Elizaria^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Generium-Next, LLC (Russia)

Manufactured By

Generium, JSC (Russia)

Or

Generium-Next, LLC (Russia)

Packaging and Quality Control Release

Generium, JSC (Russia)

Or

Generium-Next, LLC (Russia)

ATC Code

L04AA25 (Eculizumab)

Active Substance

Eculizumab (Rec.INN registered by WHO)

Dosage Form

Elizaria®

Concentrate for solution for infusion 10 mg/1 ml: vial 30 ml 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear, colorless liquid.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate heptahydrate, sodium chloride, polysorbate 80, water for injections – up to 1 ml.

30 ml – glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressive agent

Pharmacological Action

Eculizumab suppresses the terminal activity of human complement, having a high affinity for its C5 component. As a result, the cleavage of the C5 component into C5a and C5b and the formation of the terminal complement complex C5b-9 are completely blocked. Thus, Eculizumab restores the regulation of complement activity in the blood and prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria. On the other hand, terminal complement deficiency is associated with an increased frequency of infections caused by encapsulated microorganisms, mainly meningococcal infection. At the same time, Eculizumab maintains the levels of early complement activation products necessary for the opsonization of microorganisms and the elimination of immune complexes.

Administration of the drug to patients is accompanied by a rapid and stable decrease in terminal complement activity. In most patients with paroxysmal nocturnal hemoglobinuria, a plasma eculizumab concentration of approximately 35 µg/ml is sufficient to completely inhibit intravascular hemolysis induced by terminal complement activation.

Pharmacokinetics

Human antibodies are broken down into small peptides and amino acids by the action of lysosomal enzymes in the cells of the reticuloendothelial system.

Due to its large molecular weight (148 kDa), Eculizumab is not excreted unchanged in the urine. The mean clearance is 0.31±0.12 ml/h/kg, the mean V_d is 110.3±17.9 ml/kg, and the mean T_1/2 is 11.3±3.4 days. Based on these data, a steady state is reached after 49-56 days.

The pharmacodynamic activity of eculizumab was directly proportional to its plasma concentration. When the plasma concentration of eculizumab was maintained at ≥35 µg/ml, almost complete blockade of hemolytic activity was observed in most patients.

Indications

Paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome.

ICD codes

Dosage Regimen

Administer as an intravenous infusion over 25-45 minutes.

Do not administer as an intravenous bolus injection.

The treatment course consists of an initial phase followed by a maintenance phase.

Initial phase: administer 600 mg once weekly for 4 weeks.

On week 5, administer a 900 mg dose.

Maintenance phase: administer 900 mg every 14 ± 2 days, starting two weeks after the last initial phase dose.

For pediatric patients with paroxysmal nocturnal hemoglobinuria, determine the dose based on body weight.

Monitor LDH activity every 12-16 days to assess hemolysis and guide dosing.

Dilute the concentrate only with 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose solution for injection.

Consider the sodium content (5.00 mmol per vial) for patients on a strict salt-restricted diet.

Adverse Reactions

Blood and lymphatic system disorders common – thrombocytopenia; uncommon – coagulopathy, erythrocyte agglutination.

Benign, malignant and unspecified neoplasms: uncommon – myelodysplastic syndrome, melanoma.

Cardiac disorders: uncommon – palpitations.

Vascular disorders: uncommon – hematoma, decreased blood pressure, hot flush.

Ear and labyrinth disorders: uncommon – tinnitus, dizziness.

Endocrine disorders: uncommon – hyperthyroidism.

Eye disorders: uncommon – conjunctival irritation, blurred vision.

Gastrointestinal disorders: common – abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting; uncommon – abdominal distension, gastroesophageal reflux, gum pain.

Metabolism and nutrition disorders: uncommon – decreased appetite, anorexia.

Hepatobiliary disorders: uncommon – jaundice.

Nervous system disorders: very common – headache; common – peripheral dizziness, dysgeusia, paresthesia; uncommon – syncope.

Respiratory, thoracic and mediastinal disorders: common – cough, nasal mucosal edema, pain in the larynx and pharynx; uncommon – hemoptysis, rhinorrhea.

Psychiatric disorders: uncommon – unusual dreams, anxiety, depression, insomnia, mood swings, sleep disorders.

Renal and urinary disorders: common – dysuria; uncommon – renal function impairment.

Skin and subcutaneous tissue disorders: common – alopecia, dry skin, pruritus, rash; uncommon – hyperhidrosis, petechiae, skin pigmentation disorder, skin eruptions.

Musculoskeletal and connective tissue disorders: common – arthralgia, back pain, myalgia, neck pain, pain in extremity; uncommon – bone pain, joint swelling, muscle spasms, trismus.

Infections and infestations: common – infections of the upper respiratory tract, gastrointestinal tract and urinary tract, including viral infections, oral herpes, sepsis, including meningococcal sepsis, septic shock; uncommon – lower respiratory tract infections, sinusitis, tooth and gum tissue infections, abscesses and subcutaneous tissue inflammation, fungal infections.

Immune system disorders: uncommon – allergic reactions.

Reproductive system and breast disorders: common – spontaneous penile erection; uncommon – menstrual cycle disorders.

General disorders and administration site conditions: common – chest discomfort, chills, asthenia, non-specific reactions at the injection site, edema, pyrexia; uncommon – chest pain, influenza-like illness, paresthesia at the injection site.

Investigations: uncommon – increased AST, increased alanine aminotransferase, increased gamma-glutamyltransferase.

Contraindications

Active infection or carriage of Neisseria meningitidis; lack of vaccination against Neisseria meningitidis; breastfeeding period.

With caution

Active systemic infections, impaired liver and kidney function.

Use in Pregnancy and Lactation

Use during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus.

It is recommended to discontinue breastfeeding during treatment and for 5 months after its completion.

Use in Hepatic Impairment

With caution: impaired liver function.

Use in Renal Impairment

With caution: impaired renal function.

Pediatric Use

For patients with paroxysmal nocturnal hemoglobinuria under 18 years of age, the dose is determined based on the child’s weight.

Geriatric Use

Can be prescribed to patients over 65 years of age. Elderly patients do not require a special dosage regimen or special precautions, although clinical experience in treating this age group is limited.

Special Precautions

Use should be under the supervision of a hematologist. Do not administer IV bolus!

The mechanism of action of the drug suggests an increased risk of developing meningococcal infection (Neisseria meningitidis) during its use. Any serotypes, including atypical ones, such as Y, W135 and X, can be considered pathogenic. To reduce the likelihood of infection, all patients should be vaccinated against meningococcus 2 weeks before use, and also revaccinated in accordance with the standards existing in the Russian Federation. A conjugated tetravalent vaccine against serotypes A, C, Y and W135 is most preferred. In some cases, vaccination does not provide sufficient protective effect. All patients should be informed about the early symptoms of meningococcal infection and the need to seek immediate medical attention.

Patients should be warned about the possibility of infection activation during treatment and its possible symptoms.

IV administration of the drug, as well as the administration of other protein drugs, may be accompanied by hypersensitivity reactions, including anaphylaxis. If a severe infusion reaction develops, the administration should be stopped and symptomatic therapy should be prescribed.

LDH activity should be determined every 12-16 days to monitor the severity of intravascular hemolysis and adjust the dose.

Patients for whom therapy with the drug has been discontinued should be under medical supervision to monitor the intensity of intravascular hemolysis.

For patients on a strict salt-free diet, it should be borne in mind that each vial contains 5.00 mmol of sodium.

Drug Interactions

Can only be mixed with 0.9% sodium chloride solution, 0.45% sodium chloride solution or 5% dextrose (glucose) solution for injection.

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.