the bottle are acceptable. The prepared solution will be transparent or slightly cloudy. Do not use if foreign particles are present.
5. Turn the bottle over for 15 seconds to allow the solution to flow downwards towards the stopper. Insert the syringe needle into the inverted bottle so that the end of the needle is near the bottle cap in the solution. Before removing the needle, fully pull out the syringe plunger to remove all the solution from the inverted bottle.
6. Replace needle No. 18 with needle No. 25 for subcutaneous injections.
7. Remove air, large bubbles and excess solution to obtain the required dose (0.6 or 1.2 ml). A thin layer of small bubbles may remain on the surface of the solution in the syringe. Since the solution has a certain viscosity, the duration of the injection can be 5–10 s. The vial contains 0.6 ml (75 mg) or 1.2 ml (150 mg) of Xolair.
8. Injections are performed subcutaneously, into the deltoid muscle of the arm or into the thigh.

The drug must be used immediately after dilution. The chemical and physical stability of the opened drug is maintained for 8 hours at a temperature of 2 to 8 °C and for 4 hours at a temperature of 30 °C.

Omalizumab

The effectiveness of omalizumab therapy should be assessed after at least 12 weeks of treatment.

Omalizumab is intended for long-term therapy. Discontinuation of the drug usually leads to the return of elevated levels of free IgE and the development of corresponding symptoms.

Total IgE levels increase during treatment and remain elevated for one year after cessation of therapy. Thus, the IgE level when re-determined during omalizumab therapy cannot serve as a guide for selecting the dose of the drug. To set the dose of the drug after interruption of treatment for a period of less than 1 year, one should focus on the concentration of IgE in the blood serum established before the administration of the initial dose of the drug. If treatment with omalizumab is interrupted for 1 year or more, the total concentration of IgE in the blood serum should be determined again to establish the dose of the drug. Doses of omalizumab should be adjusted if significant changes in body weight occur.

When using omalizumab, as when using any other protein-containing drugs, local or systemic allergic reactions, including anaphylactic reactions, may occur. Anaphylaxis following administration of omalizumab has been reported in both premarketing clinical trials and postmarketing reports. Signs and symptoms noted in these cases included bronchospasm, hypotension, urticaria, and/or swelling of the throat or tongue. Some of these cases were life-threatening. In premarketing clinical trials, the incidence of anaphylaxis associated with omalizumab was estimated to be 0.1%, and in postmarketing trials it was at least 0.2%. Cases of anaphylaxis have been observed both after the first dose of omalizumab and after a year of regular use. Before administering omalizumab, it is necessary to prepare in advance the appropriate resuscitation equipment and medications necessary to relieve hypersensitivity reactions. Patients should be informed about the possibility of developing anaphylactic reactions and appropriate medical supervision of patients should be provided. If a patient develops a severe hypersensitivity reaction, omalizumab should be discontinued.

Caution should be exercised when using the drug in patients with diabetes mellitus, glucose-galactose malabsorption syndrome, fructose intolerance or sucrose/isomaltase deficiency. The sucrose content in 1 dose of omalizumab (150 mg) is 108 mg.

Omalizumab should not be used to treat acute attacks of asthma, acute bronchospasm or status asthmaticus.

In patients with allergic diseases other than bronchial asthma, the safety and effectiveness of the drug have not been established.

The use of omalizumab has not been studied in patients with high IgE syndrome, allergic bronchopulmonary aspergillosis, for the prevention of anaphylactic reactions, atopic dermatitis, allergic rhinitis or food allergies.

Experience with omalizumab in patients over 65 years of age is limited. However, there is no data indicating the need to adjust the dose of the drug in patients of this age.

Impact on the ability to drive vehicles and operate machinery

Patients who experience dizziness or other central nervous system disorders while taking omalizumab should refrain from driving or operating machinery while using the drug.

Side effects of Xolair

Adverse reactions identified during clinical studies when using Xolair were classified by organs and systems and frequency: often (1/100, ≤1/10); sometimes (1/1000, ≤1/100); rare (≤1/1000). Infections and infestations: rarely - parasitic infections. From the immune system: rarely - anaphylactic reactions, angioedema and other allergic conditions. From the nervous system: often - headache; sometimes - dizziness, drowsiness, paresthesia. Vascular disorders: sometimes - postural hypotension, hot flashes. From the gastrointestinal tract: sometimes - nausea, diarrhea, dyspepsia. From the skin and subcutaneous tissues: sometimes - urticaria, rash, itching, photosensitivity, alopecia. From the respiratory system: often - pharyngitis, cough, allergic bronchospasm; sometimes - laryngeal edema, allergic granulomatous vasculitis. From the blood and lymphatic system: rarely - idiopathic severe thrombocytopenia. From the musculoskeletal system and connective tissue: sometimes - arthralgia, myalgia, swelling of the joints. General disorders and local reactions: often - pain, swelling, erythema, itching at the injection site; sometimes - weight gain, fatigue, flu-like symptoms, swelling of the upper extremities. Change in blood platelet count. When using Xolair in clinical studies, several patients experienced a decrease in platelet counts below normal levels, which was not accompanied by bleeding or a decrease in hemoglobin. In none of the cases were there any episodes of bleeding or persistent decrease in platelet count.

Special instructions for the use of Xolair

General Xolair is not intended for the treatment of exacerbations of asthma, acute bronchospasm or status asthmaticus. Xolair has not been studied in patients with hyperIgE syndrome or allergic bronchopulmonary aspergillosis or for the prevention of anaphylactic reactions. To date, the effect of Xolair has not been sufficiently studied in atopic dermatitis, allergic rhinitis or food allergies. Xolair should be used with caution in patients with autoimmune diseases, diseases associated with the accumulation of immune complexes, or in patients with impaired liver and/or kidney function. It is not recommended to suddenly stop using systemic or inhaled corticosteroids after starting Xolair therapy. Doses of corticosteroids should be reduced gradually and under the direct supervision of a physician. Patients with diabetes mellitus, patients with reduced absorption of glucose-galactose syndrome, fructose intolerance or sucrase-isomaltase deficiency should be warned that 1 dose of 150 mg of Xolair contains 108 mg of sucrose. Allergic reactions When using omalizumab, as with other drugs containing protein, local or systemic allergic reactions, including anaphylaxis, may occur. Therefore, before administering the drug, you need to prepare the medications necessary to help with anaphylactic reactions. As with all humanized monoclonal antibodies derived from recombinant DNA, patients may occasionally develop antibodies to omalizumab. Parasitic infections IgE is involved in the immunological response to some infections. In patients at high risk of contracting helminth infections, caution must be exercised, especially in endemic regions. A placebo-controlled study found a slight increase in the incidence of helminthic infestations in patients treated with omalizumab, although the course, severity, and response to treatment were unchanged. If anthelmintic treatment is ineffective, discontinuation of Xolair should be considered. Use during pregnancy or breastfeeding. It is known that IgG molecules penetrate the placental barrier. The use of Xolair during pregnancy and lactation is possible only if the expected benefit to the mother outweighs the potential risk to the fetus/child. Children. The safety and effectiveness of Xolair in children under 12 years of age have not been established, so the drug should not be used in this category of patients. The ability to influence reaction speed when driving vehicles or working with other mechanisms. Patients using the drug Xolair should be informed that if they experience dizziness, fatigue or drowsiness, they should not drive vehicles or operate other machinery.

Xolair (omalizumab)

Marketing authorization holder: NOVARTIS PHARMA, AG (Switzerland)

Production, packaging and release quality control: NOVARTIS PHARMA STEIN, AG (Switzerland)

Solvent production and packaging: TAKEDA AUSTRIA, GmbH (Austria)

ATX code: R03DX05 (Omalizumab)

Active substance: omalizumab (omalizumab) Rec.INN registered by WHO

Release form, packaging and composition of the drug Xolair®

Lyophilisate for preparing a solution for subcutaneous administration, white or almost white; the attached solvent is a clear, colorless liquid.

Excipients: sucrose – 108 mg, L-histidine – 1.3 mg, L-histidine hydrochloride monohydrate – 2.1 mg, polysorbate 20 – 0.4 mg.

Solvent: water for injection – 2 ml.

Colorless glass bottles with a capacity of 6 ml (1) complete with solvent (amp. 2 ml 1 pc.) - cardboard packs.

Clinical and pharmacological group: Recombinant humanized monoclonal antibodies (IgG1)

Pharmacotherapeutic group: Other agents for systemic use in obstructive respiratory diseases

pharmachologic effect

Omalizumab is a humanized monoclonal antibody produced from recombinant DNA; selectively binds to immunoglobulin (IgE). Omalizumab is an IgG1 kappa antibody containing a human structural backbone with the complementarity-determining regions of a murine IgE-binding antibody.

Omalizumab binds to IgE and prevents its interaction with the high-affinity FcεRI receptor. Thus, there is a decrease in the amount of free IgE, which is the trigger for the cascade of allergic reactions.

When using the drug in patients with atopic bronchial asthma, there is a noticeable decrease in the number of FcεRI receptors on the surface of basophils.

When using omalizumab in patients with moderate to severe atopic bronchial asthma, there was a significant reduction in the frequency of exacerbations of bronchial asthma (defined as a worsening of bronchial asthma requiring the use of systemic corticosteroids or doubling the initial dose of inhaled corticosteroids) and a reduction in the need for inhaled corticosteroids compared with placebo. When using omalizumab for 16 weeks, with a gradual reduction in the dose of inhaled or oral corticosteroids, a significant decrease in the frequency of exacerbations of bronchial asthma and a decrease in the need for inhaled corticosteroids was also observed compared with placebo.

In patients with bronchial asthma and perennial allergic rhinitis who received corticosteroid therapy, when using omalizumab for 28 weeks, there was a decrease in the severity of symptoms of bronchial asthma and perennial allergic rhinitis, as well as an improvement in pulmonary function parameters.

In some patients with chronic idiopathic urticaria, autoimmune antibodies to the IgE and FcεRI receptor were isolated from the blood serum. These antibodies are capable of activating basophils or mast cells, which leads to the release of histamine.

One hypothesis for the mechanism of action of omalizumab in patients with chronic idiopathic urticaria is a decrease in the concentration of free IgE in the blood and then in the skin. As a result, signal transmission through FcεRI receptors is reduced and, consequently, the activation of cells involved in the inflammatory response is suppressed. Thus, the incidence and severity of symptoms of chronic idiopathic urticaria is reduced. In addition, it is believed that a decrease in the concentration of circulating IgE leads to rapid nonspecific desensitization of mast cells in the skin, and FcεRI receptors support this reaction through negative feedback.

Pharmacokinetics

After subcutaneous administration, the absolute bioavailability of omalizumab averages 62%. After a single subcutaneous administration to adults and adolescents with bronchial asthma, absorption of omalizumab occurs slowly, with Cmax achieved on average after 7-8 days.

When used in doses greater than 0.5 mg/kg, the pharmacokinetics of omalizumab is linear. After repeated administration of omalizumab over a period of 0 to 14 days at steady state, the AUC was 6 times higher than after a single dose.

In vitro, omalizumab forms a complex with IgE of a certain size. No formation of precipitating complexes or complexes with a molecular weight exceeding 1 million daltons was observed in vitro or in vivo.

After subcutaneous administration, the apparent Vd was 78±32 ml/kg. The distribution of omalizumab in patients with chronic idiopathic urticaria was similar to that in patients with atopic asthma.

Experimental studies did not reveal specific accumulation of omalizumab in any organs or tissues.

Clearance of omalizumab includes both the clearance of IgG itself and clearance by specific binding and formation of complexes with the target ligand – free serum IgE.

Hepatic elimination of IgG involves degradation in the liver reticuloendothelial system and liver endothelial cells. Intact IgG is also excreted in the bile. T1/2 of omalizumab from plasma averages 24-26 days, apparent clearance at Css averages 2.4-3 ml/kg/day.

Based on a population pharmacokinetic model in patients with CIC, the serum half-life of omalizumab at steady-state concentrations averaged 24 days, and the apparent clearance at steady-state averaged 240 ml/day (corresponding to 3.0 ml/kg/day for a patient with body weight 80 kg).

In addition, with a doubling of body weight, an approximately twofold increase in apparent clearance was observed.

Indications of the active substances of the drug Xolair®

Treatment of persistent moderate to severe atopic bronchial asthma, the symptoms of which are not sufficiently controlled by the use of inhaled corticosteroids in patients aged 6 years and older.

Treatment of chronic idiopathic urticaria, resistant to therapy with histamine H1 receptor blockers, in patients aged 12 years and older.

Dosage regimen

The method of administration and dosage regimen of a particular drug depend on its release form and other factors. The optimal dosage regimen is determined by the doctor. The compliance of the dosage form of a particular drug with the indications for use and dosage regimen should be strictly observed.

Enter s.c. The dose and frequency of administration are determined based on the initial IgE concentration (IU/ml) measured before the start of treatment, as well as the patient’s body weight (kg). Depending on these indicators, the recommended dose of the drug is from 75 to 600 mg once every 2 or 4 weeks in accordance with the treatment regimen. The dose should be adjusted if there are significant changes in body weight.

Side effect

Determination of the categories of frequency of development of adverse reactions: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (<1/1000).

Infectious and parasitic diseases: often - nasopharyngitis, sinusitis, upper respiratory tract infections, including viral etiology, urinary tract infections; rarely – parasitic infestations.

From the immune system: rarely - anaphylactic reactions and other allergic conditions, including angioedema, the development of antibodies to omalizumab; frequency unknown - anaphylaxis and anaphylactoid reactions (noted both during the first and repeated use of the drug in most cases within 2 hours after subcutaneous injection, in some patients more than 2 hours after administration of omalizumab), serum sickness (may include increased body temperature, lymphadenopathy), allergic granulomatous vasculitis (Churg-Strauss syndrome).

From the nervous system: very often – headache; often – headache in the paranasal sinuses; uncommon – dizziness, drowsiness, paresthesia, syncope. In clinical studies in children 6-12 years old, headache was very common.

From the cardiovascular system: infrequently - postural hypotension, hot flashes. In controlled clinical trials, thromboembolic complications, including stroke, transient ischemic attacks, myocardial infarction, unstable angina, and death from cardiovascular causes (including death from unknown causes), were observed in patients treated with omalizumab. When analyzing the main cardiovascular risk factors, the risk ratio was 1.32.

From the respiratory system: infrequently – cough, allergic bronchospasm; rarely - laryngeal edema.

From the digestive system: infrequently - nausea, diarrhea, dyspepsia. In clinical studies, children 6-12 years old often have pain in the upper abdomen.

From the skin and subcutaneous tissues: infrequently - urticaria, rash, itching, photosensitivity; rarely – angioedema; frequency unknown.

From the hematopoietic system: frequency unknown - severe idiopathic thrombocytopenia.

From the musculoskeletal system: often – arthralgia, myalgia, pain in the extremities, musculoskeletal pain; frequency unknown - swelling of the joints.

General reactions: often - increased body temperature; uncommon – weight gain, feeling tired, swelling of the hands, flu-like condition. In clinical studies in children 6-12 years old, increased body temperature is very common.

Local reactions: often - reactions at the injection site, such as pain, erythema, itching, swelling, bleeding, urticaria.

Contraindications for use

Hypersensitivity to omalizumab; patients with atopic bronchial asthma under the age of 6 years; patients with chronic idiopathic urticaria under the age of 12 years.

Use during pregnancy and breastfeeding

No specific studies have been conducted on the use of omalizumab in pregnant women. Experimental studies did not reveal any direct or indirect negative effects on the course of pregnancy, the development of the embryo and fetus, the course of labor and the development of newborns. It is known that IgG molecules penetrate the placental barrier.

It is unknown whether omalizumab is excreted into human breast milk. Please note that human IgG is excreted in breast milk. It is unknown whether omalizumab is excreted into human breast milk. A risk to breastfed neonates/infants cannot be excluded and omalizumab should not be used during breastfeeding. If omalizumab is necessary, breastfeeding should be discontinued.

Use for liver dysfunction

Use with caution in patients with impaired liver function.

Use for renal impairment

Use with caution in patients with impaired renal function.

Use in children

Contraindications: patients with atopic bronchial asthma under the age of 6 years; patients with chronic idiopathic urticaria under the age of 12 years.

special instructions

Use with caution in patients with impaired liver and/or kidney function, with autoimmune diseases or diseases associated with the accumulation of immune complexes, as well as in patients with an increased risk of developing helminth infestations (especially in endemic areas). When using omalizumab, as with any other protein-containing drugs, local or systemic allergic reactions, including anaphylactic reactions, may occur.

Before administering omalizumab, it is necessary to prepare in advance the appropriate resuscitation equipment and medications necessary to relieve hypersensitivity reactions.

Patients should be informed about the possibility of developing anaphylactic reactions and appropriate medical supervision of patients should be provided.

Should not be used to treat acute attacks of bronchial asthma, acute bronchospasm or status asthmaticus.

In rare cases, the formation of antibodies to omalizumab has been observed.

In rare cases, patients with severe bronchial asthma may develop systemic hypereosinophilic syndrome or allergic eosinophilic granulomatous vasculitis (Churg-Strauss syndrome), for the treatment of which systemic corticosteroid therapy is usually used.

In rare cases, in patients receiving anti-asthmatic drugs, incl. omalizumab, systemic eosinophilia or vasculitis may occur or develop. These cases are usually associated with a reduction in the dose of oral corticosteroids.

The physician should be alert for the development of severe eosinophilia, vasculitic rash, worsening of pulmonary symptoms, pathology of the paranasal sinuses, cardiac complications and/or nephropathy in such patients.

If the above severe immune system disorders develop, the possibility of discontinuing omalizumab should be considered.

In patients receiving therapy with humanized monoclonal antibodies, incl. omalizumab, in rare cases, the development of serum sickness and similar conditions was observed, which is a manifestation of delayed allergic reactions of type 3. The onset of the development of such conditions was usually observed 1-5 days after the first or subsequent injections, as well as during long-term therapy. Symptoms suggestive of serum sickness include arthritis/arthralgia, rash (urticaria or other forms), fever, and lymphadenopathy. As a prevention and treatment of this pathology, it is possible to use antihistamines and corticosteroids. The patient should be informed about the possibility of developing this condition and warned about the need to consult a doctor if possible symptoms appear.

The use of omalizumab has not been studied in patients with hyperIgE syndrome, allergic bronchopulmonary aspergillosis, for the prevention of anaphylactic reactions, atopic dermatitis, allergic rhinitis or food allergies.

Treatment with systemic or inhaled corticosteroids should not be abruptly discontinued after initiation of treatment with omalizumab. The dose of these drugs used simultaneously with omalizumab is reduced gradually under the supervision of a physician.

Impact on the ability to drive vehicles and machinery

Patients who experience dizziness, fatigue, syncope or drowsiness while taking omalizumab should refrain from driving vehicles and machinery.

Drug interactions

Omalizumab should not be mixed with any medications or solutions.

Order a product

Xolair drug interactions

Since the clearance of omalizumab does not involve the cytochrome P450 system, efflux pump systems or protein binding machinery, there is little potential for interactions with other drugs. Specific drug interaction studies, including vaccines, have not been conducted for Xolair. Xolair's interaction with drugs used to treat asthma is unlikely. In clinical studies, Xolair is usually used in combination with inhaled and oral corticosteroids, inhaled short- and long-acting β-agonists, leukotriene modifiers, theophylline and oral antihistamines. There is no evidence that the safety of Xolair was decreased when combined with these or other anti-asthma drugs. Regarding the use of Xolair in combination with specific immunotherapy (antisensitizing therapy), existing data are limited.