Genolar^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Generium-Next, LLC (Russia)

Manufactured By

Generium, JSC (Russia)

Or

Pharmstandard-UfaVITA OJSC (Russia)

Primary Packaging

Generium, JSC (Russia)

Or

Pharmstandard-UfaVITA OJSC (Russia)

Secondary Packaging

Generium, JSC (Russia)

Or

Generium-Next, LLC (Russia)

Or

Pharmstandard-UfaVITA OJSC (Russia)

Quality Control Release

Generium, JSC (Russia)

Or

Generium-Next, LLC (Russia)

Or

Pharmstandard-UfaVITA OJSC (Russia)

ATC Code

R03DX05 (Omalizumab)

Active Substance

Omalizumab (Rec.INN registered by WHO)

Dosage Form

Genolar®

Lyophilisate for solution for subcutaneous administration 150 mg: fl. in a kit with solvent

Dosage Form, Packaging, and Composition

Lyophilisate for the preparation of a solution for subcutaneous administration in the form of an amorphous mass from white to white with a slight brownish-yellowish tint; after reconstitution – a clear or opalescent, colorless or brownish-yellowish solution; solvent – a colorless, transparent liquid without odor.

Excipients: sucrose, L-histidine, L-histidine hydrochloride monohydrate, polysorbate 20.

Solvent water for injections – 2 ml (ampoules).

150 mg – vials (1) in a kit with solvent (amp. 2 ml 1 pc.) – contour cell packaging (1) – cardboard packs^x.

^xFor first opening control, the pack valves are fixed with self-adhesive labels.

Clinical-Pharmacological Group

Recombinant humanized monoclonal antibodies (IgG₁)

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases, other drugs for the treatment of obstructive airway diseases for systemic use

Pharmacological Action

Omalizumab is a humanized monoclonal antibody produced using recombinant DNA technology; it selectively binds to immunoglobulin (IgE). Omalizumab is an IgG1 kappa antibody containing a human framework with murine antibody-derived complementarity-determining regions that bind IgE.

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

When the drug is used in patients with atopic bronchial asthma, a marked decrease in the number of FcεRI receptors on the surface of basophils is noted.

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

In patients with bronchial asthma and perennial allergic rhinitis receiving corticosteroid therapy, the use of omalizumab for 28 weeks resulted in a reduction in the severity of asthma and perennial allergic rhinitis symptoms, as well as an improvement in lung function parameters.

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

One hypothesis for the mechanism of action of omalizumab in patients with chronic idiopathic urticaria is a reduction in the concentration of free IgE in the blood, and subsequently in the skin. As a result, signaling via FcεRI receptors is reduced and, consequently, the activation of cells involved in the inflammatory response is suppressed. Thus, the frequency and severity of chronic idiopathic urticaria symptoms are reduced. Furthermore, it is believed that the reduction in circulating IgE concentration leads to rapid nonspecific desensitization of mast cells in the skin, and FcεRI receptors maintain this reaction via 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, the absorption of omalizumab is slow, with C_max reached on average after 7-8 days.

At doses above 0.5 mg/kg, the pharmacokinetics of omalizumab are linear. After multiple administrations of omalizumab over a period of 0 to 14 days at steady state, the AUC was 6 times higher than after a single dose administration.

In vitro, omalizumab forms a complex of a certain size with IgE. The formation of precipitating complexes and complexes with a molecular weight exceeding 1 million daltons was not observed in vitro or in vivo.

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

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

The clearance of omalizumab includes both IgG clearance itself and clearance through specific binding and complex formation with the target ligand – free serum IgE.

Hepatic elimination of IgG involves degradation in the reticuloendothelial system of the liver and hepatic endothelial cells. Intact IgG is also excreted in bile. The T_1/2 of omalizumab from plasma averages 24-26 days, and the apparent clearance at C_ss averaged 2.4-3 ml/kg/day.

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

Furthermore, a twofold increase in body weight resulted in an approximately twofold increase in apparent clearance.

Indications

Treatment of persistent atopic bronchial asthma of moderate and severe course, the symptoms of which are inadequately controlled with 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.

ICD codes

Dosage Regimen

Administered subcutaneously. The dose and frequency of administration are determined based on the baseline 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 ranges from 75 to 600 mg once every 2 or 4 weeks in accordance with the treatment regimen. The dose should be adjusted with significant changes in body weight.

Adverse Reactions

Definition of categories of frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (<1/1000).

Infections and parasitic diseases: common – nasopharyngitis, sinusitis, upper respiratory tract infections, including viral etiology, urinary tract infections; rare – parasitic infestations.

Immune system disorders: rare – anaphylactic reactions and other allergic conditions, including angioedema, formation of antibodies to omalizumab; frequency unknown – anaphylaxis and anaphylactoid reactions (observed both upon first and subsequent uses of the drug, in most cases within 2 hours after subcutaneous injection, in some patients more than 2 hours after omalizumab administration), serum sickness (may include fever, lymphadenopathy), allergic granulomatous vasculitis (Churg-Strauss syndrome).

Nervous system disorders: very common – headache; common – sinus headache; uncommon – dizziness, drowsiness, paresthesia, syncope. In clinical studies in children 6-12 years old very common – headache.

Cardiovascular system disorders: uncommon – postural hypotension, flushing. In controlled clinical trials in patients receiving omalizumab treatment, the development of thromboembolic complications was observed, including stroke, transient ischemic attacks, myocardial infarction, unstable angina, death from cardiovascular causes (including fatal outcome for unknown reasons). When analyzing the main cardiovascular risk factors, the risk ratio was 1.32.

Respiratory system disorders uncommon – cough, allergic bronchospasm; rare – laryngeal edema.

Gastrointestinal disorders: uncommon – nausea, diarrhea, dyspeptic symptoms. In clinical studies in children 6-12 years old common – pain in the upper abdomen.

Skin and subcutaneous tissue disorders: uncommon – urticaria, rash, pruritus, photosensitivity; rare – angioedema; frequency unknown.

Blood and lymphatic system disorders frequency unknown – severe idiopathic thrombocytopenia.

Musculoskeletal and connective tissue disorders : common – arthralgia, myalgia, pain in extremities, musculoskeletal pain; frequency unknown – joint swelling.

General disorders and administration site conditions: common – fever; uncommon – weight gain, feeling of tiredness, swelling of the hands, influenza-like illness. In clinical studies in children 6-12 years old very common – fever.

Administration site reactions: common – injection site reactions such as pain, erythema, pruritus, swelling, bleeding, urticaria.

Contraindications

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

Use in Pregnancy and Lactation

No specific studies on the use of omalizumab in pregnant women have been conducted. In experimental studies, no direct or indirect adverse effects on the course of pregnancy, embryonic and fetal development, the course of labor, and the development of newborns were identified. It is known that IgG molecules cross the placental barrier.

It is not known whether Omalizumab is excreted in human breast milk. It should be taken into account that human IgG is excreted in breast milk. It is not known whether Omalizumab is excreted in human breast milk. The risk to breastfed newborns/infants cannot be excluded, therefore Omalizumab should not be used during breastfeeding. If it is necessary to use omalizumab, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in patients with impaired liver function.

Use in Renal Impairment

Use with caution in patients with impaired renal function.

Pediatric Use

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

Special Precautions

Use with caution in patients with impaired liver and/or kidney function, with autoimmune diseases or diseases associated with immune complex accumulation, as well as in patients with an increased risk of helminthic 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, appropriate resuscitation equipment and medications necessary to manage hypersensitivity reactions should be prepared in advance.

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

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

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

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

In rare cases, in patients receiving anti-asthma medications, including Omalizumab, systemic eosinophilia or vasculitis may appear or develop. These cases are generally associated with a reduction in the dose of oral corticosteroids.

The physician should be alert to the development of marked eosinophilia, vasculitic rash, worsening of pulmonary symptoms, sinus pathology, cardiac complications, and/or nephropathy in such patients.

In case of development of the above severe immune system disorders, the possibility of discontinuing omalizumab should be considered.

In patients treated with humanized monoclonal antibodies, including omalizumab, the development of serum sickness and similar conditions has been rarely observed, which is a manifestation of delayed type 3 allergic reactions. The onset of such conditions was usually noted on days 1-5 after the first or subsequent injections, as well as during long-term therapy. Symptoms suggestive of serum sickness development include arthritis/arthralgia, rash (urticaria or other forms), fever, and lymphadenopathy. The use of antihistamines and corticosteroids is possible for the prevention and treatment of this condition. 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 hyperimmunoglobulin E syndrome, allergic bronchopulmonary aspergillosis, for the prevention of anaphylactic reactions, in atopic dermatitis, allergic rhinitis, or in food allergies.

Therapy with systemic or inhaled corticosteroids should not be abruptly discontinued after starting treatment with omalizumab. The dose of these drugs used concomitantly with omalizumab should be reduced gradually under medical supervision.

Effect on ability to drive vehicles and operate machinery

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

Drug Interactions

Omalizumab should not be mixed with any other drugs or solutions.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.