Hemlibra®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEMLIBRAÒ (HEMLIBRAÒ)

Composition:

Active substance: emicizumab;

1 vial contains 12 mg/0.4 mL or 30 mg/1 mL or 60 mg/0.4 mL or 105 mg/0.7 mL or 150 mg/1 mL of emicizumab;

Excipients: L-histidine, L-aspartic acid, L-arginine, poloxamer 188, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: sterile, clear liquid, colorless to slightly yellowish, without preservatives.

Pharmacotherapeutic group.

Agents affecting the blood and hematopoietic system. Antihemorrhagic agents. Vitamin K and other hemostatic agents. Other hemostatic agents for systemic use. Emicizumab.

ATC code B02B X06.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Hemlibra® binds activated factor IX and factor X, restoring the deficient function of activated factor VIII, which is necessary for effective hemostasis.

Pharmacokinetics.

Emicizumab demonstrated dose-proportional pharmacokinetics following subcutaneous administration over a dose range of 0.3 mg/kg (0.1 of the approved recommended loading dose) to 6 mg/kg. After multiple subcutaneous injections of emicizumab at a loading dose of 3 mg/kg once weekly for the first 4 weeks, the mean (± SD) trough plasma concentration of emicizumab was 52.6 ± 13.6 µg/mL, achieved by week 5. Information on steady-state mean (± SD) plasma concentrations of emicizumab with recommended maintenance doses is presented in Table 1.

Table 1

Mean (± SD) steady-state concentrations following the emicizumab loading dose depending on the maintenance regimen

AUCss,τ – area under the plasma concentration-time curve at steady state over the dosing interval (τ = 1, 2 or 4 weeks); Cmax,ss – maximum plasma concentration of the drug at steady state; Cmin,ss – minimum plasma concentration of the drug at steady state.

Absorption

After subcutaneous administration, mean (± SD) absorption half-life values were 1.6 ± 1 day. Absolute bioavailability following subcutaneous administration at a dose of 1 mg/kg ranged from 80.4% to 93.1%. Similar pharmacokinetic profiles were observed after subcutaneous administration in the abdominal area, arm, and thigh (see section "Method of administration and dosage").

Distribution

Mean apparent volume of distribution (% coefficient of variation [%CV]) was 10.4 L (26%).

Elimination

Mean apparent clearance (%CV) was 0.27 L/day (28.4%), and mean apparent elimination half-life (± SD) was 26.9 ± 9.1 days.

Special populations

The pharmacokinetics of emicizumab are not affected by patient age (1 to 77 years), race (Caucasian – 62.7%, Mongoloid – 22.9%, and Negroid – 8%), inhibitor status (inhibitors present in 50%), mild hepatic impairment (defined as total bilirubin levels 1–1.5 times above the upper limit of normal (ULN), any level of aspartate aminotransferase (AST)), moderate hepatic impairment (defined as total bilirubin levels 1.5–3 times above ULN and any level of AST), mild renal impairment (defined as creatinine clearance of 60–89 mL/min), or moderate renal impairment (defined as creatinine clearance of 30–59 mL/min). The use of emicizumab in patients with severe hepatic or renal impairment has not been studied.

In children under 6 months of age, predicted emicizumab concentrations were 19–33% lower than in older patients, particularly when receiving a maintenance dose of 3 mg/kg body weight every 2 weeks or 6 mg/kg body weight every 4 weeks.

Children

The efficacy and safety of Hemlibra® in children have been established. The use of Hemlibra® in children with hemophilia A is supported by results from two randomized trials (HAVEN 1 and HAVEN 3) and two non-comparative trials (HAVEN 2 and HAVEN 4). Across all clinical trials, only one age group of children was included: 47 adolescents aged 12 to 18 years. Only in the HAVEN 2 trial were children from multiple age groups included – 55 children aged 2 to 12 years and 5 children aged 1 month to 2 years. No differences in drug efficacy were observed among children of different age groups.

Minimum steady-state plasma concentrations of emicizumab were comparable in adults and children aged 6 months and older receiving body weight-adjusted equivalent doses. Lower emicizumab concentrations are expected in children under 6 months of age.

Body weight. Apparent clearance and volume of distribution of emicizumab increased with increasing body weight (from 9 to 156 kg). Dosing in milligrams per kilogram (mg/kg) provides similar emicizumab exposures across the entire range of body weights.

Immunogenicity

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods may hinder meaningful comparisons of antibody formation rates between the studies described below and other studies, including those involving Hemlibra® or other emicizumab products.

Based on clinical trial data for Hemlibra®, anti-emicizumab antibodies were detected in 5.1% of patients (34/668). Participants received emicizumab for a median interquartile range (IQR) of 103.1 (82.4–148.1) weeks. Samples for anti-drug antibody testing were collected at the start of treatment and periodically throughout the study.

Impact of anti-drug antibodies on pharmacokinetics

Antibody-positive samples were further tested for neutralizing anti-emicizumab antibodies using a modified chromogenic FVIII assay. Overall, 668 patients were tested for anti-emicizumab antibodies. Anti-emicizumab antibodies were detected in 5.1% of patients (34/668), and neutralizing antibodies developed in 2.7% of patients (18/668) in vitro. Among these 2.7% (18/668), neutralizing anti-emicizumab antibodies had no clinically significant impact on the pharmacokinetics of Hemlibra® in 2.1% of patients (14/668), whereas decreased emicizumab plasma concentrations were observed in 0.6% of patients (4/668).

Impact of anti-drug antibodies on pharmacodynamics

One patient (1/668; 0.1%) developed neutralizing anti-emicizumab antibodies, resulting in reduced emicizumab plasma concentrations and subsequent loss of efficacy (manifested as breakthrough bleeding) 5 weeks after starting treatment. Treatment with Hemlibra® in this patient was discontinued prematurely (see section "Special precautions").

Clinical characteristics.

Indications.

Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children from birth onwards with haemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors.

Contraindications.

Hypersensitivity to emicizumab or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

Interaction studies with other medicinal products

No studies of interactions between Hemlibra® and other medicinal products have been conducted.

Hypocoagulation with concomitant use of aPCC

Clinical experience indicates that there is an interaction between Hemlibra® and activated prothrombin complex concentrate (aPCC) (see section "Special warnings and precautions for use").

Effect of the medicinal product on laboratory test results

Hemlibra® restores the activity of activated factor VIII (aFVIII) cofactor. Laboratory tests assessing the intrinsic pathway of coagulation cascade activation (e.g., activated partial thromboplastin time (aPTT)) measure overall clotting time, including the time required for thrombin-mediated activation of FVIII to aFVIII, and thus yield an artificially shortened clotting time when Hemlibra® is administered, as thrombin activation is no longer required. This artificially shortened intrinsic clotting time will continue to affect the results of all one-stage factor assays based on aPTT, including one-stage factor VIII activity assays. However, one-stage assays using chromogenic or immunological methods are not influenced by Hemlibra® and may be used for monitoring coagulation parameters during treatment, with important caveats regarding chromogenic factor VIII activity assays as described below.

Chromogenic factor VIII activity assays may be manufactured using either human or bovine coagulation proteins. Assays containing human coagulation factors are sensitive to Hemlibra® but may overestimate the clinical haemostatic potential of Hemlibra®. In contrast, assays based on bovine coagulation factors are insensitive to Hemlibra® (activity is not measured) and can be used to monitor endogenous or infused factor VIII activity, as well as to determine inhibitors against FVIII.

Hemlibra® retains activity in the presence of factor VIII inhibitors, which may lead to falsely negative results in the Bethesda assay for functional inhibition of FVIII using clotting methods. In contrast, the chromogenic Bethesda assay using bovine FVIII, which is insensitive to Hemlibra®, may be used instead.

Due to the long half-life of Hemlibra®, its effect on coagulation parameters may persist for up to 6 months after the last dose (see section "Pharmacological properties").

Special precautions for use.

Thrombotic microangiopathy associated with HEMLIBRA® and activated prothrombin complex concentrate (aPCC)

Cases of thrombotic microangiopathy (TMA) have been reported in patients receiving prophylactic doses of HEMLIBRA® when activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more at a mean cumulative dose > 100 IU/kg/24 hours. In clinical studies, TMA was reported in 0.8% of patients (3 out of 391) and in 8.1% of patients (3 out of 37) who received at least one dose of aPCC. In the ADAMTS13 assay, patients exhibited thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury without signs of overt thrombosis.

Clinical improvement was observed within one week after discontinuation of aPCC. One patient continued HEMLIBRA® treatment after resolution of TMA.

For patients receiving prophylactic treatment with HEMLIBRA®, the benefits and risks should be carefully weighed if administration of aPCC is required. Due to the long half-life of HEMLIBRA®, the potential for interaction with aPCC may persist for up to 6 months after the last dose. Monitoring for the development of TMA is recommended during aPCC administration. Treatment with aPCC should be discontinued immediately and prophylaxis with HEMLIBRA® should be interrupted if clinical and/or laboratory signs suggestive of TMA occur; appropriate treatment should be initiated based on clinical judgment. The potential benefits and risks of continuing HEMLIBRA® prophylaxis after resolution of TMA should be evaluated on a case-by-case basis.

Thromboembolic events associated with HEMLIBRA® and aPCC

Cases of thrombosis have been reported in patients receiving prophylactic doses of HEMLIBRA® when aPCC was administered for 24 hours or more at a mean cumulative dose > 100 IU/kg/24 hours. In clinical studies, thrombotic events were reported in 0.5% of patients (2 out of 391) and in 5.4% of patients (2 out of 37) who received at least one dose of aPCC.

No thrombotic event required anticoagulant therapy. Signs of improvement or recovery were observed within one week after discontinuation of aPCC. One patient continued HEMLIBRA® treatment after resolution of thrombosis.

For patients receiving prophylactic treatment with HEMLIBRA®, the benefits and risks should be carefully weighed if aPCC administration is required. Due to the long half-life of HEMLIBRA®, the potential for interaction with aPCC may persist for up to 6 months after the last dose. Monitoring for thromboembolic events is recommended during aPCC administration. Treatment with aPCC should be discontinued immediately and prophylaxis with HEMLIBRA® should be interrupted if clinical symptoms, imaging findings, or laboratory signs suggestive of thromboembolism occur; appropriate treatment should be initiated based on clinical judgment. The potential benefits and risks of continuing HEMLIBRA® prophylaxis after resolution of a thrombotic event should be evaluated individually in each case.

Immunogenicity

Treatment with HEMLIBRA® may induce the formation of antibodies against the drug. Anti-emictuzumab antibodies were reported in 5.1% of patients (34 out of 668) treated with HEMLIBRA® in clinical studies. Most patients with anti-emictuzumab antibodies did not experience changes in HEMLIBRA® plasma concentrations or increased bleeding episodes; however, in rare cases (<1% prevalence), the presence of neutralizing antibodies with reduced plasma concentrations may be associated with loss of efficacy (see section "Pharmacokinetics").

Patients should be monitored for clinical signs of loss of efficacy (i.e., increased breakthrough bleeding). If such signs occur, the cause should be promptly evaluated and consideration should be given to changing the treatment regimen if neutralizing antibodies to emicizumab are suspected.

Effect on coagulation test results

HEMLIBRA® affects laboratory tests of the intrinsic pathway of coagulation cascade activation, including activated clotting time (ACT), activated partial thromboplastin time (aPTT), and all assays based on aPTT, including one-stage factor VIII (FVIII) activity assays (Table 2). Therefore, coagulation tests of the intrinsic pathway using clotting-based methods should not be used for monitoring HEMLIBRA® activity, dose adjustment for replacement therapy, anticoagulation monitoring, or FVIII inhibitor titration in patients receiving HEMLIBRA® (see section "Interaction with other medicinal products and other forms of interaction"). Coagulation tests affected and not affected by HEMLIBRA® are listed in Table 2.

Table 2

Coagulation test results affected and not affected by HEMLIBRA®

* For important information on the determination of FVIII activity by chromogenic method, see section "Interaction with other medicinal products and other forms of interaction".

Use during pregnancy or breastfeeding.

Pregnancy

There are no available data on the risk of major congenital malformations or miscarriage associated with the use of Hemlibra® in pregnant women. Reproductive studies with emicizumab in animals have not been conducted. It is not known whether Hemlibra® can cause fetal harm or affect reproductive capacity when administered to pregnant women. Hemlibra® may be used during pregnancy only if the potential benefit to the woman outweighs the potential risk to the fetus.

For any pregnancy, there is a background risk of congenital malformations, fetal loss, or other adverse outcomes. The estimated background risk of major congenital malformations or miscarriage in the target populations is unknown. In the general US population, the estimated risk of major congenital malformations or miscarriage during clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Breastfeeding

There is no information available on the excretion of emicizumab into human breast milk, its potential effect on the breastfed child, or its effect on milk production. It is known that human IgG is present in human breast milk. The benefits of breastfeeding for child development and health should be weighed against the mother's clinical need for Hemlibra®, the potential for adverse effects in the breastfed child, and the mother's overall health condition.

Contraception

Women of reproductive potential should use contraceptive methods during treatment with Hemlibra®.

Ability to influence reaction speed when driving or operating machinery.

There are no data indicating that treatment with Hemlibra® leads to an increased incidence of adverse reactions that could impair the ability to drive or operate machinery.

Method of Administration and Dosage

For subcutaneous use only.

The recommended loading dose is 3 mg/kg body weight, administered subcutaneously once weekly for the first 4 weeks. After this period, the drug should be administered at one of the following maintenance doses:

• 1.5 mg/kg body weight once weekly, or
• 3 mg/kg body weight once every two weeks, or
• 6 mg/kg body weight once every four weeks.

The choice of maintenance dose should be based on the preference of the healthcare provider, considering regimens that may improve patient adherence to the treatment schedule.

Prophylactic use of bypassing agents should be discontinued one day prior to initiating prophylactic treatment with Hemlibra®.

Prophylactic administration of factor VIII (FVIII) products may continue during the first week of prophylactic treatment with Hemlibra®.

Missed Dose

If a dose of Hemlibra® is missed, it should be administered as soon as possible, followed by resumption of the regular dosing schedule. Do not administer two doses on the same day to compensate for a missed dose.

Special Dosage Recommendations

Children

Dose adjustment in children is not recommended. There are no data available from clinical studies in infants under 1 year of age.

Elderly Patients

Clinical studies of Hemlibra® included an insufficient number of patients aged 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in response between elderly and younger patients.

Preparation and Administration

Hemlibra® is intended for use under the supervision of a physician. After appropriate training in subcutaneous injection techniques, a patient may self-administer the injection or have it administered by a caregiver, if deemed appropriate by the physician. Self-administration is not recommended for children under 7 years of age.

Detailed instructions for preparation and administration of Hemlibra® are provided below (see section "Instructions for Use").

Before administration, visually inspect Hemlibra® for the presence of particulate matter or discoloration. Hemlibra® for subcutaneous administration is a solution ranging from colorless to slightly yellow. Do not use the product if visible particles are present or if discoloration occurs.

To withdraw Hemlibra® from the vial and administer it subcutaneously, a syringe, a filtered transfer needle, and an injection needle are required.

Refer to the section "Instructions for Use" below for guidance on handling Hemlibra® when multiple vials are used in combination.

Do not mix Hemlibra® from vials with different concentrations (i.e., 30 mg/mL and 150 mg/mL) in the same injection.

See below for criteria for selecting the recommended medical device. Hemlibra® doses up to 1 mL should be administered using a 1 mL syringe. A 1 mL syringe meeting the following criteria may be used: clear polypropylene or polycarbonate syringe with a Luer-Lock tip (if unavailable, a Luer-Slip tip syringe may be used), graduated in 0.01 mL increments, sterile, for injection use only, single-use, latex-free, and pyrogen-free.

Hemlibra® injections with volumes from 1 mL to 2 mL should be administered using 2 mL or 3 mL syringes meeting the following criteria: clear polypropylene or polycarbonate syringe with a Luer-Lock tip (if unavailable, a Luer-Slip tip syringe may be used), graduated in 0.1 mL increments, sterile, for injection use only, single-use, latex-free, and pyrogen-free.

A filtered transfer needle meeting the following criteria must be used: stainless steel needle with Luer-Lock connection (if unavailable, a Luer-Slip connection may be used), sterile, 18G, 1 to 1½ inches in length, with a single-bevel or blunt (or semi-blunt) tip, single-use, latex-free, equipped with a 5-micron filter, and pyrogen-free.

An injection needle meeting the following criteria may be used: stainless steel needle with Luer-Lock connection (if unavailable, a Luer-Slip connection may be used), sterile, 26G (acceptable range: 25–27G), preferably 3/8 inch in length with a maximum of ½ inch, single-use, latex-free, pyrogen-free, and equipped with a safety shield.

Each new injection of Hemlibra® should be administered at a different anatomical site (outer aspect of the upper arm, thigh, or any abdominal quadrant), distinct from the site used for the previous injection. Do not administer injections into moles, scars, or into tender, bruised, erythematous, hardened, or damaged skin areas. Subcutaneous injection into the outer aspect of the upper arm should be performed only by a caregiver or healthcare professional.

Any unused portion of Hemlibra® remaining in a single-use vial should be discarded.

Storage of Hemlibra®:

• Store Hemlibra® at 2–8°C in the original packaging to protect from light. Do not freeze. Do not shake.
• Prior to injection, unopened vials of Hemlibra® may be removed from and returned to the refrigerator. The temperature and total cumulative time Hemlibra® is stored outside the refrigerator must not exceed 30°C and 7 days (at temperatures up to 30°C).
• After drawing into a syringe, any unused Hemlibra® remaining in the vial must be discarded if not used immediately.

Instructions for Use

Inspection of Hemlibra® and Components of the Supply Kit

• Gather all components listed below to prepare and administer the injection.

• Check the expiration date on the carton, vial label, and supply kit as indicated below. Do not use the product or the components listed below if this date has passed.

• Do not use the product if:

  • the medicinal product is cloudy, opaque, or deeply colored;
  • the medicinal product contains particles;
  • the cap over the stopper is missing.

• Inspect the supply kit components for damage. Do not use if components are damaged or have been dropped on the floor.

• Place the supply kit components on a clean, well-lit, flat working surface.

Preparing the syringe for injection

• Do not store Hemlibra® in the syringe.
• Hemlibra® in the syringe must be administered immediately by subcutaneous injection.

Important information on post-injection care:

• Do not rub the injection site after administration.
• If there is any bleeding at the injection site, apply a sterile cotton ball or gauze and press firmly for at least 10 seconds until bleeding stops.
• If a hematoma (a small area of bruising under the skin) develops, you may also apply an ice pack to the injection site, pressing it gently. If bleeding does not stop, please contact your doctor.

Disposal of used Hemlibra® vials, needles, and syringes

Important: Always store the sharps disposal container out of the reach of children.

• Immediately after use, place used needles and syringes into a sharps disposal container. Do not dispose of any open needles or syringes with household waste.
• If you do not have a sharps disposal container, you may use a household container that:
  • is made of heavy-duty plastic;
  • has a tight-fitting, puncture-resistant lid to prevent leakage of sharp objects;
  • is stable and can stand upright during use;
  • is leak-proof;
  • is clearly labeled to indicate the presence of hazardous waste inside.
• When your sharps disposal container is nearly full, follow local guidelines for proper disposal of the sharps container.
• Do not dispose of any used sharps container with household waste unless permitted by local regulations. Do not reuse your sharps disposal container.

Step-by-step instructions for administering Hemlibra® injection

• Hold the syringe by the barrel with the transfer needle pointing upward.
• Carefully pull the transfer needle cap away from you (see Fig. 16). Do not discard the cap. Place the transfer needle cap on a clean, flat surface. After withdrawing the medication solution, the cap must be replaced back onto the transfer needle.
• Do not touch the tip of the needle and do not place it on any surface after removing the cap. || Step 4. Insert air into the vial | |

| * Place the vial on a flat working surface and insert the transfer needle with syringe straight down through the center of the vial stopper (see Fig. 17). |

• Move the protective shield forward 90º in the direction away from the syringe barrel. * Holding the syringe in one hand, press the protective shield downward firmly and confidently onto the broad surface until a click is heard (see Fig. 32). ||

| * If you did not hear a click, check whether the needle is completely covered by the protective shield (see Fig. 33). * Always keep your fingers behind the protective shield and away from the needle. * Do not detach the injection needle from the syringe. |

Step 17. Dispose of (discard) the used syringe and needle (see Fig. 34)

• Remove the syringe and transfer needle from the first vial. * With one hand, insert the transfer needle into the cap and direct it upward so that the cap covers the needle (see Fig. 35). * As soon as the cap covers the transfer needle, with one hand guide it toward the syringe to securely close it and prevent accidental needlestick injury. | || Step B. Remove the transfer needle | | | |

| | * Hold the new vial on a flat working surface and insert the new transfer needle with the syringe centrally into the vial stopper in a downward direction (see Fig. 39). | | |

| | | * Keep the transfer needle in the vial and turn the vial upside down (see Fig. 40). | | |

| | | * With the needle pointing upward, inject air from the syringe into the vial above the solution. * Continue pressing with your finger on the syringe plunger (see Fig. 41). * Do not inject air into the solution, as this may cause air bubbles or foam in the product. | | | Step F. Draw Hemlibra® into the syringe | | | | | |

| | * Position the tip of the needle downward so that it is inside the solution. * Slowly pull back on the plunger, avoiding formation of air bubbles or foam. Fill the syringe with more than the required amount for the prescribed dose (see Fig. 42). * Be careful: do not pull the plunger out of the syringe. Note: Before proceeding to the next steps, ensure that sufficient Hemlibra® is drawn into the syringe to deliver the full dose. If not all Hemlibra® can be drawn, return the vial to an upright position to access the remaining solution. | | | | Do not use the transfer needle for administering Hemlibra® injection, as this may cause injury such as pain and bleeding. | | | | | | | Repeat steps A–F for each additional vial until more than the required amount for the prescribed dose of Hemlibra® is obtained. After completing these steps, leave the transfer needle in the vial and return to Step 6. Continue with the remaining steps (Steps 7–17). | | | | | | | | | |

Children.

Hemlibra® should be administered to children according to the instructions provided in the section "Dosage and Administration".

Overdose.

Experience with Hemlibra® overdose is limited. Accidental overdose may lead to hypercoagulability.

In case of accidental overdose, seek immediate medical advice and remain under medical supervision.

Adverse Reactions

The following serious adverse reactions are described in other sections of the instruction:

• Thrombotic microangiopathy associated with the use of HEMLIBRA® and activated prothrombin complex concentrate (aPCC) (see section "Special Warnings and Precautions for Use").
• Thromboembolism associated with the use of HEMLIBRA® and activated prothrombin complex concentrate (aPCC) (see section "Special Warnings and Precautions for Use").

Clinical Trial Data

Because clinical trials are conducted under widely varying conditions, the frequency of adverse reactions observed in the clinical trials of a drug cannot be directly compared with the frequency in the clinical trials of another drug and may not reflect the frequency observed in practice.

Overall, adverse reactions in children treated with HEMLIBRA® were similar in type to those observed in adult patients with hemophilia A.

The adverse reactions listed below are based on pooled data from two randomized trials in adults and adolescents (HAVEN 1 and HAVEN 3), one single-arm trial in adults and adolescents (HAVEN 4), one single-arm trial in children (HAVEN 2), and a dose-finding trial, in which a total of 391 male individuals with hemophilia A received at least one dose of HEMLIBRA® for routine prophylaxis. Of these, 281 patients (72%) were adults aged 18 years and older, 50 (13%) were adolescents aged 12 to 18 years, 55 (14%) were children aged 2 to 12 years, and 5 patients (1%) were children aged 1 month to 2 years. The median duration of treatment across all studies was 34.1 weeks (range: 0.1–224.4 weeks).

The most commonly reported adverse reactions observed in ≥10% of patients treated with HEMLIBRA® were injection site reactions, headache, and arthralgia.

Four patients (1%) in the clinical trials receiving HEMLIBRA® prophylaxis discontinued treatment due to adverse reactions, including thrombotic microangiopathy, skin necrosis, superficial vein thrombophlebitis, headache, and injection site reactions.

Table 3

Adverse reactions reported in ≥5% of patients based on pooled clinical trial data for HEMLIBRA®

* Include injection site bruising, injection site discomfort, injection site erythema, injection site hematoma, injection site induration, injection site pain, injection site pruritus, injection site rash, injection site reactions, injection site swelling, injection site urticaria, and injection site warmth.

Characteristics of aPCC treatment in all clinical studies

During aPCC treatment, 130 cases were observed in 36 patients, of which 37 cases (10%) involved aPCC administration at a mean cumulative dose > 100 IU/kg/24 hours for 24 hours or longer; two out of 13 cases were associated with thrombotic events and three out of 13 cases were associated with TMA (Table 5). In the remaining cases, thrombotic events and TMA were not observed during aPCC treatment.

Table 4

Characteristics of aPCC treatment* in all clinical studies

* A case of FVIII exposure is defined as all FVIII doses received by a patient for any reason and within a 36-hour treatment gap.

a Thrombotic event.

b Thrombotic microangiopathy.

Description of selected adverse reactions

Injection site reactions

Overall, injection site reactions (ISRs) were reported in 85 patients (22%). All ISRs observed during clinical studies with Hemlibra^® were mild to moderate in intensity, and 93% resolved without treatment. The most frequently reported ISRs were injection site erythema (11%), injection site pruritus (4%), and injection site pain (4%).

Other less common (< 1%) reactions

Rhabdomyolysis

Rhabdomyolysis was reported in two adult patients who had asymptomatic elevations in serum creatine kinase levels without associated renal or musculoskeletal symptoms. In both cases, rhabdomyolysis occurred following increased physical activity.

Post-marketing experience

The following adverse reactions have been identified during post-marketing use of Hemlibra^®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: rash, urticaria, angioedema.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life

24 months.

Storage conditions

Store at 2 to 8°C in the original packaging to protect from light. Do not freeze. Do not shake. Keep out of reach of children.

Incompatibilities

No incompatibility of Hemlibra^® with the recommended syringes and needles has been observed.

Packaging

12 mg/0.4 mL, or 30 mg/1 mL, or 60 mg/0.4 mL, or 105 mg/0.7 mL, or 150 mg/1 mL in a vial.

One vial per carton.

Prescription status

Prescription only.

Manufacturer

F. Hoffmann-La Roche Ltd

Manufacturer's name and address of the place of business:

Wurmisweg, 4303 Kaiseraugst, Switzerland