Turoctocog Alfa

Registered South African indications:

• Treatment, prophylaxis and peri-operative management of bleeding in patients with haemophilia A (congenital factor VIII deficiency)

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Known allergic reaction to hamster protein

South African recommendations

 Caution in the following patient groups:

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly

Traceability

• In order to improve traceability of biological medicines, the name and the batch number of the administered product should be clearly recorded

Hypersensitivity

• Patients using turoctocog alfa may experience allergic-type hypersensitivity reactions due to the presence of traces of hamster proteins
• Upon experiencing hypersensitivity symptoms, immediate discontinuation of turoctocog alfa is advised. Patients should contact their healthcare provider or seek emergency medical care
• Early signs of a reaction include hives, generalised urticaria, chest tightness, wheezing, hypotension, and anaphylaxis
• If a patient goes into shock, established medical shock treatment protocols should be followed

Inhibitors in haemophilia A treatment

• In the treatment of haemophilia A, the formation of neutralising antibodies, known as inhibitors, against factor VIII is a recognized complication. These inhibitors are typically IgG immunoglobulins targeting the procoagulant activity of factor VIII and are measured in Bethesda Units (BU) per ml of plasma
• The likelihood of developing inhibitors is tied to the severity of haemophilia A and the exposure to factor VIII, with the highest risk observed within the first 50 exposure days. However, the risk persists over the patient's lifetime, albeit less common after initial exposure
• The impact of inhibitor development varies with the inhibitor's titre. High titre inhibitors pose a significant risk of inadequate clinical response, while low titre inhibitors present a lesser risk
• It is crucial for all haemophilia A patients receiving factor VIII treatments to be closely monitored for inhibitors through clinical observations and laboratory tests. If factor VIII activity levels are not as expected, or if bleeding isn't controlled with a standard dose, testing for inhibitors is advised
• In cases where high levels of inhibitors are detected, factor VIII treatments may not be effective, and alternative therapeutic approaches should be explored. Treatment and management should be overseen by healthcare professionals experienced in haemophilia care and the handling of factor VIII inhibitors

Paediatric population

• Cautions for turoctocog alfa, apply to both adults and children

Excipient related considerations

• Turoctocog alfa contains 30.5mg sodium per reconstituted vial, equivalent to 1.5% of the WHO-recommended maximum daily intake of 2g sodium for an adult
• Contains sucrose (12mg per vial)

Ability to drive and use machines

• Turoctocog alfa has no influence on the ability to drive and use machines

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

South African registered indications and dosages

Treatment should be under the supervision of a doctor experienced in the treatment of haemophilia

Treatment, prophylaxis and peri-operative management of bleeding in patients with haemophilia A (congenital factor VIII deficiency)

On-demand treatment

In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal or IU/dL) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

Guide for dosing in bleeding episodes and surgery

Degree of haemorrhage/Type of surgical procedure	FVIII level required (%) (IU/dL)	Frequency of doses (hours)/Duration of therapy (days)
Haemorrhage
Mild Mild haemorrhage, Early haemorrhage into muscles/joints Early haemorrhages in the oral cavity, muscle bleeding or oral bleeding	20-40	Repeat every 12-24hrs, at least 1 day, until the bleeding episode as indicated by pain is resolved or healing achieved
Moderate Moderate haemorrhage, more extensive haemarthrosis, haemorrhage into muscles/joints, haemorrhages in the oral cavity or haematoma	30-60	Repeat injection every 12–24hrs for 3-4 days or more until pain and acute disability are resolved
Major Severe, life/limb threatening haemorrhage, gastro-intestinal bleeding, intracranial, intraabdominal or intrathoracic haemorrhages or fractures	60-100	Repeat injection every 8-24hrs until threat is resolved
Surgery
Minor surgery Including tooth extraction	30-60	Every 24hrs, at least 1 day, until healing is achieved
Major surgery (intracranial, intraabdominal, intrathoracic or joint replacement surgery)	80-100 (pre-and post-operative)	Repeat injection every 8-24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/dL)

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Recommended admin rate: 1-2ml/min

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The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and the patient’s clinical condition

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The number of units of factor VIII administered is expressed in international units (IU), which are related to the current WHO standard for factor VIII products. The activity of factor VIII in plasma is expressed either as percentage (relative to normal level human plasma) or in international units (relative to an international standard for factor VIII in plasma)

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One international unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml normal human plasma

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On-demand treatment
The calculation of the required dose of factor VIII is based on the empirical finding that 1 international unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dL. The required dose is determined using the following formula:

Required units = body weight (kg) x desired factor VIII rise (%) (IU/dL) x 0.5 (IU/kg per IU/dL)

The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case

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- Long-term prophylaxis against bleeding in patients with severe haemophilia A

• IV: Usual doses: 20-40 IU/kg body weight every second day OR 20-50 IU/kg body weight 2-3 times weekly; Recommended admin rate: 1-2ml/min; In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary

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See additional prescribing points for treatment monitoring

Paed. forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Treatment should be under the supervision of a doctor experienced in the treatment of haemophilia

Treatment, prophylaxis and peri-operative management of bleeding in patients with haemophilia A (congenital factor VIII deficiency)

12 years and older

• See adult dosages

- Long term prophylaxis against bleeding

Younger than 12 years

• IV: 25-50 IU/kg body weight every second day OR 25-60 IU/kg body weight 3 times weekly; Recommended admin rate: 1-2ml/min

12 years and older

• See adult dosages

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There is limited experience of major surgery in paediatric patients

South African recommendations

Pregnancy

• Caution
• No animal reproductive studies have been conducted with turoctocog alfa
• Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy is not available. Therefore, turoctocog alfa should only be used during pregnancy if clearly indicated

Breastfeeding

• Caution
• Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during breastfeeding is not available. Therefore, turoctocog alfa should only be used during breastfeeding if clearly indicated

Fertility

• It is not known if turoctocog alfa can affect fertility

South African recommendations

• Caution; no information available

South African recommendations

• Caution; no information available

South African recommendations

• Caution; no information available
  There is no experience in patients > 65 years

Blood and Lymphatic System Disorders

Very common

• FVIII inhibition

Psychiatric Disorders

Uncommon

• Insomnia

Nervous System Disorders

Uncommon

• Headache
• Dizziness
• Burning sensation

Cardiac Disorders

Uncommon

• Sinus tachycardia
• Acute myocardial infarction

Vascular Disorders

Uncommon

• Hypertension
• Lymphoedema
• Hyperaemia

Common

• Flushing
• Superficial thrombophlebitis

Skin and Subcutaneous Tissue Disorders

Common

• Rash
• Erythematous rash

Uncommon

• Rash
• Lichenoid keratosis
• Skin burning sensation

Musculoskeletal and Connective Tissue Disorders

Uncommon

• Musculoskeletal stiffness
• Arthropathy
• Pain in extremity
• Musculoskeletal pain

Common

• Haemarthrosis
• Muscle haemorrhage

Respiratory, Thoracic and Mediastinal Disorders

Common

• Cough

General Disorders and Administration Site Conditions

Common

• Injection site reactions
  - Injection site erythema
  - Injection site extravasation
  - Injection site pruritus
• Pyrexia
• Catheter site erythema

Uncommon

• Fatigue
• Feeling hot
• Peripheral oedema
• Pyrexia

Investigations

Common

• Increased hepatic enzymes
  - Alanine aminotransferase
  - Aspartate aminotransferase
  - Gamma-glutamyltransferase
  - Bilirubin
• Anti-factor VIII antibody positive

Uncommon

• Increased heart rate

Gastrointestinal Disorders

Common

• Vomiting

Injury, Poisoning and Procedural Complications

Common

• Incorrect dose administered
• Infusion-related reaction

Uncommon

• Contusion

Product Issues

Common

• Thrombosis in device

None known

• Factor VIII levels should be measured at baseline, and as peaks 15-30 minutes after infusion to assess target level achievement
  - When administered as a continuous infusion, additionally monitor at least daily while on continuous infusion therapy
  - In long-term prophylaxis, trough factor VIII measurements are required to tailor treatment
  - Patients with low-titer inhibitors who are treated with factor VIII concentrate products require regular monitoring of factor VIII levels and inhibitor titers to confirm that the response is consistent
• FVIII trough levels
  - Measure FVIII trough levels as this may aid in calculation of subsequent doses. Subsequent doses ought to be determined based on the individual patient's FVIII half-life and their factor recovery
• Heart rate
• Blood pressure (before and during IV administration)
• Haemoglobin/haematocrit

Additional observations

• Signs of hypersensitivity reactions
• Signs and symptoms of intravascular haemolysis
• Lower than expected factor VIII recovery or reduced half-life are early signs of inhibitor formation

Treatment monitoring

• During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated injections
• Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives
• Dose based on body weight may require adjustment in underweight or overweight patients. In a single dose pharmacokinetic study in adult patients the maximum exposure (C_max) and the total exposure (AUC) increased with increasing body mass index (BMI) indicating that dose adjustments may be required. An increase in dose may be required for underweight patients (BMI <18.5kg/m² ) and a decrease in dose may be required for obese patients (BMI ≥30kg/m² ), but there is insufficient data to recommend specific dose adjustments
• In case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable
• When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor VIII activity in patients’ blood samples, plasma factor VIII activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay
• Also, there can be significant discrepancies between assay results obtained by aPTT-based one stage clotting assay and the chromogenic assay according to European Pharmacopoeia. This is of importance particularly when changing the laboratory and/or reagents used in the assay

Human coagulation factor VIII (rDNA), turoctocog alfa, is a glycoprotein that has the same structure as human factor VIII when activated, and post-translational modifications that are similar to those of the plasma-derived molecule. When injected into a haemophilia patient, factor VIII binds to endogenous von Willebrand factor in the patient’s circulation. The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of bleeding tendencies.