Hemlibra^® (Solution) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

Chugai Pharma Manufacturing, Co.Ltd. (Japan)

Or

Samsung Biologics, Co. Ltd. (Republic of Korea)

Packaging and Quality Control Release

F.Hoffmann-La Roche, Ltd (Switzerland)

Or

DOBROLEK, LLC (Russia)

ATC Code

B02BX06 (Emicizumab)

Active Substance

Emicizumab (Rec.INN registered by WHO)

Dosage Forms

	Hemlibra®	Solution for subcutaneous injection 30 mg/1 ml: vial 1 pc.
		Solution for subcutaneous injection 60 mg/0.4 ml: vial 1 pc.
		Solution for subcutaneous injection 105 mg/0.7 ml: vial 1 pc.
		Solution for subcutaneous injection 150 mg/1 ml: vial 1 pc.

Dosage Form, Packaging, and Composition

Solution for subcutaneous injection as a clear or opalescent, colorless to yellowish liquid.

Excipients : L-histidine – 3.1 mg, L-aspartic acid – to adjust pH to 6.0, L-arginine – 26.1 mg, poloxamer 188 – 0.5 mg, water for injections – to 1 ml.

1 ml – colorless glass vials (1) – cardboard packs^×.

^× A protective holographic sticker is applied to the packaging for first-opening control.
Protective first-opening control labels are applied to the pack (in case of packaging by DOBROLEK LLC).

Solution for subcutaneous injection as a clear or opalescent, colorless to yellowish liquid.

Excipients : L-histidine – 1.2 mg, L-aspartic acid – to adjust pH to 6.0, L-arginine – 10.5 mg, poloxamer 188 – 0.2 mg, water for injections – to 0.4 ml.

0.4 ml – colorless glass vials (1) – cardboard packs^×.

^× A protective holographic sticker is applied to the packaging for first-opening control.
Protective first-opening control labels are applied to the pack (in case of packaging by DOBROLEK LLC).

Solution for subcutaneous injection as a clear or opalescent, colorless to yellowish liquid.

Excipients : L-histidine – 2.2 mg, L-aspartic acid – to adjust pH to 6.0, L-arginine – 18.3 mg, poloxamer 188 – 0.4 mg, water for injections – to 0.7 ml.

0.7 ml – colorless glass vials (1) – cardboard packs^×.

^× A protective holographic sticker is applied to the packaging for first-opening control.
Protective first-opening control labels are applied to the pack (in case of packaging by DOBROLEK LLC).

Solution for subcutaneous injection as a clear or opalescent, colorless to yellowish liquid.

Excipients : L-histidine – 3.1 mg, L-aspartic acid – to adjust pH to 6.0, L-arginine – 26.1 mg, poloxamer 188 – 0.5 mg, water for injections – to 1 ml.

1 ml – colorless glass vials (1) – cardboard packs^×.

^× A protective holographic sticker is applied to the packaging for first-opening control.
Protective first-opening control labels are applied to the pack (in case of packaging by DOBROLEK LLC).

Clinical-Pharmacological Group

Monoclonal antibodies. Hemostatic agent

Pharmacotherapeutic Group

Hemostatic agents; vitamin K and other hemostatic agents; other systemic hemostatic agents

Pharmacological Action

Bispecific humanized monoclonal antibodies based on immunoglobulin G4 (IgG4), produced by Chinese hamster ovary cells using recombinant DNA technology.

Emicizumab binds activated factor IX with factor X to replace the function of the missing activated factor VIII, which is necessary for effective hemostasis.

Emicizumab has no structural similarity or homologous sequences with factor VIII (FVIII) and, accordingly, does not induce or enhance the formation of direct FVIII inhibitors.

Prophylaxis with emicizumab shortens aPTT and increases the FVIII activity level determined by the chromogenic method using other human coagulation factors.

These pharmacodynamic markers do not reflect the true hemostatic effect of emicizumab in vivo (aPTT is excessively shortened, the FVIII activity level may be overestimated), but they indicate the presence of a procoagulant effect of emicizumab.

Emicizumab can cause an immune response. The appearance of antibodies with neutralizing potential may be associated with loss of efficacy.

Pharmacokinetics

After subcutaneous administration, the absorption half-life in patients with hemophilia A was 1.6 days.

The mean (± standard deviation (SD)) minimum plasma concentrations of emicizumab reached 52.6±13.6 µg/ml at week 5 after multiple subcutaneous injections of emicizumab at a dose of 3 mg/kg once weekly in patients with hemophilia A. The mean C_ss values were 51.2 µg/ml, 46.9 µg/ml and 38.5 µg/ml when using emicizumab at a maintenance dose of 1.5 mg/kg once weekly, 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks, respectively.

In healthy volunteers, the absolute bioavailability after subcutaneous administration at a dose of 1 mg/kg ranged from 80.4% to 93.1% depending on the injection site. The pharmacokinetic profiles after subcutaneous administration of emicizumab into the abdomen, upper outer arm and thigh were similar. Emicizumab can be administered alternately into these areas.

In patients with hemophilia A after multiple subcutaneous injections, the apparent V_d, calculated according to population pharmacokinetic analysis data, was 10.4 L.

The metabolism of emicizumab has not been studied. IgG antibodies are predominantly catabolized by lysosomal proteolysis, then the antibody breakdown products (amino acids) are excreted or used by the body.

After a single subcutaneous administration to healthy volunteers, T_1/2 was approximately 4-5 weeks.

After multiple subcutaneous injections in patients with hemophilia A, the apparent clearance was 0.271 L/day, apparent T_1/2 – 26.9 days.

Emicizumab demonstrated dose-proportional pharmacokinetics in patients with hemophilia A after subcutaneous administration in the dose range of 0.3-6 mg/kg once weekly.

Indications

For routine prophylaxis to prevent or reduce the frequency of bleeding episodes: in hemophilia A (hereditary factor VIII deficiency) with factor VIII inhibitors; in severe hemophilia A (hereditary factor VIII deficiency, FVIII<1%) without factor VIII inhibitors.

ICD codes

Dosage Regimen

Administer the initial loading dose of 3 mg/kg subcutaneously once weekly for the first 4 weeks.

Select one of the following maintenance doses after the initial 4-week period.

Administer a maintenance dose of 1.5 mg/kg subcutaneously once weekly.

Alternatively, administer a maintenance dose of 3 mg/kg subcutaneously once every 2 weeks.

Alternatively, administer a maintenance dose of 6 mg/kg subcutaneously once every 4 weeks.

Base the choice of maintenance regimen on physician and patient/caregiver preference to ensure treatment adherence.

Rotate subcutaneous injection sites between the abdomen, thigh, and upper arm.

Calculate the dose based on the patient’s current body weight.

Select the appropriate vial strength to deliver the required volume accurately.

Do not mix with other medicinal products in the same syringe.

Visually inspect the solution for particulate matter and discoloration prior to administration.

Adverse Reactions

Nervous system disorders very common – headache.

Gastrointestinal system disorders: common – diarrhea.

Musculoskeletal system disorders very common – arthralgia; common – myalgia.

Skin and subcutaneous tissue disorders uncommon – skin necrosis.

Cardiovascular system disorders uncommon – superficial vein thrombophlebitis.

Blood and lymphatic system disorders uncommon – thrombotic microangiopathy (TMA).

Infectious and parasitic diseases : uncommon – cavernous sinus thrombosis.

General disorders common – pyrexia.

Local reactions very common – injection site reactions.

Contraindications

Hypersensitivity to emicizumab, pregnancy, breastfeeding period.

With caution

Severe renal impairment and severe hepatic impairment.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Use with caution in severe hepatic impairment.

Use in Renal Impairment

Use with caution in severe renal impairment.

Pediatric Use

The drug is approved for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

Patients receiving concomitant prophylaxis with emicizumab and activated prothrombin complex concentrate (aPCC) should be monitored for the development of TMA.

The treating physician should immediately discontinue aPCC and interrupt emicizumab therapy if clinical symptoms and/or laboratory parameters consistent with TMA occur, and provide treatment as clinically indicated. After complete resolution of TMA, the treating physician and the patient/caregiver should assess the benefit-risk ratio of resuming emicizumab prophylaxis.

In a clinical study, cases of thrombotic events were reported in patients receiving emicizumab prophylaxis when aPCC was administered at a median cumulative dose of >100 U/kg/24 h for >24 h. None of the cases required anticoagulant therapy, which is not typical for the usual management of thrombotic events. Signs of improvement or resolution of events were observed after discontinuation of aPCC.

Patients receiving concomitant prophylaxis with emicizumab and aPCC should be monitored for the development of thromboembolism. The treating physician should immediately discontinue aPCC and interrupt emicizumab therapy if clinical symptoms, imaging data and/or laboratory parameters consistent with thrombotic events occur, and provide treatment as clinically indicated. After complete resolution of the thrombotic event, the treating physician and the patient/caregiver should assess the benefit-risk ratio of resuming emicizumab prophylaxis.

Treatment with bypassing agents should be discontinued one day before starting emicizumab therapy.

Treating physicians should discuss the exact doses and schedule of administration of bypassing agents with all patients and/or caregivers if their use is required during emicizumab prophylaxis. The duration of treatment with bypassing agents and their dosing will depend on the location and volume of bleeding, as well as the clinical condition of the patient.

The use of aPCC should be avoided, except when other treatment options/alternative agents are not available. If a patient receiving emicizumab prophylaxis requires the use of aPCC, its dose and administration regimen are determined individually by the physician and depend on the clinical situation.

Due to the long T_1/2 of emicizumab, the effect on blood coagulation test results may persist for up to 6 months after the last dose is administered.

Drug Interactions

Clinical experience indicates the existence of a drug interaction between emicizumab and activated prothrombin complex concentrate (aPCC).

When recombinant activated factor VII (rFVIIa) or FVIII is used concomitantly with emicizumab, there is a possibility of hypercoagulability. Emicizumab increases the blood’s ability to clot, thus the dose of clotting factor required to achieve hemostasis may be lower than without emicizumab prophylaxis.

Emicizumab replaces the cofactor activity of the missing activated factor VIII (FVIIIa) in the tenase complex.

In laboratory coagulation tests based on the intrinsic pathway of coagulation (e.g., aPTT measurement), the total clotting time is determined, which includes the time required for activation of FVIII (formation of FVIIIa) by thrombin. When emicizumab is used, activation by thrombin is not required, so the result of such tests will be an excessively shortened clotting time. The excessively shortened clotting time (via the intrinsic pathway) will subsequently distort the results of all tests based on aPTT and intended to determine one of the blood coagulation factors, such as the one-stage FVIII activity assay.

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.