Hemlibra 30 mg/mL solution for injection
Hemlibra 150 mg/mL solution for injection
Hemlibra 30 mg/mL solution for injection
Each mL of solution contains 30 mg of emicizumab*
Each vial of 1 mL contains 30 mg of emicizumab at a concentration of 30 mg/mL.
Hemlibra 150 mg/mL solution for injection
Each mL of solution contains 150 mg of emicizumab*
Each vial of 0.4 mL contains 60 mg of emicizumab at a concentration of 150 mg/mL.
Each vial of 0.7 mL contains 105 mg of emicizumab at a concentration of 150 mg/mL.
Each vial of 1 mL contains 150 mg of emicizumab at a concentration of 150 mg/mL.
* produced by recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture
For the full list of excipients, see section 6.1
Solution for injection.
Colourless to slightly yellow solution.
Hemlibra is indicated for routine prophylaxis of bleeding episodes in patients with haemophilia A with factor VIII inhibitors.
Hemlibra can be used in all age groups.
Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia and/or bleeding disorders.
Posology
Treatment (including routine prophylaxis) with bypassing agents (e.g. aPCC and rFVIIa) should be discontinued the day before starting Hemlibra therapy (see section 4.4).
The recommended dose is 3 mg/kg once weekly for the first 4 weeks (loading dose), followed by 1.5 mg/kg once weekly (maintenance dose), administered as a subcutaneous injection.
The patient dose (in mg) and volume (in mL) should be calculated as follows:
● Loading dose (3 mg/kg) once weekly for the first 4 weeks:
Patient bodyweight (kg) x dose (3 mg/kg) = total amount (mg) of emicizumab to be administered
● Followed by a maintenance dose (1.5 mg/kg) once weekly from week 5 on:
Patient bodyweight (kg) x dose (1.5 mg/kg) = total amount (mg) of emicizumab to be administered
The total volume of Hemlibra to be injected subcutaneously is calculated as follows:
Total amount (mg) of emicizumab to be administered ÷ vial concentration (mg/mL) = total volume of Hemlibra (mL) to be injected.
Different Hemlibra concentrations (30 mg/mL and 150 mg/mL) should not be combined when making up the total volume to be administered.
A volume greater than 2 mL per injection should not be administered.
Examples:
Patient's bodyweight of 60 kg:
● Loading dose (first 4 weeks) example: 60 kg x 3 mg/kg = 180 mg of emicizumab needed for the loading dose.
● To calculate the volume to be administered divide calculated dose 180 mg by 150 mg/mL: 180 mg of emicizumab ÷ 150 mg/mL = 1.20 mL of 150 mg/mL Hemlibra concentration to be injected.
● Choose appropriate dosage and volume from vial strengths available.
● Maintenance dose (from week 5 on) example: 60 kg x 1.5 mg/kg = 90 mg of emicizumab needed for the maintenance dose.
● To calculate the volume to be administered divide calculated dose 90 mg by 150 mg/mL: 90 mg of emicizumab ÷ 150 mg/mL = 0.6 mL of 150 mg/mL Hemlibra concentration to be injected.
● Choose appropriate dosage and volume from vial strengths available.
Patient's bodyweight of 16 kg:
● Loading dose (first 4 weeks) example: 16 kg x 3 mg/kg = 48 mg of emicizumab needed for the loading dose.
● To calculate the volume to be administered divide calculated dose 48 mg by 150 mg/mL: 48 mg of emicizumab ÷ 150 mg/mL = 0.32 mL of 150 mg/mL Hemlibra concentration to be injected.
● Choose appropriate dosage and volume from vial strengths available.
● Maintenance dose (from week 5 on) example: 16 kg x 1.5 mg/kg = 24 mg of emicizumab needed for the maintenance dose.
● To calculate the volume to be administered divide calculated dose 24 mg by 30 mg/mL: 24 mg of emicizumab ÷ 30 mg/mL = 0.8 mL of 30 mg/mL Hemlibra concentration to be injected.
● Choose appropriate dosage and volume from vial strength available.
Duration of treatment
Hemlibra is intended for long-term prophylactic treatment.
Dosage adjustments during treatment
No dosage adjustments of Hemlibra are recommended.
Delayed or missed doses
If a patient misses a scheduled weekly subcutaneous injection of Hemlibra, the patient should be instructed to take the missed dose as soon as possible, up to a day before the day of the next scheduled dose. The patient should then administer the next dose on the usual scheduled dosing day. The patient should not take a double dose to make up for a missed dose.
Special populations
Paediatric
No dose adjustments are recommended in paediatric patients (see section 5.2). There are no data in patients less than 1 year of age.
Elderly
No dose adjustments are recommended in patients ≥ 65 years of age (see section 5.2). There are no data in patients over 75 years old.
Renal and hepatic impairment
No dose adjustments are recommended in patients with mild renal or mild and moderate hepatic impairment (see section 5.2). Emicizumab has not been studied in patients with moderate or severe renal impairment or severe hepatic impairment
Management in the perioperative setting
The safety and efficacy of emicizumab have not been formally eva luated in the surgical setting. If bypassing agents (e.g. aPCC and rFVIIa) are required in the perioperative period, please refer to the dosing guidance on the use of bypassing agents in section 4.4.
Immune tolerance induction (ITI)
The safety and efficacy of emicizumab in patients receiving ongoing immune tolerance induction have not yet been established. No data are available.
Method of administration
Hemlibra is for subcutaneous use only, and it should be administered using appropriate aseptic technique (see section 6.6).
The injection should be restricted to the recommended injection sites: the abdomen, the upper outer arms and the thighs (see section 5.2).
Administration of Hemlibra subcutaneous injection in the upper outer arm should be performed by a caregiver or healthcare professional.
Alternating the site of injection may help prevent or reduce injection site reactions (see section 4.8). Hemlibra subcutaneous injection should not be administered into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars.
During treatment with Hemlibra, other medicinal products for subcutaneous administration should, preferably, be injected at different anatomical sites.
Administration by the patient and/or caregiver
Hemlibra is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous injection technique, a patient may self-inject Hemlibra, or the patient's caregiver may administer it, if their physician determines that it is appropriate.
The physician and the caregiver should determine the appropriateness of the child self-injecting Hemlibra. However, self-administration is not recommended for children below 7 years of age.
For comprehensive instructions on the administration of Hemlibra, see section 6.6 and package leaflet.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Traceability
In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Thrombotic microangiopathy associated with Hemlibra and activated prothrombin complex concentrate
Cases of thrombotic microangiopathy (TMA) were reported from a clinical trial in patients receiving Hemlibra prophylaxis when on average a cumulative amount of >100U/kg/24 hours of activated prothrombin complex concentrate (aPCC) for 24 hours or more was administered (see section 4.8). Treatment for the TMA events included supportive care with or without plasmapheresis and haemodialysis. Evidence of improvement was seen within one week following discontinuation of aPCC and interruption of Hemlibra. This rapid improvement is distinct from the usual clinical course observed in atypical hemolytic uremic syndrome and classic TMAs, such as thrombotic thrombocytopenic purpura (see section 4.8). One patient resumed Hemlibra following resolution of TMA and continued to be treated safely.
Patients receiving Hemlibra prophylaxis should be monitored for the development of TMA when administering aPCC. The physician should immediately discontinue aPCC and interrupt Hemlibra therapy if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming Hemlibra prophylaxis following complete resolution of TMA on a case-by-case basis. In case a bypassing agent is indicated in a patient receiving Hemlibra prophylaxis, see below for dosing guidance on the use of bypassing agents.
Caution should be used when treating patients who are at high risk for TMA (e.g. have a previous medical history or family history of TMA), or those who are receiving concomitant medications known to be a risk factor for the development of TMA (e.g. ciclosporin, quinine, tacrolimus).
Thromboembolism associated with Hemlibra and activated prothrombin complex concentrate
Serious thrombotic events were reported from a clinical trial in patients receiving Hemlibra prophylaxis when on average a cumulative amount of >100U/kg/24 hours of aPCC for 24 hours or more was administered (see section 4.8). No cases required anticoagulation therapy. Following discontinuation of aPCC and interruption of Hemlibra, evidence of improvement or resolution was seen within one month (see section 4.8). One patient resumed Hemlibra following resolution of thrombotic event and continued to be treated safely.
Patients receiving Hemlibra prophylaxis should be monitored for the development of thromboembolism when administering aPCC. The physician should immediately discontinue aPCC and interrupt Hemlibra therapy if clinical symptoms, imaging, and/or laboratory findings consistent with thrombotic events occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming Hemlibra prophylaxis following complete resolution of thrombotic events on a case-by-case basis. In case a bypassing agent is indicated in a patient receiving Hemlibra prophylaxis, see below for dosing guidance on the use of bypassing agents.
Guidance on the use of bypassing agents in patients receiving Hemlibra prophylaxis
Treatment with bypassing agents should be discontinued the day before starting Hemlibra therapy.
Physicians should discuss with all patients and/or caregivers the exact dose and schedule of bypassing agents to use, if required while receiving Hemlibra prophylaxis.
Hemlibra increases the patient's coagulation potential. The bypassing agent dose required may therefore be lower than that used without Hemlibra prophylaxis. The dose and duration of treatment with bypassing agents will depend on the location and extent of bleeding, and the patient's clinical condition. Use of aPCC should be avoided unless no other treatment options/alternatives are available. If aPCC is indicated in a patient receiving Hemlibra prophylaxis, the initial dose should not exceed 50 U/kg and laboratory monitoring is recommended (including but not restricted to renal monitoring, platelet testing, and eva luation of thrombosis). If bleeding is not controlled with the initial dose of aPCC up to 50 U/kg, additional aPCC doses should be administered under medical guidance or supervision with consideration made to laboratory monitoring for the diagnosis of TMA or thromboembolism and verification of bleeds prior to repeated dosing. The total aPCC dose should not exceed 100 U/kg in the first 24-hours of treatment. Treating physicians must carefully weigh the risk of TMA and thromboembolism against the risk of bleeding when considering aPCC treatment beyond a maximum of 100 U/kg in the first 24-hours.
In clinical trials, no cases of TMA or thrombotic events were observed with use of activated recombinant human FVII (rFVIIa) alone in patients receiving Hemlibra prophylaxis.
Bypassing agent dosing guidance should be followed for at least 6 months following discontinuation of Hemlibra prophylaxis (see section 5.2).
Effects of emicizumab on coagulation tests
Emicizumab replaces the tenase cofactor activity of activated factor VIII (FVIIIa). Coagulation laboratory tests based on intrinsic clotting, including the activated clotting time (ACT), activated partial thromboplastin time (e.g. aPTT), measure the total clotting time including time needed for activation of FVIII to FVIIIa by thrombin. Such intrinsic pathway based tests will yield overly shortened clotting times with emicizumab, which does not require activation by thrombin. The overly shortened intrinsic clotting time will then disturb all single factor assays based on aPTT, such as the one stage FVIII activity assay (see section 4.4, Table 1). However, single factor assays utilising chromogenic or immuno-based methods are not affected by emicizumab and may be used to monitor coagulation parameters during treatment, with specific considerations for FVIII chromogenic activity assays as described below.
Chromogenic factor VIII activity tests may be manufactured with either human or bovine coagulation proteins. Assays containing human coagulation factors are responsive to emicizumab but may overestimate the clinical haemostatic potential of emicizumab. In contrast, assays containing bovine coagulation factors are insensitive to emicizumab (no activity measured) and can be used to monitor endogenous or infused factor VIII activity, or to measure anti FVIII inhibitors.
Emicizumab remains active in the presence of inhibitors against factor VIII and so will produce a false negative result in clotting based Bethesda assays for functional inhibition of factor VIII. Instead, a chromogenic Bethesda assay utilising a bovine based factor VIII chromogenic test that is insensitive to emicizumab may be used.
These two pharmacodynamic markers do not reflect the true haemostatic effect of emicizumab in vivo (aPTT is overly shortened and reported factor VIII activity may be overestimated) but provide a relative indication of the pro-coagulant effect of emicizumab.
In summary, intrinsic pathway clotting-based laboratory test results in patients treated with Hemlibra should not be u
