Activated Recombinant Coagulation Factor VIIa (Eptacog Alfa)

Registered South African indications:

• Haemophilia with inhibitors to coagulation factor VIII and factor IX
  - Patients suffering life- or limb-threatening bleeds or requiring surgery and in home-treatment setting for early intervention to treat mild to moderate bleeding episodes
• Bleeding episodes and for the prevention of bleeding
  - In patients with congenital FVII deficiency undergoing surgery or invasive procedures
  - In those patients undergoing surgery or invasive procedures with Glanzmann’s thrombasthenia with or without antibodies to GP IIb-IIIa and/or HLA, and with past or present refractoriness to platelet transfusions, or where platelets are not readily available
  - In those patients with acquired haemophilia undergoing surgery or invasive procedures

Contraindications

South African recommendations & Recommendations in other jurisdictions

• Known hypersensitivity to eptacog alfa (the active ingredient) or any of its excipients
• Hypersensitivity to mouse, hamster or bovine protein

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Disseminated intravascular coagulopathy 
• Coronary heart disease
• Post-operative use
• Crush injury
• Septicaemia
• Neonates

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

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

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

Haemophilia A or B with inhibitors or expected to have a high anamnestic response

• IV: Initial: 90µg/kg body weight, bolus given as a slow injection over 2-5min, as soon as possible at the start of a bleeding episode; Further doses may be repeated as required; Dose interval: 2-3hrs to obtain haemostasis; If continued therapy is needed, the dose interval can be increased successively once effective haemostasis is achieved to every 4, 6, 8 or 12hrs for as long as treatment is judged as being indicated

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The duration of treatment and the interval between injections will vary with the severity of the haemorrhage, the invasive procedures or surgery being performed

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- Mild to moderate bleeding episodes (including home therapy)

Two regimens recommended

• IV: 2-3 injections of 90µg (4.5KIU)/kg body weight, bolus given as a slow injection over 2-5min, at 3hr intervals; If further treatment is required: One additional dose of 90μg/kg body weight can be administered; Treatment duration: Home treatment should not exceed 24hrs
  OR
• IV: Single injection of 270µg/kg body weight, bolus given as a slow injection over 2-5min; Treatment duration: Home treatment should not exceed 24hrs

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Early intervention has been shown to be efficacious in the treatment of mild to moderate joint, muscle and mucocutaneous bleeds

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If continued therapy beyond 24 hours is indicated the haemophilia treatment centre should be contacted

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- Serious bleeding episodes

• IV: Initial: 90µg (4.5KIU)/kg body weight, bolus given as a slow injection over 2-5min, every 2nd hr until clinical improvement is observed; Then: Every 3hrs for 1-2 days if continued therapy is indicated; Thereafter: Every 4, 6, 8 or 12hrs for as long as treatment is judged as being indicated; In major bleeding episode: May be treated for 2-3 weeks but can be extended beyond this if clinically warranted

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As the dosage varies according to the type and severity of the haemorrhages, the above recommendation is a guideline for the initial dosage

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- Surgery/ invasive procedure

• IV: Initial: 90µg (4.5KIU)/kg body weight, bolus given as a slow injection over 2-5min, immediately before the procedure; Repeat after 2hrs and then at 2-3hr intervals for the first 24-48hrs depending on the surgery performed and the clinical status of the patient; In major surgery: Dosage should be continued at 2-4hr intervals for 6-7 days; Dose interval may then be increased to 6-8hrs for another 2 weeks of treatment

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Patients undergoing major surgery may be treated for up to 2-3 weeks until healing has occurred

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For patients with factor IX inhibitors or acquired antibodies to factor VIII, only experience of the use of eptacog alfa in minor surgery exists

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Acquired haemophilia

• IV: Initial: 90µg/kg body weight, bolus given as a slow injection over 2-5min, as soon as possible at the start of a bleeding episode; Further doses may be given as required; Initial dose interval should be 2-3hrs; Once haemostasis has been achieved, the dose interval can be increased successively: To every 4, 6, 8 or 12hrs for as long as treatment is judged to be indicated

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The duration of treatment and the interval between injections will vary with the severity of the haemorrhage, the invasive procedures or the surgery being performed

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Factor VII deficiency
- Treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures

• IV: 15-30µg/kg body weight, bolus given as a slow injection over 2-5min, every 4-6hrs until haemostasis is achieved; Dose and frequency of injections should be adapted to each individual

Glanzmann’s thrombasthenia
- Treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures

• IV: 90µg (range 80-120µg)/kg body weight, bolus given as a slow injection over 2-5min at intervals of 2hrs (1.5-2.5hrs); At least 3 doses should be administered to secure effective haemostasis

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The recommended route of administration is bolus injection as lack of efficacy may appear in connection with continuous infusion

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For those patients who are not refractory, platelets are the first line treatment for Glanzmann’s thrombasthenia

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No requirement for monitoring of eptacog alfa therapy. Severity of bleeding condition and clinical response to eptacog alfa administration must guide dosing requirements

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See additional prescribing points for administration directions

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

Paed. dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Haemophilia A or B with inhibitors or expected to have a high anamnestic response

• See adult dosage

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Current clinical experience does not warrant a general differentiation in dosing between children below 18 years and adults, although young children (below 12 years) have faster clearance than adults. Therefore, higher doses of rFVIIa may be needed in paediatric patients to achieve similar plasma concentrations as in adult patients

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Factor VII deficiency
- Treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures

• See adult dosage

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Limited clinical experience in long term prophylaxis has been gathered in the paediatric population below 12 years of age, with a severe clinical phenotype

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Dose and frequency of injections for prophylaxis should be based on clinical response and adapted to each individual

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See additional prescribing points for administration directions

Pregnancy

South African recommendations & Recommendations in other jurisdictions

• Caution
• Safety in pregnancy has not been established
• As a precautionary measure, it is preferable to avoid the use of eptacog alfa during pregnancy 
• Data on a limited number of exposed pregnancies within approved indications indicate no adverse effects of eptacog alfa on pregnancy or on the health of the foetus/new-born child
• To date, no other relevant epidemiological data are available 
• Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition, or postnatal development 
• It is not known whether eptacog alfa can affect reproduction capacity

Breastfeeding

South African recommendations & Recommendations in other jurisdictions

• Caution; not recommended 
• It is not known whether eptacog alfa is excreted in human breast milk 
• The excretion of eptacog alfa in milk has not been studied in animals 
• A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with eptacog alfa should be made taking into account the benefit of breastfeeding to the child and the benefit of eptacog alfa therapy to the woman 

Fertility

South African recommendations & Recommendations in other jurisdictions

• Data from non-clinical studies as well as post-marketing data show no indication that eptacog alfa has a harmful effect on male or female fertility 

Renal Impairment

• Caution; not information available

Hepatic Impairment

South African recommendations & Recommendations in other jurisdictions

• Caution; no dose adjustment recommended

Elderly

South African recommendations & Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  There is no clinical experience with the administration of a single dose of 270μg/kg body weight in elderly patients

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache

Cardiovascular Disorders

• Myocardial infarction
• Cerebral infarction
• Cerebral ischaemia
• Cerebral artery occlusion
• Cerebrovascular accident
• Renal artery thrombosis
• Peripheral ischaemia
• Peripheral arterial thrombosis 
• Intestinal ischaemia
• Angina pectoris
• Deep vein thrombosis
• Thrombosis
• Pulmonary embolism
• Thromboembolic events of the liver including portal vein thrombosis
• Renal vein thrombosis
• Thrombophlebitis
• Superficial thrombophlebitis
• Intestinal ischaemia
• Intracardiac thrombus

Gastrointestinal Disorders

•   Nausea

Skin and subcutaneous disorders

• Rash
• Pruritus 
• Urticarial
• Flushing
• Angioedema
• Pyrexia 
• Injection site reaction

Immune, Blood and Lymphatic System Disorders

• Disseminated intravascular coagulation
• Elevated levels of D-dimer 
• Decreased levels of AT 
• Coagulopathy
• Hypersensitivity
• Anaphylactic reaction

• Prothrombin complex concentrates
• Antifibrinolytics 
• Recombinant factor XIII

• Prothrombin time
• Factor VII coagulant activity 

Administration directions

• Keep the plunger rod pushed completely in. Turn the syringe with the vial upside down. Stop pushing the plunger rod and let it move back on its own while the reconstituted solution fills the syringe. Pull the plunger rod slightly downwards to draw the mixed solution into the syringe
• While holding the vial upside down, tap the syringe gently to let any air bubbles rise to the top. Push the plunger rod slowly until all air bubbles are gone. If the entire dose is not required, use the scale on the syringe to see how much mixed solution is withdrawn
• Unscrew the vial adaptor with the vial
• Eptacog alfa is now ready for injection. Locate a suitable site, and slowly inject into a vein over a period of 2–5 minutes without removing the needle from the injection site

Activated recombinant coagulation factor VII binds to exposed tissue factor. This complex activates factor IX into factor IXa and factor X into factor Xa, leading to the initial conversion of small amounts of prothrombin into thrombin. Thrombin leads to the activation of platelets and factors V and VIII at the site of injury and to the formation of the haemostatic plug by converting fibrinogen into fibrin.

Injection (per ml) 1mg

• NovoSeven (Novo Nordisk) originator

Injection (per ml) 2mg

• NovoSeven (Novo Nordisk) originator

Injection (per ml) 5mg

• NovoSeven (Novo Nordisk) originator