HEMLIBRA

Emicizumab is a humanized recombinant monoclonal antibody that mimics the function of the coagulation Factor VIII and it has the capacity to bind simultaneously to activated Factor IX and Factor X. The ability of Emicizumab to bind to all these three different factors allows it to overcome immunogenicity and unstable hemostatic efficacy produced by previous Factor VII agents.

Emicizumab was originated as an improved form of hBS23 and it was approved on November 16, 2017. 1, 8 It was created by Chugai Pharmaceuticals Co.

The main function of

Emicizumab is the prevention of bleeding episodes.

Thus, Emicizumab is approved for the routine prophylaxis to prevent or reduce the frequency of bleeding episodes of adult and pediatric patients with hemophilia A with or without Factor VIII inhibitors.

Hemophilia A is a deficiency of coagulation Factor VIII which causes a serious bleeding disorder.

The standard treatment is done with the administration of recombinant or serum-deriver Factor VIII which induces the formation of anti-factor VIII alloantibodies (Factor VIII inhibitors) and renders the standard treatment ineffective.

Emicizumab mimics the function of coagulation factor VIII, therefore it binds to the activated form of Factor IX (Factor IXa).

This binding forms a complex that will later bind to the X factor of the coagulation factor.

The ability of

Emicizumab to interact with both factors (Factor IXa and Factor X) activates the coagulation cascade that will subsequently lead to the segmentation of fibrinogen into fibrin and the formation of blood clots.

The effect of

Emicizumab is translated into the restoration of the blood coagulation process and, therefore, in the reduction of hemorrhagic episodes.

The activity of emicizumab can also produce changes in activated clotting time (ACT), activated partial thromboplastin time (aPTT) and one-step Factor VIII activity.

In addition, the unique bispecific structure of Emicizumab prevents the formation of Factor VIII inhibitors or their effect.

In the first clinical trials, emicizumab was tried on previously treated adult and pediatric patients of hemophilia A with FVIII inhibitors.

In this trials, the annualized bleeding rate requiring treatment with coagulation factors was reduced by 87% when compared to untreated patients.

Those clinical trials were followed by a second round on previously treated patients of severe hemophilia A without FVIII inhibitors.

In this trial, the annualized bleed rate was reduced by 96% when compared to untreated patients.

Subcutaneous administration of

Emicizumab presents a very high bioavailability ranging from 80.4% to 93.1% when administered Subcutaneous in a dose of 1 mg/kg.

In clinical trials, at the same dose, Emicizumab presented a linear exposure which concentration peaked 1-2 weeks after administration and presented a profile framed by a Cmax of 5.92 mcg/ml and an AUC of 304 mcg day/ml.

After subcutaneous administration, the absorption half-life was 1.7 days and the pharmacokinetic profile seemed to be shared when the medication was administered in the abdomen, upper arm, and thigh.

The apparent volume of distribution is 11.4 L when administered Subcutaneous and there are reports indicating that this value can increase with increasing body weight.

When emicizumab is administered

Intravenous, the volume of distribution at steady state is 106 ml/kg.

Emicizumab is a monoclonal antibody and thus, it is thought to be internalized in endothelial cells bound to Fc receptor and rescued from metabolism by recycling.

Later, they are degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis.

The elimination of

Emicizumab was monophasic in clinical trials.

Emcicizumab presents a long half-life ranging from 27.8-34.4 days.

The apparent clearance is 0.24 L/day when administered in multiple subcutaneous injections and there are reports indicating that this value can increase with increasing body weight.

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The administration of

Emicizumab has reported cases of microangiopathy and thrombotic events with concomitant use of activated prothrombin complex concentrate at doses higher of 100 U/kg/24 hours.

There are also reports of injection site reaction, headaches and arthralgia.

Genotoxicity and carcinogenicity studies have not been performed as it is not expected that emicizumab can have any interaction with DNA, or chromosomal material.

Recommended loading dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by a maintenance dose of: 1.5 mg/kg once every week, or 3 mg/kg once every two weeks, or 6 mg/kg once every four weeks.

Information for important preparation and administration instructions. 2.1 Recommended Dosage For subcutaneous use only.

The recommended loading dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by a maintenance dose of: 1.5 mg/kg once every week, or 3 mg/kg once every two weeks, or 6 mg/kg once every four weeks.

The selection of a maintenance dose should be based on healthcare provider preference with consideration of regimens that may increase patient adherence.

Discontinue the prophylactic use of bypassing agents the day before starting HEMLIBRA prophylaxis.

The prophylactic use of factor

VIII (FVIII) products may be continued during the first week of HEMLIBRA prophylaxis.

Missed Dose If a dose of

HEMLIBRA is missed administer as soon as possible and then resume usual dosing schedule.

Do not administer two doses on the same day to make up for a missed dose. 2.2 Preparation and Administration HEMLIBRA is intended for use under the guidance of a healthcare provider.

After proper training in subcutaneous injection technique, a patient may self-inject, or the patient's caregiver may administer HEMLIBRA, if a healthcare provider determines that it is appropriate.

Self-administration is not recommended for children less than 7 years of age.

HEMLIBRA "Instructions for Use" contains more detailed instructions on the preparation and administration of HEMLIBRA.

Visually inspect

HEMLIBRA for particulate matter and discoloration before administration.

HEMLIBRA for subcutaneous administration is a colorless to slightly yellow solution.

Do not use if particulate matter is visible or product is discolored.

A syringe, a transfer needle with filter and an injection needle are needed to withdraw HEMLIBRA solution from the vial and inject it subcutaneously.

Refer to the

HEMLIBRA " Instructions for Use " for handling instructions when combining vials.

Do not combine

HEMLIBRA vials of different concentrations (i.e. 30 mg/mL and 150 mg/mL) in a single injection.

Please see below the selection criteria for the recommended device options: Administer doses of HEMLIBRA up to 1 mL with a 1 mL syringe.

A 1 mL syringe fulfilling the following criteria may be used: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip, graduation 0.01 mL, sterile, for injection only, single-use, latex-free and non-pyrogenic, commercially available in the US.

Administer doses of

HEMLIBRA greater than 1 mL and up to 2 mL with a 2 mL or 3 mL syringe.

A 2 mL or 3 mL syringe fulfilling the following criteria may be used: Transparent polypropylene or polycarbonate syringe with Luer-Lock tip, graduation 0.1 mL, sterile, for injection only, single-use, latex-free, and non-pyrogenic, commercially available in the US.

A transfer needle with a filter fulfilling the following criteria should be used: Stainless steel needle with Luer-Lock connection, sterile, 18 gauge, length to 1½ inch, single bevel or semi-blunted tip, single-use, latex-free, containing a 5-micron filter and non-pyrogenic, commercially available in the US.

An injection needle fulfilling the following criteria may be used: Stainless steel with Luer-Lock connection, sterile, 26 gauge (acceptable range: 25 – 27 gauge), length preferably ⅜ inch or maximal length ½ inch, single-use, latex-free and non-pyrogenic, including needle safety feature, commercially available in the US.

Administer each injection at a different anatomic location (upper outer arms, thighs, or any quadrant of abdomen) than the previous injection.

An injection should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

Administration of

HEMLIBRA in the upper outer arm should only be performed by a caregiver or healthcare provider.

Discard any unused

HEMLIBRA remaining in the single-dose vial.

HEMLIBRA (emicizumab-kxwh) injection is available as a sterile, preservative-free, colorless to slightly yellow solution in single-dose vials in the following dosage strengths: Strength Nominal Volume Concentration Package Size (per carton) Cap Color NDC 12 mg 0.4 mL 30 mg/mL 1 vial Grey 50242-927-01 30 mg 1 mL 30 mg/mL 1 vial Sky Blue 50242-920-01 60 mg 0.4 mL 150 mg/mL 1 vial Purple 50242-921-01 105 mg 0.7 mL 150 mg/mL 1 vial Turquoise 50242-922-01 150 mg 1 mL 150 mg/mL 1 vial Brown 50242-923-01 300 mg 2 mL 150 mg/mL 1 vial Yellow 50242-930-01 Storage and Handling Store HEMLIBRA vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

Do not shake.

Prior to administration, if needed, unopened vials of HEMLIBRA may be stored out of and then returned to refrigeration.

The temperature and total combined time out of refrigeration should not exceed 30°C (86°F) and 7 days (at a temperature below 30°C [86°F]), respectively.

Once removed from the vial, discard HEMLIBRA if not used immediately.

Discard any unused

HEMLIBRA vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

Do not shake.

Prior to administration, if needed, unopened vials of HEMLIBRA may be stored out of and then returned to refrigeration.

The temperature and total combined time out of refrigeration should not exceed 30°C (86°F) and 7 days (at a temperature below 30°C [86°F]), respectively.

Once removed from the vial, discard HEMLIBRA if not used immediately.

Discard any unused

Risk Summary There are no available data on HEMLIBRA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage.

Animal reproduction studies have not been conducted with emicizumab-kxwh.

It is not known whether

HEMLIBRA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

HEMLIBRA should be used during pregnancy only if the potential benefit for the mother outweighs the risk to the fetus.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

In the

U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively.

The safety and efficacy of

HEMLIBRA have been established in pediatric patients.

Use of HEMLIBRA in pediatric patients with hemophilia A is supported by two randomized trials (HAVEN and HAVEN 3) and two single-arm trials (HAVEN and HAVEN 4).

All clinical trials included pediatric patients in the following: 47 adolescents (12 years up to less than 18 years).

HAVEN 2 included pediatric patients in the following age groups: 55 children (2 years up to less than 12 years) and five infants (1 month up to less than 2 years).

No differences in efficacy were observed between the different age groups.

The steady-state plasma trough concentrations of emicizumab-kxwh were comparable in adult and pediatric patients older than 6 months at equivalent weight-based doses.

Lower concentrations of emicizumab-kxwh were predicted in pediatric patients less than 6 months old.

In general, the adverse reactions in HEMLIBRA-treated pediatric patients were similar in type to those seen in adult patients with hemophilia A.

Clinical studies of

HEMLIBRA did not include a sufficient number of patients aged and over to determine whether they respond differently from younger patients.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.