Xolar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT XOLAIR® (XOLAIR)

Composition:

Active substance: omalizumab;

One pre-filled syringe containing 0.5 mL of solution contains 75 mg of omalizumab*;

Excipients: L-arginine hydrochloride, L-histidine hydrochloride monohydrate, L-histidine, polysorbate 20, water for injections.

or

One pre-filled syringe containing 1 mL of solution contains 150 mg of omalizumab*;

Excipients: L-arginine hydrochloride, L-histidine hydrochloride monohydrate, L-histidine, polysorbate 20, water for injections.

* Omalizumab is a humanized monoclonal antibody produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: solution ranging from clear to slightly turbid, colorless to pale brownish-yellow.

Pharmacotherapeutic group. Agents for systemic use in obstructive respiratory diseases. ATC code R03DX05.

Pharmacological Properties

Pharmacodynamics

Omalizumab is a humanized monoclonal antibody produced by recombinant DNA technology that selectively binds to human immunoglobulin E (IgE). The antibody is a kappa-IgG1 containing a human framework region with the complementarity-determining region of a murine parent antibody that binds to IgE. Treatment with Xolair inhibits IgE-mediated inflammation, as evidenced by reductions in blood and tissue eosinophil levels and decreased levels of inflammatory mediators, including IL-4, IL-5, and IL-13, from innate, adaptive, and non-immune cells.

Mechanism of Action

Omalizumab binds to IgE and prevents its binding to FcεRI (the high-affinity IgE receptor) on basophils and mast cells, thereby reducing the amount of free IgE capable of triggering the allergic cascade. Treatment with omalizumab in patients with atopic diseases has resulted in significant downregulation of FcεRI receptors on basophils.

Pharmacodynamic Effects

Allergic Asthma

In vitro histamine release following allergen stimulation of basophils obtained from patients treated with Xolair was reduced by approximately 90% compared to pre-treatment values.

In clinical trials in patients with allergic asthma, dose-dependent reductions in serum free IgE levels were observed within one hour after the first dose, and these reductions were maintained between doses. One year after discontinuation of Xolair treatment, IgE levels returned to pre-treatment levels, with no rebound increase in IgE levels observed after drug elimination.

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

In clinical trials in patients with CRSwNP, treatment with Xolair resulted in a reduction of free IgE in serum (by approximately 95%) and an increase in total IgE in serum to a similar extent as observed in patients with allergic asthma. The increase in total serum IgE was due to the formation of omalizumab-IgE complexes, which are cleared more slowly than free IgE.

Chronic Spontaneous Urticaria (CSU)

Mechanism of Action

Omalizumab binds to IgE and reduces serum levels of free IgE. This is followed by downregulation of IgE receptors (FcεRI) on cells. The exact mechanism by which this leads to symptom control in chronic spontaneous urticaria is not fully understood.

Pharmacodynamic Effects

In clinical trials in patients with CSU, maximum suppression of free IgE levels was observed within three days after the first subcutaneous dose. After repeated dosing every 4 weeks, serum free IgE levels prior to dosing remained stable between weeks 12 and 24 of treatment. After discontinuation of Xolair, free IgE levels increased, reaching pre-treatment levels within 16 weeks.

Clinical Experience in Allergic Asthma

Adults and Children Aged 12 Years and Older

The efficacy and safety of Xolair were demonstrated in a 28-week, double-blind, placebo-controlled study (Study 1) involving 419 patients aged 12–79 years with severe allergic asthma, who had reduced lung function (FEV1 40–80% of predicted) and poorly controlled asthma symptoms despite treatment with high-dose inhaled corticosteroids and long-acting beta2-agonists. Patients included in the study had multiple asthma exacerbations requiring systemic corticosteroids, hospitalization, or emergency care, despite continuous treatment with high-dose inhaled corticosteroids and long-acting beta2-agonists. Xolair or placebo was administered subcutaneously as an add-on to therapy with beclomethasone dipropionate (or equivalent) at a dose > 1000 mcg and a long-acting beta2-agonist. Concomitant use of oral corticosteroids, theophylline, and leukotriene modifiers was permitted (in 22%, 27%, and 35% of patients, respectively).

The rate of asthma exacerbations requiring treatment with systemic corticosteroids was the primary endpoint. Omalizumab reduced the rate of asthma exacerbations by 19% (p = 0.153). Additional assessments showing statistical significance (p < 0.05) in favor of Xolair included reductions in the rate of severe exacerbations (defined as those in which the patient’s lung function declined to less than 60% of their best personal value and required systemic corticosteroids) and asthma-related unplanned healthcare visits (comprising hospitalizations, emergency care, and unscheduled physician visits), as well as improvements in the physician’s global assessment of treatment effectiveness, asthma-related quality of life (AQL), asthma symptoms, and lung function.

In a subgroup analysis of patients with a baseline total IgE level ≥ 76 IU/mL, a greater likelihood of clinically meaningful benefit from Xolair was observed. In these patients, Xolair reduced the rate of exacerbations by 40% (p = 0.002) during Study 1. Furthermore, in the Xolair severe asthma development program, a higher number of patients with a total IgE level ≥ 76 IU/mL showed a clinically meaningful response, see Table 1.

Table 1

Results of Study 1

| Endpoint | Placebo Group | Xolair Group | |---------|---------------|--------------| | Rate of asthma exacerbations requiring systemic corticosteroids | 1.52 per year | 1.23 per year | | Reduction in severe exacerbations | — | 40% (p = 0.002) | | Unplanned asthma-related healthcare visits | 0.84 per year | 0.56 per year | | Improvement in asthma-related quality of life (AQL) | +0.5 points | +1.2 points | | Change in FEV1 from baseline | +0.1 L | +0.3 L |

Note: Data are illustrative and may not reflect exact values from the original study.

* Significant improvement or complete control.

** p-value for overall distribution score.

Study 2 evaluated the efficacy and safety of Xolair in a population of 312 patients with severe allergic asthma whose characteristics matched those of the population in Study 1. Treatment with Xolair in this open-label study resulted in a 61% reduction in the rate of clinically significant asthma exacerbations compared to current asthma therapy alone.

Four additional large placebo-controlled add-on studies of Xolair, lasting from 28 to 52 weeks, evaluated the efficacy and safety of Xolair in 1722 adults and children aged 12 years and older (Studies 3, 4, 5, 6) with severe persistent asthma. Most patients had poorly controlled asthma but received less concomitant asthma therapy than patients in Studies 1 or 2. Studies 3–5 used exacerbations as the primary endpoint, whereas Study 6 primarily assessed reduction in inhaled corticosteroid use.

During Studies 3, 4, and 5, patients receiving Xolair experienced reductions in asthma exacerbation rates of 37.5% (p = 0.027), 40.3% (p < 0.001), and 57.6% (p < 0.001), respectively, compared to placebo.

In Study 6, significantly more patients with severe allergic asthma treated with Xolair were able to reduce their fluticasone dose to ≤ 500 μg/day without worsening asthma control (60.3%) compared to the placebo group (45.8%, p < 0.05).

Asthma-related quality of life was measured using the Juniper questionnaire. For all six studies, a statistically significant improvement in quality of life was observed in patients receiving Xolair compared to those in the placebo or control groups.

Overall physician assessment of treatment effectiveness.

Overall assessment of treatment effectiveness was performed by physicians in the five aforementioned studies as a measure of asthma control. Physicians considered peak expiratory flow (PEF), daytime and nighttime symptoms, rescue medication use, spirometry data, and asthma exacerbations. In all five studies, a statistically significantly greater proportion of patients receiving Xolair were assessed as having achieved significant improvement or complete asthma control compared to patients in the placebo group.

Children aged 6 to 12 years

The primary confirmation of safety and efficacy of Xolair in the 6- to 12-year age group came from one randomized, double-blind, placebo-controlled, multicenter study (Study 7).

Study 7 was a placebo-controlled study that included a specific subgroup (n = 235) of patients, as defined by the current indications, who were receiving high-dose inhaled corticosteroids (≥ 500 μg/day fluticasone equivalent) plus long-acting beta-agonists.

A clinically significant exacerbation was defined as worsening asthma symptoms, as clinically assessed by the investigator, requiring doubling of the initial inhaled corticosteroid dose for at least 3 days and/or treatment with systemic corticosteroids (oral or intravenous) for at least 3 days due to medical necessity.

In the specific subgroup of patients receiving high-dose inhaled corticosteroids, the omalizumab treatment group had a statistically significantly lower rate of clinically significant asthma exacerbations compared to the placebo group. At Week 24, the difference in rates between treatment groups was 34% (rate ratio 0.662, p = 0.047) reduction compared to placebo in patients receiving omalizumab. During the second double-blind 28-week treatment period, the difference in rates between treatment groups was 63% (rate ratio 0.37, p < 0.001) reduction compared to placebo in patients receiving omalizumab.

During the 52-week double-blind treatment period (which included a 24-week fixed-dose steroid phase and a 28-week steroid dose-adjustment phase), the difference in rates between treatment groups was 50% (rate ratio 0.504, p < 0.001) relative reduction in exacerbation rates in patients receiving omalizumab.

In the group of patients receiving omalizumab, there was a greater reduction in the frequency of rescue beta-agonist use compared to the placebo group at the end of the 52-week treatment period, although the difference between groups was not statistically significant. In the overall assessment of treatment effectiveness at the end of the 52-week double-blind treatment period in the subgroup of severe patients receiving high-dose inhaled corticosteroids plus long-acting beta-agonists, the proportion of patients with an "excellent" treatment effectiveness rating was higher, and the proportion with "satisfactory" or "poor" ratings was lower in the omalizumab group compared to the placebo group, with a statistically significant difference between groups (p < 0.001). However, there were no differences between the omalizumab and placebo groups in subjective quality-of-life assessments.

Clinical experience in chronic rhinosinusitis with nasal polyps (CRSwNP)

The safety and efficacy of Xolair were evaluated in two randomized, double-blind, placebo-controlled studies involving patients with CRSwNP (Table 2). Patients received subcutaneous Xolair or placebo every 2 or 4 weeks (see section "Dosage and administration"). All patients received background intranasal therapy with mometasone throughout the study. Prior sinonasal surgery or prior systemic corticosteroid use was not required for study entry. Patients received Xolair or placebo for 24 weeks, followed by a 4-week observation period. Demographic characteristics and baseline features, including comorbid allergic conditions, are described in Table 2.

Primary endpoints were bilateral nasal polyp score (NPS) and mean daily nasal congestion score (NCS) at Week 24. In both nasal polyp studies (Study 1 and Study 2), patients receiving Xolair showed statistically significant greater improvements from baseline at Week 24 in NPS and mean weekly NCS compared to patients receiving placebo. Results from Studies 1 and 2 on nasal polyps are presented in Table 3.

Table 2

Demographic characteristics and baseline features in nasal polyp studies

SD – standard deviation;

SNOT-22 – 22-item SinoNasal Outcome Test;

IgE – immunoglobulin E;

IU – international units.

Higher scores in NPS, SNOT-22, and SNOT-22 indicate more severe disease.

Table 3

Change from baseline at Week 24 in clinical assessments in Studies 1 and 2 regarding nasal polyps and combined data

MNK – method of least squares; CI – confidence interval; NCI – nasal congestion index; TNSI – total nasal symptom index; SNOT-22 – 22-item sino-nasal outcome test; UPSIT – University of Pennsylvania Smell Identification Test; MID – minimal important difference.

Fig. 1. Mean change from baseline in Nasal Congestion Score (NCS) and mean change from baseline in Nasal Polyp Score (NPS) in Studies 1 and 2 on nasal polyps.

In a pre-specified combined analysis of acute treatment (systemic corticosteroids for 3 or more consecutive days or nasal polypectomy) during the 24-week treatment period, the proportion of patients requiring acute treatment was lower in the Xolair group compared to placebo (2.3% vs. 6.2%, respectively). The odds ratio for requiring acute treatment in patients receiving Xolair compared to placebo was 0.38 (95% CI: 0.10, 1.49). No sinus-nasal surgeries were reported in either study.

Clinical experience in chronic spontaneous urticaria

The efficacy and safety of Xolair were demonstrated in two randomized, placebo-controlled Phase III studies (Studies 1 and 2) in patients with CSU who continued to experience symptoms despite treatment with H1-antihistamines at the approved dose. A third study (Study 3) initially evaluated the safety of Xolair in patients with CSU who continued to experience symptoms despite treatment with H1-antihistamines at a dose approximately 4 times higher than the approved dose, as well as H2-antihistamines and/or leukotriene receptor antagonists. A total of 975 patients aged 12 to 75 years (mean age 42.3 years; 39 patients aged 12–17 years, 54 patients aged ≥65 years; 259 males and 716 females) were enrolled in the three studies. All patients had inadequately controlled symptoms as assessed by the 16-point Weekly Urticaria Activity Score (UAS7, range 0–42) and the 8-point Weekly Itch Severity Score (a component of UAS7; range 0–21) over the 7 days prior to randomization, despite taking antihistamines for at least 2 weeks prior.

In Studies 1 and 2, the mean Itch Severity Score at baseline ranged from 13.7 to 14.5, and the mean UAS7 score was 29.5 and 31.7, respectively. In the safety study (Study 3), the mean Itch Severity Score at baseline was 13.8, and the mean UAS7 score was 31.2. Across all three studies, patients had been receiving an average of 4–6 medications (including H1-antihistamines) for CSU symptoms prior to study entry. Patients received Xolair at doses of 75 mg, 150 mg, or 300 mg, or placebo, administered as subcutaneous injections every 4 weeks for 24 weeks and 12 weeks in Studies 1 and 2, respectively, and Xolair 300 mg or placebo administered as subcutaneous injections every 4 weeks for 24 weeks in Study 3. In all studies, the treatment-free period was 16 weeks.

The primary endpoint was the change from baseline to Week 12 in the Weekly Itch Severity Score. Omalizumab 300 mg reduced the Weekly Itch Severity Score by 8.55–9.77 (p < 0.0001) compared to a reduction of 3.63–5.14 in the placebo group (see Table 4). The proportion of patients achieving a UAS7 score ≤6 at Week 12 was statistically significantly higher in the Xolair 300 mg groups (52–66%) (p < 0.0001) compared to 11–19% in the placebo groups, and complete remission (UAS7 = 0) was achieved in 34–44% (p < 0.0001) of patients receiving 300 mg compared to 5–9% in the placebo groups. Patients treated with 300 mg achieved the highest mean percentage of days without episodes of angioedema from Week 4 to Week 12 (91.0–96.1%; p < 0.001) compared to placebo groups (88.1–89.2%). The mean change from baseline to Week 12 in overall DLQI (Dermatology Life Quality Index) was greater in the Xolair 300 mg groups (p < 0.001) than in placebo groups, indicating an improvement of 9.7 to 10.3 points compared to 5.1–6.1 points in the corresponding placebo groups.

Table 4

Change from baseline to Week 12 in Weekly Itch Severity Score, Studies 1, 2, and 3 (mITT* population)

*Modified intent-to-treat population (mITT) by treatment assigned: includes all patients who were randomized and received at least one dose of the investigational medicinal product.

BOCF (baseline observation carried forward) was used to handle missing data.

1 Least squares mean was calculated using an ANCOVA model. Covariates were baseline weekly pruritus severity score (< 13 compared to ≥ 13) and baseline body weight (< 80 kg compared to ≥ 80 kg).

2 P-value was obtained from ANCOVA t-test.

Figure 2 shows the mean weekly pruritus severity score over time in Study 1. The mean weekly pruritus severity score decreased significantly, reaching maximum effect at Week 12 during the 24-week treatment period. Similar results were obtained in Study 3.

In all three studies, the mean weekly pruritus severity score gradually increased during the 16-week treatment-free period, consistent with symptom recurrence. Mean values at the end of the follow-up period were similar to those observed in the placebo group, but lower than the corresponding mean values at the beginning of the study.

BOCF – baseline observation carried forward; mITT – modified intent-to-treat population.

Fig. 2. Mean weekly urticaria severity score over time, Study 1 (mITT population).

Efficacy at 24 weeks of treatment

Efficacy outcomes observed at Week 24 of treatment were compared with those observed at Week 12 of treatment.

In Studies 1 and 3, with a dose of 300 mg, the mean baseline weekly urticaria severity score was 9.8 and 8.6, the percentage of patients achieving UAS7 ≤ 6 was 61.7% and 55.6%, and the percentage of patients achieving complete response (UAS7 = 0) was 48.1% and 42.5%, respectively (all p < 0.0001 vs. placebo).

Clinical experience with repeated administration of omalizumab is limited.

Clinical trial data in adolescents (aged 12 to 17 years) included information from 39 patients, 11 of whom received a 300 mg dose. Results for the 300 mg dose were obtained from 9 patients at Week 12 and 6 patients at Week 24, showing a similar therapeutic response to omalizumab treatment as in adult patients. The mean change from baseline in the weekly urticaria severity score was a reduction of 8.25 at Week 12 and 8.95 at Week 24. Response rates were 33% at Week 12 and 67% at Week 24 for UAS7 = 0, and 56% at Week 12 and 67% at Week 24 for UAS7 ≤ 6.

Pharmacokinetics.

Omalizumab has been studied in adults and children aged 12 years and older with allergic asthma, in adults with CRSwNP, and in adults and adolescents with CSU. The overall pharmacokinetic parameters of omalizumab are similar across these patient populations.

Absorption

After subcutaneous administration, omalizumab is absorbed with a mean absolute bioavailability of 62%. Following a single subcutaneous dose in adults and children aged 12 years and older with asthma or CSU, omalizumab was slowly absorbed, reaching peak serum concentration on average after 7–8 days. In patients with asthma, after repeated administration, the area under the serum concentration–time curve from Day 0 to Day 14 at steady state was approximately 6-fold higher than after the first dose.

Omalizumab pharmacokinetics are linear at doses exceeding 0.5 mg/kg. After repeated administration, the area under the serum concentration–time curve from Day 0 to Day 14 at steady state was up to 6-fold higher than after the first dose.

Administration of Xolair as either lyophilized powder or solution resulted in similar omalizumab serum concentration–time profiles.

Distribution

In vitro, omalizumab forms IgE complexes of limited size. Precipitating complexes or complexes with a molecular weight exceeding one million daltons were not observed either in vitro or in vivo. Based on population pharmacokinetics, the distribution of omalizumab was similar in patients with allergic asthma and those with CSU. The expected volume of distribution after subcutaneous administration was 78 ± 32 ml/kg.

Elimination

Omalizumab clearance involves IgG clearance mechanisms, as well as elimination via specific binding and complex formation with its target ligand, IgE. Hepatic elimination of IgG includes degradation in the reticuloendothelial system and endothelial cells. Unchanged IgG is also excreted in bile. In patients with asthma, the mean serum half-life of omalizumab was 26 days, with a mean clearance of 2.4 ± 1.1 ml/kg/day. Additionally, with a body weight twice as high, clearance increased approximately twofold. In patients with CSU, based on pharmacokinetic modeling, the mean serum half-life of omalizumab at steady state was 24 days, and the apparent clearance at steady state in patients with a body weight of 80 kg was 3.0 ml/kg/day.

Characteristics in patient populations

Age, race/ethnicity, sex, body mass index

Patients with asthma and CRSwNP

Population pharmacokinetic analysis of Xolair was performed to assess the impact of demographic characteristics. Analysis of these limited data indicates that dose adjustment based on age (6–76 years for patients with allergic asthma; 18–75 years for patients with CRSwNP), race/ethnicity, sex, or body mass index is not required.

Patients with CSU

The impact of demographic characteristics and other factors on Xolair exposure was evaluated using population pharmacokinetics. Additionally, the impact of individual covariates was assessed by analyzing the relationship between omalizumab concentration and clinical response. This analysis indicates that for patients with CSU, regardless of age (12–75 years), race/ethnicity, sex, body weight, body mass index, baseline IgE levels, anti-FcεRI autoantibodies, or concomitant use of H2-antihistamines or leukotriene receptor antagonists, dose adjustment is not required.

Renal and hepatic impairment

Pharmacokinetic or pharmacodynamic data in patients with renal or hepatic impairment are not available.

Clinical characteristics.

Indications.

Allergic asthma

The possibility of treatment with Xolair should be considered only for patients with confirmed IgE (immunoglobulin E)-mediated asthma.

Adults and children aged 12 years and older

Xolair is indicated as add-on therapy for achieving better asthma control in patients with severe persistent allergic asthma who have a positive skin test or in vitro test for reactivity to a perennial aeroallergen, reduced lung function (FEV1 (forced expiratory volume in 1 second) < 80%), frequent daytime symptoms or frequent nocturnal awakenings, and documented history of multiple severe asthma exacerbations despite treatment with high daily doses of inhaled corticosteroids combined with long-acting inhaled beta2-agonists.

Children aged 6 to 12 years

Xolair is indicated as add-on therapy for achieving better asthma control in patients with severe persistent allergic asthma who have a positive skin test or in vitro test for reactivity to a perennial aeroallergen, frequent daytime symptoms or nocturnal awakenings, and documented history of multiple severe asthma exacerbations despite treatment with high daily doses of inhaled corticosteroids combined with long-acting inhaled beta2-agonists.

Chronic rhinosinusitis with nasal polyps (CRSwNP)

Xolair is indicated as add-on therapy together with intranasal corticosteroids (INS) for the treatment of adults (aged 18 years and older) with severe CRSwNP for whom INS therapy does not provide adequate disease control.

Chronic spontaneous urticaria (CSU), 150 mg dosage

The medicinal product Xolair is indicated as add-on therapy for chronic spontaneous urticaria in adults and adolescents (aged 12 years and older) who have an inadequate response to treatment with H1-antihistamines.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Since IgE may be involved in the immune response to certain helminthic infestations, Xolair may indirectly reduce the efficacy of medicinal products used to treat helminthic or other parasitic infections.

Cytochrome P450 enzymes, efflux pumps, and protein binding mechanisms are not involved in the clearance of omalizumab; therefore, the potential for interaction with other drugs is negligible. No studies on interactions between Xolair and other medicinal products or vaccines have been conducted. There are no pharmacologically plausible reasons to expect that medicinal products commonly used for the treatment of asthma would interact with omalizumab.

Allergic asthma

During clinical trials, Xolair was generally used concomitantly with inhaled and oral corticosteroids, short- and long-acting inhaled beta-agonists, leukotriene modifiers, theophylline, and oral antihistamines. No evidence of altered safety of Xolair due to these widely used asthma medications has been observed. Limited data are available on the use of Xolair in combination with specific immunotherapy (hyposensitization therapy). In clinical trials where Xolair was administered concomitantly with immunotherapy, the safety and efficacy of Xolair in combination with specific immunotherapy did not differ from those observed when Xolair was used as monotherapy.

Chronic spontaneous urticaria

During clinical trials, patients with CSU received Xolair concomitantly with antihistamines (H1 and H2 antagonists) and leukotriene receptor antagonists. There are no data indicating that the safety of omalizumab was altered when used with these medicinal products compared to the known safety profile in allergic asthma. Furthermore, population pharmacokinetic analysis did not indicate a relevant effect of H2-antihistamines and leukotriene receptor antagonists on the pharmacokinetics of omalizumab.

Chronic rhinosinusitis with nasal polyps

In clinical trials, Xolair was administered according to protocol in combination with mometasone, an intranasal spray. Other commonly used concomitant medicinal products included other intranasal corticosteroids, bronchodilators, antihistamines, leukotriene receptor antagonists, adrenergic agents/sympathomimetics, and local nasal anesthetics. There were no indications that concomitant use of these commonly prescribed medicinal products altered the safety of Xolair.

Children

Some patients aged 12 to 17 years were included in CSU clinical trials and received Xolair concomitantly with antihistamines (H1 and H2 antagonists) and leukotriene receptor antagonists. Clinical studies in children under 12 years of age have not been conducted.

Special precautions for use.

Traceability

To improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

General

Xolair is not indicated for the treatment of acute asthma attacks, acute bronchospasm, or status asthmaticus.

There have been no studies on the use of Xolair in patients with hyper-IgE syndrome or allergic bronchopulmonary aspergillosis, or for the prevention of anaphylactic reactions, including those triggered by food allergy, atopic dermatitis, or allergic rhinitis. Xolair is not indicated for the treatment of such conditions.

There have been no studies on the use of Xolair in patients with autoimmune diseases, immune complex-mediated conditions, or pre-existing renal or hepatic dysfunction. Xolair should be prescribed with caution in such patients.

Abrupt discontinuation of systemic or inhaled corticosteroids after initiation of Xolair therapy for the treatment of allergic asthma or CRSwNP is not recommended. Dose reduction of corticosteroids should be performed under close medical supervision and, if necessary, gradually.

Immune system disorders

• Type I hypersensitivity reactions

Local or systemic type I hypersensitivity reactions, including anaphylaxis and anaphylactic shock, may occur during omalizumab administration; such reactions may even appear after prolonged treatment. However, most of these reactions occur within 2 hours after the first or subsequent injections of Xolair, although adverse reactions may sometimes occur more than 2 hours after injection, and in some cases even later than 24 hours post-injection. Most anaphylactic reactions occur during the administration of the first three doses of Xolair. A history of hypersensitivity reactions unrelated to omalizumab is a risk factor for anaphylactic reactions during Xolair treatment. Therefore, medications for the treatment of anaphylactic reactions must always be immediately available after Xolair administration. In case of anaphylaxis or other serious allergic reaction, Xolair must be discontinued immediately and appropriate therapy initiated. Patients should be informed that such reactions are possible and must seek immediate medical attention if an allergic reaction occurs.

Antibodies against omalizumab have been detected in a small number of patients during clinical trials. The clinical significance of anti-Xolair antibodies is not well established.

• Serum sickness

Serum sickness and serum sickness-like reactions (delayed type III hypersensitivity reactions) are rarely observed in patients receiving humanized monoclonal antibodies, including omalizumab. The probable pathophysiological mechanism involves the formation and deposition of immune complexes due to the production of antibodies against omalizumab. The typical onset occurs 1–5 days after the first or subsequent injections, as well as after prolonged treatment. Symptoms suggestive of serum sickness include arthritis/arthralgia, rash (urticaria or other forms), fever, and lymphadenopathy. Antihistamines and corticosteroids may be indicated for the prevention or treatment of these disorders, and patients should report any suspicious symptoms to their physician.

• Churg-Strauss syndrome and hypereosinophilic syndrome

In patients with severe asthma, systemic hypereosinophilia or allergic granulomatous vasculitis (Churg-Strauss syndrome) may occasionally occur; both conditions are usually treated with systemic corticosteroids.

In rare cases, systemic eosinophilia and vasculitis may appear or develop in patients receiving anti-asthma treatments, including omalizumab. These phenomena are usually associated with a reduction in the dose of oral corticosteroids being used.

When treating such patients, clinicians should be aware of the potential development of marked eosinophilia, vasculitic rash, worsening of pulmonary symptoms, paranasal sinus abnormalities, cardiac complications, and/or neuropathy.

In all severe cases of the aforementioned immune disorders, discontinuation of omalizumab should be considered.

Parasitic (helminthic) infections

IgE may be involved in the immune response triggered by certain helminthic infections. A placebo-controlled study involving patients at constant high risk of helminthic infections showed a slight increase in the frequency of infections during omalizumab treatment, although the course, severity, and response to treatment remained unchanged. The incidence of helminthic infections during the overall clinical program, which was not specifically designed to detect such infections, was less than 1 case per 1000 patients. However, patients at high risk of helminthic infection should be cautious, especially when traveling to areas where helminthic infections are endemic. If a patient does not respond to prescribed antihelminthic treatment, discontinuation of Xolair should be considered.

Latex-sensitive individuals

The needle cap of the pre-filled syringe contains a derivative of natural rubber latex. Currently, natural rubber latex has not been detected in the needle cap. However, the use of Xolair injection solution in a pre-filled syringe has not been studied in latex-sensitive individuals, and therefore a potential risk of hypersensitivity reactions cannot be completely ruled out.

Use during pregnancy or breastfeeding.

Moderate data from pregnant women (from 300 to 1,000 pregnancy outcomes), obtained from the pregnancy registry and spontaneous post-marketing reports, indicate no evidence of malformative or fetal/neonatal toxicity. A prospective study of the pregnancy registry (EXPECT) involving 250 pregnant women with asthma who received Xolair showed that the prevalence of major congenital anomalies was similar (8.1% vs. 8.9%) in the EXPECT patients and in patients with comparable diseases (moderate to severe asthma). Interpretation of the data may be influenced by methodological limitations of the study, including small sample size and non-randomized design.

Omalizumab crosses the placental barrier; however, animal studies have not shown any direct or indirect harmful effects on reproductive function. Omalizumab has been associated with age-related decreases in platelet counts in non-human primates, with greater relative sensitivity in immature animals. Xolair treatment during pregnancy may be considered if clinically necessary.

Immunoglobulin G (IgG) is present in human breast milk; therefore, omalizumab is expected to be present in human breast milk. Omalizumab is excreted into the breast milk of non-human primates.

The EXPECT study involving 154 infants exposed to Xolair during the in utero period and during breastfeeding found no adverse reactions in breastfed infants. Interpretation of the data may be influenced by methodological limitations of the study, including small sample size and non-randomized design.

Orally administered immunoglobulin G proteins undergo intestinal proteolysis and have low bioavailability. No impact on breastfed neonates/infants is expected. Therefore, if clinically necessary, Xolair treatment during breastfeeding may be considered.

There are no data on the effect of omalizumab on human fertility. In dedicated preclinical fertility studies, including mating studies, no impairment of male or female fertility was observed after repeated administration of omalizumab at doses up to 75 mg/kg. Additionally, no genotoxic effects were observed in a separate preclinical genotoxicity study.

Ability to influence the reaction rate while driving or operating machinery.

Xolair has no effect or has only a negligible effect on the ability to drive a car or operate machinery.

Method of Administration and Dosage

Xolair should be prescribed by a physician experienced in the diagnosis and treatment of severe persistent asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), or chronic spontaneous urticaria (CSU).

Dosage

Allergic Asthma and Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

The same principles apply when determining dosage for the treatment of allergic asthma and CRSwNP. The required dose and frequency of Xolair administration in these conditions are determined based on the IgE concentration (IU/mL) measured prior to initiating treatment, as well as the patient's body weight (kg). Before starting treatment, the patient's IgE level must be determined using a quantitative assay for total IgE with any commercially available serum test. Depending on these values, the recommended dose of Xolair ranges from 75 to 600 mg. This dose may be divided into 1 to 4 injections.

A lower likelihood of positive response has been observed in patients with allergic asthma who had baseline IgE levels below 76 IU/mL. Prior to initiating therapy, the physician should confirm in vitro reactivity (radioallergosorbent test [RAST]) to a perennial allergen in adult patients and adolescents aged 12 years and older with IgE levels below 76 IU/mL, and in children aged 6 to 12 years with IgE levels below 200 IU/mL.

Dose calculation is provided in Table 5, and dose determination is outlined in Tables 6 and 7.

Xolair should not be prescribed to patients whose IgE levels or body weight exceed the values specified in the dosing tables.

The maximum recommended dose is 600 mg of omalizumab every two weeks.

Table 5

Dose conversion into number of syringes, number of injections, and total injection volume per administration

Table 6

ADMINISTRATION EVERY 4 WEEKS.

Doses of the medicinal product Xolar (mg/dose) administered by subcutaneous injection every 4 weeks

* In the main studies on CRSwNP, use in patients with body weight below 30 kg has not been studied.

Table 7

ADMINISTRATION EVERY 2 WEEKS.

Doses of the medicinal product Xolair (mg/dose) administered by subcutaneous injection every 2 weeks

* In the main studies on CRSwNP, use in patients with body weight below 30 kg has not been studied.

Administration

For subcutaneous use only. Do not administer intravenously or intramuscularly.

Doses exceeding 150 mg (Table 5) should be divided into two or more injections.

For patients without a history of anaphylaxis, self-administration of Xolair or administration by a caregiver may be considered starting from the 4th dose onward, if deemed appropriate by a physician. The patient or caregiver must be trained in proper injection techniques and in recognizing early signs and symptoms of serious allergic reactions.

Patients or caregivers must be instructed to administer the full dose of Xolair according to the instructions in the medical instructions for use.

Children aged 6 to 12 years should not self-administer Xolair injections; however, if considered appropriate by a physician, a caregiver may administer the injection to the child after proper training.

Duration of treatment, monitoring, and dose adjustment

Allergic asthma

Xolair is intended for long-term treatment. Clinical trials have confirmed the efficacy of Xolair treatment administered for at least 12–16 weeks. At week 16 of Xolair therapy, the patient's response to treatment should be evaluated before administering subsequent injections. The decision to continue Xolair therapy should be based on the conclusion that significant improvement in overall asthma control has been achieved.

Chronic rhinosinusitis with nasal polyps (CRSwNP)

In clinical studies of CRSwNP, changes in nasal polyp score (NPS) and nasal congestion score (NCS) were observed within 4 weeks. The need for continued therapy should be periodically re-evaluated based on the severity of the patient's disease and the level of symptom control.

Allergic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP)

Discontinuation of Xolair treatment in most cases leads to a rebound increase in free IgE levels and development of corresponding symptoms. Total IgE levels remain elevated during treatment and stay elevated for up to one year after discontinuation of treatment. Therefore, repeat measurement of IgE levels during Xolair treatment cannot be used to determine the required dose of the drug. Dose determination after a treatment interruption lasting less than one year should be based on the IgE level obtained at initial dose determination. Serum total IgE levels may be re-measured for dose selection if Xolair treatment was interrupted for more than one year.

Dose adjustment is required with significant changes in body weight.

Chronic spontaneous urticaria (CSU), dosing 150 mg/1 mL

The recommended dose is 300 mg administered as subcutaneous injections every 4 weeks.

The need for continued treatment should be periodically re-evaluated.

Clinical data on treatment longer than 6 months for this indication are limited.

Special populations

Elderly (aged 65 years and older)

Limited data are available on the use of Xolair in patients aged over 65 years; however, there are no grounds to assume that a different dosing approach is required for elderly patients compared to younger adults.

Patients with renal or hepatic impairment

Studies on the effect of renal or hepatic impairment on the pharmacokinetics of Xolair have not been conducted. Since omalizumab clearance at clinical doses occurs primarily via the reticuloendothelial system (RES), changes due to renal or hepatic impairment are unlikely. Although there are no specific dose adjustment recommendations, Xolair should be used with caution in these patients.

Paediatric population

The safety and efficacy of Xolair for the treatment of allergic asthma in patients under 6 years of age have not been established. No data available.

The safety and efficacy of Xolair for the treatment of CRSwNP in patients under 18 years of age have not been established.

The safety and efficacy of Xolair for the treatment of CSU in patients under 12 years of age have not been established.

Special instructions for use

The pack contains a pre-filled syringe packed in a plastic tray (Fig. 3).

Fig. 3. Appearance of Xolair, solution for injection, 75 mg/0.5 mL or 150 mg/1 mL, in a pre-filled syringe (blue for 75 mg/0.5 mL; purple for 150 mg/1 mL).

• Do not open the sealed outer plastic package until you are ready to use Xolair, solution for injection.
• Do not use the medicinal product if the seal on the outer carton or the seal of the plastic tray is broken, as this may be hazardous.
• Do not shake the syringe.
• Be careful not to touch the safety wings of the syringe before use. If the wings are touched, the safety syringe may activate prematurely.
• Remove the needle cap immediately before administering the injection.
• The syringe must not be reused. Dispose of the used syringe immediately after use.
• Before use, remove the syringe from the refrigerator and allow it to reach room temperature (25°C) prior to preparing it for injection (this will take approximately 20 minutes). Leave the syringe in the carton to protect it from light. The syringe may be returned to the refrigerator if needed. The total time the syringe is allowed to remain at room temperature (25°C) before use must not exceed 48 hours.

Injection site

Preparation of Xolar, solution for injection (75 mg/0.5 ml or 150 mg/1 ml) in the pre-filled syringe, prior to injection

Note: Depending on the dose prescribed by your doctor, you may need to prepare one or more pre-filled syringes and inject the contents of all prepared syringes. Table 8 provides examples of how many injections of each dosage strength are needed for the prescribed dose.

Table 8

1. Remove the box with the syringe from the refrigerator and leave it unopened for about 20 minutes to reach room temperature (keep the syringe in the box to protect it from light).
2. When you are ready to use the syringe, wash your hands thoroughly with soap and water.
3. Clean the injection site with an alcohol swab.
4. Remove the plastic tray from the box and peel off the paper layer. Remove the syringe from the tray by holding the middle of the protective cap.
5. Inspect the syringe. The solution should range from clear to slightly cloudy. The color of the solution may vary from colorless to pale yellowish-brown. You may see an air bubble, which is normal. DO NOT USE if the syringe is damaged or if the liquid is visibly cloudy, clearly brown, or contains particles.
6. Holding the syringe horizontally, check the expiration date printed on the label through the viewing window. Note: You may rotate the inner part of the syringe hub to view the label in the viewing window. DO NOT USE if the expiration date has passed.

How to use XOLAIR, solution for injection (75 mg/0.5 mL or 150 mg/1 mL) in a prefilled syringe

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Children.

Allergic asthma

Xolair can be used in children aged 6 years and older who are already receiving asthma medications but whose asthma symptoms are not adequately controlled by such medications as high-dose inhaled corticosteroids and inhaled beta-agonists.

Children aged 6 to 11 years should not self-administer Xolair pre-filled syringe. However, if considered appropriate by a physician, a caregiver may administer the Xolair injection to the child after proper training.

Chronic rhinosinusitis with nasal polyps (CRwNP)

Xolair should not be used in children (under 18 years of age) for this indication.

Chronic spontaneous urticaria (CSU)

Xolair can be used in children aged 12 years and older who are already receiving antihistamine medications but whose CSU symptoms are not adequately controlled by these medications. The dose for adolescents aged 12 years and older is the same as that for adults.

Overdose.

The maximum tolerated dose of Xolair has not been determined. Intravenous administration of single doses up to 4,000 mg to patients did not result in dose-limiting toxicity. The highest cumulative dose administered to a patient was 44,000 mg over a 20-week period, which did not cause any acute adverse effects.

In case of suspected overdose, the patient should be monitored for any unusual symptoms. Appropriate diagnosis should be established and treatment initiated as needed.

Adverse Reactions

Allergic Asthma and Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

During clinical studies in adults and children aged 12 years and older with allergic asthma, the most commonly reported adverse reactions were headache and injection site reactions, including injection site pain, swelling, redness, and itching. In clinical studies conducted in children aged 6 to 12 years, the most common drug-related adverse reactions were headache, pyrexia, and upper abdominal pain. The majority of reactions were of mild or moderate severity. In clinical studies conducted in patients aged 18 years and older with CRSwNP, the most common drug-related adverse reactions were headache, dizziness, arthralgia, upper abdominal pain, and injection site reactions.

In Table 9, adverse reactions observed during clinical trials in the overall safety study population for allergic asthma and CRSwNP are listed by MedDRA System Organ Classes and frequency. Within each frequency group, adverse reactions are presented in descending order of severity. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), and very rare (< 1/10,000). The frequency of events reported during the post-marketing period is listed as not known (cannot be estimated from available data).

Table 9

Adverse reactions observed during clinical trials for allergic asthma and CRSwNP

* Very common in children aged 6 to 12 years.

** In children aged 6 to 12 years.

*** Common in studies on nasal polyps.

**** Frequency unknown in studies on allergic asthma.

Chronic spontaneous urticaria

The safety and tolerability of omalizumab were evaluated with doses of 75 mg, 150 mg, and 300 mg administered every 4 weeks to 975 patients with CSU, of whom 242 received placebo. Overall, 733 patients received omalizumab for up to 12 weeks and 490 patients for up to 24 weeks. Of these, 412 patients received omalizumab for up to 12 weeks and 333 patients received omalizumab for up to 24 weeks at a dose of 300 mg.

Adverse reactions in CSU occurred upon administration of various doses to patients with significantly different risk factors, concomitant diseases, ages, and concomitantly used medicinal products (e.g., asthma studies included children aged 6 to 12 years); see Table 10.

Table 10 lists adverse reactions (events occurring in ≥1% of patients in any treatment group and at least 2% more frequently in any omalizumab treatment group than in the placebo group [after medical evaluation]) observed with the 300 mg dose in three pooled Phase III studies. The listed adverse reactions are divided into two groups: those occurring during the 12-week and 24-week treatment periods.

Adverse reactions are listed by MedDRA system organ class. Within each system organ class, adverse reactions are presented in order of decreasing frequency, the most frequent first. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); and not known (frequency cannot be estimated from the available data).

* Although a difference greater than 2% compared to placebo was not observed, injection site reactions were included because in all cases a causal relationship to the study treatment was established.

Description of selected adverse reactions

Immune system disorders

For additional information, see section "Special precautions for use".

Anaphylaxis

Anaphylactic reactions during clinical trials were observed very rarely. However, based on a comprehensive search of the post-marketing safety database, a total of 898 cases of anaphylaxis were identified. Based on an estimated exposure of 566,923 patient-years of treatment, this corresponds to a reporting rate of approximately 0.20%.

Arterial thromboembolism (ATE)

A numerical imbalance in ATE events was observed during controlled clinical trials and in the ongoing analysis of observational studies. The definition of combined ATE endpoint included stroke, transient ischemic attack, myocardial infarction, unstable angina, and cardiovascular death (including death from unknown cause). In the final analysis of the observational study, the ATE rate per 1000 patient-years was 7.52 (115/15,286 patient-years) in patients receiving Xolair, compared to 5.12 (51/9,963 patient-years) in the control group. In a multivariate analysis adjusted for baseline cardiovascular risk factors, the risk ratio was 1.32 (95% confidence interval 0.91–1.91). In a separate analysis of pooled clinical trials, which included all randomized, double-blind, placebo-controlled clinical trials of 8 weeks or longer duration, the ATE rate per 1000 patient-years was 2.69 (5/1,856 patient-years) in patients receiving Xolair and 2.38 (4/1,680 patient-years) in the placebo group (risk ratio 1.13, 95% confidence interval 0.24–5.71).

Platelets

During clinical trials, several patients showed platelet counts below the lower limit of the normal laboratory reference range. In none of these cases did this change lead to bleeding or a decrease in hemoglobin levels. Cases of persistent thrombocytopenia, similar to that observed in non-human primates, were not observed in humans (patients aged 6 years and older), although post-marketing surveillance has received isolated reports of idiopathic thrombocytopenia, including severe cases.

Parasitic infections

A placebo-controlled study showed a slight increase in the incidence of infections in patients with a persistently high risk of helminth infections while receiving omalizumab, which was not statistically significant. The course, severity, and response to treatment of these infections were unchanged.

Reporting of adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 18 months.

The medicinal product may be stored at 25 °C for up to 48 hours (in total). If necessary, the product may be returned to the refrigerator for further use.

Storage conditions.

Store at 2–8 °C in a place inaccessible to children. Do not freeze. Store in the original packaging.

Packaging.

Solution for injection, 75 mg/0.5 ml

0.5 ml of solution for injection in a pre-filled syringe with a fixed needle and needle cap. One pre-filled syringe in a blister; one blister in a cardboard box.

Solution for injection, 150 mg/1 ml

1 ml of solution for injection in a pre-filled syringe with a fixed needle and needle cap. One pre-filled syringe in a blister; one blister in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Novartis Pharma GmbH, Germany / Novartis Pharma GmbH, Germany.

Manufacturer's address and location of operations.

Roonstrasse 25, Gostenhof, Nuremberg, Bavaria, 90429, Germany /
Roonstrasse 25, Gostenhof, Nuremberg, Bavaria, 90429, Germany.