Emicizumab

Registered South African indications:

• Routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes in haemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment
• Moderate to severe hepatic impairment
• Elderly >77 years
• High risk for thrombotic microangiopathy (previous medical history or family history)
• Children <1 year of age

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Routine prophylaxis of bleeding episodes in haemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors
Routine prophylaxis of bleeding episodes in severe haemophilia A (congenital factor VIII deficiency, FVIII <1%) without factor VIII inhibitors

• SC: Initial: Week 1-4: 3mg/kg, weekly; Maintenance (from week 5): 1.5mg/kg, weekly OR 3mg/kg, every two weeks OR 6mg/kg, every four weeks

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Treatment should be initiated under the supervision of a medical practitioner experienced in the treatment of haemophilia and/or bleeding disorders

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The loading dose regimen is the same, irrespective of the maintenance dose regimen. The maintenance dose regimen should be selected based on physician and patient/caregiver dosing regimen preference to support adherence

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Treatment with bypassing agents (including routine prophylaxis) with bypassing agents (e.g. aPCC and rFVIIa) should be discontinued 24 hours before starting emicizumab therapy (See Additional Prescribing Points)

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Factor VIII (FVIII) prophylaxis may be continued for the first 7 days of emicizumab treatment

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Use is intended for long-term prophylactic treatment

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South African manufacturer recommendations

Routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes in haemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors

• SC: Initial: Week 1-4: 3mg/kg, weekly; Maintenance: Week 5 onwards: 1.5mg/kg, weekly; OR 3mg/kg, every two weeks; OR 6mg/kg, every four weeks

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Treatment should be initiated under the supervision of a medical practitioner experienced in the treatment of haemophilia and/or bleeding disorders

---

The maintenance dose regimen should be selected based on physician and patient/caregiver dosing regimen preference to support adherence

---

Treatment with bypassing agents should be discontinued 24 hours before starting emicizumab therapy. Factor VIII (FVIII) prophylaxis may be continued for the first 7 days of emicizumab treatment (See Additional Prescribing Points)

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Routine prophylaxis of bleeding episodes in haemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors
Routine prophylaxis of bleeding episodes in severe haemophilia A (congenital factor VIII deficiency, FVIII <1%) without factor VIII inhibitors

• See adult dosage

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There are no data in children <1 year of age. The developing hemostatic system in neonates and infants is dynamic and evolving, and the relative concentrations of pro-and anticoagulant proteins in these patients should be taken into consideration when making a benefit-risk assessment, including potential risk of thrombosis (e.g. central venous catheter-related thrombosis)

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South African manufacturer recommendations

Routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes in haemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors

• See adult dosage

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There are limited data in infants less than 1 year of age. In children <1 year, prescribe emicizumab only after carefully weighing the expected benefits and risks of using this product

Pregnancy

• Caution
• There are no clinical studies of emicizumab use in pregnant women
• Animal reproduction studies have not been conducted with emicizumab
• It is not known whether emicizumab can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity
• Emicizumab should be used during pregnancy only if the potential benefit for the mother outweighs the potential risk to the foetus taking into account that, during pregnancy and after parturition, the risk for thrombosis is increased and that several pregnancy complications are linked to an increased risk for disseminated intravascular coagulation (DIC)
• Women of childbearing potential receiving emicizumab should use effective contraception during, and for at least 6 months after cessation of emicizumab treatment

Breastfeeding

• Caution; not recommended 
• It is not known whether emicizumab is excreted in human milk
• No studies have been conducted to assess the impact of emicizumab on milk production or its presence in breast milk
• Human IgG is known to be present in human milk. A decision must be made whether to discontinue breastfeeding or to discontinue/ abstain from emicizumab therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

• Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity
• No fertility data is available in humans, thus the effect of emicizumab on male and female fertility is unknown

Renal Impairment

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; no information available

Hepatic Impairment

• Mild: No dose adjustment recommended
• Moderate: Caution; no dose adjustment recommended
• Severe: Caution; no information available

Elderly

• ≥65-77 years: No dose adjustment recommended
• >77 years: Caution; no information available

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache

Cardiovascular Disorders

• Thrombotic events (including cavernous sinus thrombosis and superficial vein thrombosis contemporaneous with skin necrosis)

Gastrointestinal Disorders

• Diarrhoea

Genitourinary Disorders

• Acute kidney injury

Musculoskeletal Disorders

• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Skin necrosis

Immune, Blood and Lymphatic System Disorders

• Thrombotic microangiopathy
• Pyrexia
• Thrombocytopenia
• Microangiopathic hemolytic anaemia

Others

• Injection site reactions 
  - Erythema
  - Pain
  - Pruritus 

• Bypassing agents
• Activated prothrombin complex concentrate (aPCC)
• Activated recombinant factor VII (rFVIIa)
• Factor VIII (FVIII)
• Ciclosporin
• Quinine
• Tacrolimus
• Antifibrinolytics 

• Coagulation parameters

None routine. Specific cases may require

• Thrombotic microangiopathy
• Platelet count
• Renal function
• Evaluation of thrombosis

Delayed or missed doses

• If a patient misses a scheduled dose, the patient should be instructed to take the missed dose as soon as possible, up to 24 hours 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 two doses on the same day to make up for a missed dose

Method of administration

• Emicizumab solution is a sterile, preservative-free, and ready to use solution for subcutaneous injection that does not need to be diluted
• Emicizumab solution should be inspected visually to ensure there is no particulate matter or discolouration prior to administration
• Emicizumab is for subcutaneous use only. Emicizumab should be administered using appropriate aseptic technique
• The injection should be restricted to the recommended injection sites: the abdomen, the upper outer arms and the thighs. No data are available on injection at other sites of the body
• Administration of emicizumab subcutaneous injection in the upper outer arm should be performed by a trained caregiver or healthcare professional
• Alternating the site of injection may help prevent or reduce injection site reactions. Emicizumab 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 emicizumab, other medicinal products for subcutaneous administration should, preferably, be injected at different anatomical sites
• A 1ml syringe should be used for an injection up to 1ml of emicizumab solution, whereas a 2-3ml syringe should be used for an injection >1ml and up to 2ml
• Selection criteria for syringes and needles are defined to ensure correct and safe administration of emicizumab. These criteria are based on handling considerations (e.g. dosing accuracy, subcutaneous injection), emicizumab characteristics (e.g. viscosity), and compatibility between emicizumab and device materials

Administration by the patient and/or caregiver

• Emicizumab is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous injection technique, a patient may self-inject emicizumab, or the patient’s caregiver may administer emicizumab, if their medical practitioner determines that it is appropriate

Guidance on the use of bypassing agents 

• Treatment with bypassing agents should be discontinued the day before starting emicizumab therapy
• Medical practitioners should discuss with all patients and/or caregivers the exact dose and schedule of bypassing agents to use, if required while receiving emicizumab prophylaxis
• Emicizumab increases the patients’ coagulation potential. The bypassing agent dose required may therefore be lower than that used without emicizumab prophylaxis. The dose and duration of treatment with bypassing agents will depend on the location and extent of bleeding and on the patient’s clinical condition
• Avoid use of aPCC unless no other treatment options/ alternatives are available. If aPCC is indicated in a patient receiving emicizumab prophylaxis, the initial dose should not exceed 50 U/kg. 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, and the total aPCC dose should not exceed 100 U/kg in the first 24-hours of treatment. Medical practitioners must carefully weigh the risk of thrombotic microangiopathy and thromboembolism against the risk of bleeding when considering aPCC treatment beyond a maximum of 100 U/kg in the first 24 hours
• Bypassing agent dosing guidance should be followed for at least 6 months following discontinuation of emicizumab prophylaxis

Concomitant administration with antifibrinolytics

• Experience with concomitant administration of antifibrinolytics with aPCC or rFVIIa in patients receiving emicizumab prophylaxis is limited
• However, the possibility of thrombotic events should be considered when systemic antifibrinolytics are used in combination with aPCC or rFVIIa in patients receiving emicizumab

Thrombotic microangiopathy (TMA) associated with emicizumab and activated prothrombin complex concentrate (aPCC)

• Cases of TMA were reported from a clinical trial in patients receiving emicizumab prophylaxis when cumulative doses over 100 U/kg in 24 hours or more of aPCC were administered
• Patients receiving emicizumab prophylaxis should be monitored for the development of TMA when administering aPCC. The medical practitioner should immediately discontinue aPCC and interrupt emicizumab therapy if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as clinically indicated
• The risks of resuming emicizumab prophylaxis following complete resolution of TMA on a case-by-case basis should be considered

Thromboembolism associated with emicizumab and aPCC

• Thrombotic events were reported from a clinical trial in patients receiving emicizumab prophylaxis when cumulative doses over 100 U/kg in 24 hours or more of aPCC were administered
• Patients receiving emicizumab prophylaxis should be monitored for the development of thromboembolism when administering aPCC. Immediately discontinue aPCC and interrupt emicizumab therapy if clinical symptoms, imaging, and/or laboratory findings consistent with thrombotic events occur, and manage as clinically indicated
• Consider the risks of resuming emicizumab prophylaxis following complete resolution of thrombotic events on a case-by-case basis

Traceability

• In order to improve traceability of emicizumab, the trade name and the batch number of the emicizumab should be clearly recorded (or stated) in the patient file
• Advise patients/caregivers to record the batch number of the product whenever emicizumab is administered outside of a healthcare setting

Emicizumab is a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure. Emicizumab bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective haemostasis. Emicizumab has no structural relationship or sequence homology to factor VIII and, as such, does not induce or enhance the development of direct inhibitors to factor VIII.

Injection (per 1ml) 30mg

• Hemlibra (Roche) Originator

Injection (per 0.4ml) 60mg

• Hemlibra (Roche) Originator

Injection (per 0.7ml) 105mg

• Hemlibra (Roche) Originator

Injection (per 1ml) 150mg

• Hemlibra (Roche) Originator