Dose limiting toxicities of Eptacog alfa (activated) have not been investigated in clinical trials.
Four cases of overdose have been reported in patients with haemophilia in 16 years. The only complication reported in connection with an overdose was a slight transient increase in blood pressure in a 16 year-old patient receiving 24 mg rFVIIa instead of 5.5 mg.
No cases of overdose have been reported in patients with acquired haemophilia or Glanzmann's thrombasthenia.
In patients with factor VII deficiency, where the recommended dose is 15 - 30 µg/kg rFVIIa, one episode of overdose has been associated with a thrombotic event (occipital stroke) in an elderly (> 80 year) male patient treated with 10 - 20 times the recommended dose. In addition, the development of antibodies against Eptacog alfa (activated) and FVII has been associated with overdose in one patient with factor VII deficiency.
The dose schedule should not be intentionally increased above the recommended doses due to the absence of information on the additional risk that may be incurred.
Eptacog alfa (activated) must not be mixed with infusion solutions or be given in a drip.
Summary of the safety profile
The most frequently reported adverse drug reactions are decreased therapeutic response, pyrexia, rash, venous thromboembolic events, pruritus and urticaria. These reactions are reported as uncommon (> 1/1,000, < 1/100).
Tabulated summary of adverse reactions
Table 1 lists adverse reactions reported during clinical trials and from spontaneous (post-marketing) reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse drug reactions reported post-marketing only (i.e. not in clinical trials) are presented with a frequency of 'not known'.
Clinical trials conducted in 484 patients (including 4297 treatment episodes) with haemophilia A and B, acquired haemophilia, factor VII deficiency or Glanzmann's thrombasthenia have shown that adverse drug reactions are common (> 1/100 to < 1/10). As the total number of treatment episodes in clinical trials is below 10,000, the lowest possible frequency of adverse drug reactions that can be assigned is rare (> 1/10,000 to < 1/1,000).
The most frequent adverse drug reactions are pyrexia and rash (uncommon: > 1/1,000 to < 1/100), and the most serious adverse drug reactions are thromboembolic events.
The frequencies of both serious and non-serious adverse drug reactions are listed by system organ classes in the table below.
Table 1 Adverse reactions from clinical trials and spontaneous (post-marketing) reports
| MedDRA system organ class | Uncommon (>1/1,000 to <1/100) | Rare (>1/10,000 to <1/1,000) | Frequency Not Known |
| Blood and lymphatic system disorders | - Disseminated intravascular coagulation - Related laboratory findings, including elevated levels of D-dimmer and decreased levels of AT - Coagulopathy | ||
| Gastrointestinal disorders | - Nausea | ||
| General disorders and administration site conditions | - Therapeutic response decreased* - Pyrexia | - Injection site reaction including injection site pain | |
| Immune system disorders | - Hypersensitivity | - Anaphylactic reaction | |
| Investigations | - Increased fibrin degradation products - Increase of alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and prothrombin | ||
| Nervous system disorders | - Headache | ||
| Skin and subcutaneous tissue disorders | - Rash (including allergic dermatitis and rash erythematous) - Pruritus and urticaria | - Flushing - Angioedema | |
| Vascular disorders | - Venous thromboembolic events (deep vein thrombosis, thrombosis at i.v. site, pulmonary embolism, thromboembolic events of the liver including portal vein thrombosis, renal vein thrombosis, thrombophlebitis, superficial thrombophlebitis and intestinal ischaemia) | - Arterial thromboembolic events (myocardial infarction, cerebral infarction, cerebral ischaemia, cerebral artery occlusion, cerebrovascular accident, renal artery thrombosis, peripheral ischaemia, peripheral arterial thrombosis and intestinal ischaemia) - Angina pectoris | - Intracardiac thrombus |
* Lack of efficacy (therapeutic response decreased) has been reported.
Description of selected adverse reactions
Inhibitory antibody formation
In post-marketing experience, there have been no reports of inhibitory antibodies against Eptacog alfa (activated) or FVII in patients with haemophilia A or B. Development of inhibitory antibodies to Eptacog alfa (activated) has been reported in a post-marketing observational registry of patients with congenital FVII deficiency.
In clinical trials of patients with factor VII deficiency, formation of antibodies against Eptacog alfa (activated) and FVII is the only adverse drug reaction reported (frequency: common (> 1/100 to < 1/10)). In some cases, the antibodies showed inhibitory effect in vitro. Risk factors that may have contributed to antibody development including previous treatment with human plasma and/or plasma-derived factor VII, severe mutation of FVII gene, and overdose of Eptacog alfa (activated), were present. Patients with factor VII deficiency treated with Eptacog alfa (activated) should be monitored for factor VII antibodies.
Thromboembolic events - arterial and venous
When Eptacog alfa (activated) is administered to patients outside approved indications, arterial thromboembolic events are common (> 1/100 to < 1/10). A higher risk of arterial thromboembolic adverse events (see table: Vascular disorders) (5.6% in patients treated with Eptacog alfa (activated) versus 3.0% in placebo-treated patients) has been shown in a meta-analysis of pooled data from placebo-controlled trials conducted outside current approved indications in various clinical settings, each of these having distinct patient characteristics and hence different underlying risk profiles.
Safety and efficacy of Eptacog alfa (activated) have not been established outside the approved indications and therefore Eptacog alfa (activated) should not be used.
Thromboembolic events may lead to cardiac arrest.
Other special populations
Patients with acquired haemophilia
Clinical trials conducted in 61 patients with acquired haemophilia with a total of 100 treatment episodes, showed that certain adverse drug reactions were reported more frequently (1% based on treatment episodes): Arterial thromboembolic events (cerebral artery occlusion, cerebrovascular accident), venous thromboembolic events (pulmonary embolism and deep vein thrombosis), angina pectoris, nausea, pyrexia, erythematous rash and investigation of increased levels of fibrin degradation products.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
Malta
ADR Reporting
Website: www.medicinesauthority.gov.mt/adrportal
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
All findings in the preclinical safety programme were related to the pharmacological effect of rFVIIa.
A potential synergistic effect of combined treatment with rFXIII and rFVIIa in an advanced cardiovascular model in cynomolgus monkey resulted in exaggerated pharmacology (thrombosis and death) at a lower dose level than when administering the individual compounds.
Eptacog alfa (activated) is indicated for the treatment of bleeding episodes and for the prevention of bleeding in those undergoing surgery or invasive procedures in the following patient groups:
- in patients with congenital haemophilia with inhibitors to coagulation factors VIII or IX > 5 Bethesda Units (BU)
- in patients with congenital haemophilia who are expected to have a high anamnestic response to factor VIII or factor IX administration
- in patients with acquired haemophilia
- in patients with congenital FVII deficiency
- in patients with Glanzmann's thrombasthenia with antibodies to GP IIb - IIIa and/or HLA, and with past or present refractoriness to platelet transfusions.
Pharmacotherapeutic group: Blood coagulation factors, ATC code: B02BD08
Mechanism of action
Eptacog alfa (activated) contains activated recombinant coagulation factor VII. The mechanism of action includes the binding of factor VIIa 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. Pharmacological doses of Eptacog alfa (activated) activate factor X directly on the surface of activated platelets, localized to the site of injury, independently of tissue factor. This results in the conversion of prothrombin into large amounts of thrombin independently of tissue factor.
Pharmacodynamic effects
The pharmacodynamic effect of factor VIIa gives rise to an increased local formation of factor Xa, thrombin and fibrin.
A theoretical risk for the development of systemic activation of the coagulation system in patients suffering from underlying diseases predisposing them to DIC cannot be totally excluded.
In an observational registry (F7HAEM-3578) covering subjects with congenital FVII deficiency, the median dose for long term prophylaxis against bleeding in 22 paediatric patients (below 12 years of age) with Factor VII deficiency and a severe clinical phenotype was 30 µg/kg (range 17 µg/kg to 200 µg/kg; the dose most often used was 30 µg/kg in 10 patients) with a median dose frequency of 3 doses per week (range 1 to 7; the dose frequency most often reported was 3 per week in 13 patients).
In the same registry 3 out of 91 surgical patients experienced thromboembolic events.
Healthy subjects
Distribution, elimination and linearity
Using the FVII clotting assay, the pharmacokinetics of rFVIIa were investigated in 35 healthy Caucasian and Japanese subjects in a dose-escalation study. Subjects were stratified according to sex and ethnic group and dosed with 40, 80 and 160 µg rFVIIa per kg body weight (3 doses each) and/or placebo. The pharmacokinetics were similar across sex and ethnic groups.
The mean steady state volume of distribution ranged from 130 to 165 ml/kg, the mean values of clearance ranged from 33.3 to 37.2 ml/h×kg.
The mean terminal half-life ranged from 3.9 to 6.0 hours.
The pharmacokinetic profiles indicated dose proportionality.
Haemophilia A and B with inhibitors
Distribution, elimination and linearity
Using the FVIIa assay, the pharmacokinetic properties of rFVIIa were studied in 12 paediatric (2 - 12 years) and 5 adult patients in non-bleeding state.
Mean volume of distribution at steady state was 196 ml/kg in paediatric patients versus 159 ml/kg in adults.
Mean clearance was approximately 50% higher in paediatric patients relative to adults (78 versus 53 ml/h×kg), whereas the mean terminal half-life was determined to 2.3 hours in both groups. Clearance appears related with age, therefore in younger patients clearance may be increased by more than 50%.
Dose proportionality was established in children for the investigated doses of 90 and 180 µg per kg body weight, which is in accordance with previous findings at lower doses (17.5 - 70 µg/kg rFVIIa).
Factor VII deficiency
Distribution and elimination
Single dose pharmacokinetics of rFVIIa, 15 and 30 μg per kg body weight, showed no significant difference between the two doses used with regard to dose-independent parameters:
Volume of distribution at steady state (280 - 290 ml/kg), half-life (2.82 - 3.11 h), total body clearance (70.8 - 79.1 ml/h×kg) and mean residence time (3.75 - 3.80 h).
The mean in vivo plasma recovery was approximately 20%.
Glanzmann's thrombasthenia
Pharmacokinetics of Eptacog alfa (activated) in patients with Glanzmann's thrombasthenia have not been investigated, but are expected to be similar to the pharmacokinetics in haemophilia A and B patients.
In pathological conditions in which tissue factor may be expressed more extensively than considered normal, there may be a potential risk of development of thrombotic events or induction of Disseminated Intravascular Coagulation (DIC) in association with Eptacog alfa (activated) treatment.
Such situations may include patients with advanced atherosclerotic disease, crush injury, septicaemia or DIC. Because of the risk of thromboembolic complications, caution should be exercised when administering Eptacog alfa (activated) to patients with a history of coronary heart disease, to patients with liver disease, to patients post-operatively, to neonates, or to patients at risk of thromboembolic phenomena or disseminated intravascular coagulation. In each of these situations, the potential benefit of treatment with Eptacog alfa (activated) should be weighed against the risk of these complications.
As recombinant coagulation factor VIIa Eptacog alfa (activated) may contain trace amounts of mouse IgG, bovine IgG and other residual culture proteins (hamster and bovine serum proteins), the remote possibility exists that patients treated with the product may develop hypersensitivity to these proteins. In such cases treatment with antihistamines i.v. should be considered.
If allergic or anaphylactic-type reactions occur, the administration should be discontinued immediately. In case of shock, standard medical treatment for shock should be implemented. Patients should be informed of the early signs of hypersensitivity reactions. If such symptoms occur, the patient should be advised to discontinue use of the product immediately and contact their physician.
In case of severe bleeds the product should be administered in hospitals preferably specialised in treatment of haemophilia patients with coagulation factor VIII or IX inhibitors, or if not possible, in close collaboration with a physician specialised in haemophilia treatment.
If bleeding is not kept under control hospital care is mandatory. Patients/carers should inform the physician/supervising hospital at the earliest possible opportunity about all usages of Eptacog alfa (activated).
Factor VII deficient patients should be monitored for prothrombin time and factor VII coagulant activity before and after administration of Eptacog alfa (activated). In case the factor VIIa activity fails to reach the expected level or bleeding is not controlled after treatment with the recommended doses, antibody formation may be suspected and analysis for antibodies should be performed. Thrombosis has been reported in FVII deficient patients receiving Eptacog alfa (activated) during surgery but the risk of thrombosis in factor VII deficient patients treated with Eptacog alfa (activated) is unknown.
No studies on the effect on the ability to drive and use machines have been performed.
Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia and/or bleeding disorders.
Posology
Haemophilia A or B with inhibitors or expected to have a high anamnestic response
Dose
Eptacog alfa (activated) should be given as early as possible after the start of a bleeding episode. The recommended initial dose, administered by intravenous bolus injection, is 90 μg per kg body weight.
Following the initial dose of Eptacog alfa (activated) further injections may be repeated. The duration of treatment and the interval between injections will vary with the severity of the haemorrhage, the invasive procedures or surgery being performed.
Paediatric population
Current clinical experience does not warrant a general differentiation in dosing between children and adults, although children 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.
Dose interval
Initially 2 - 3 hours 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 12 hours for as long as treatment is judged as being indicated.
Mild to moderate bleeding episodes (including home therapy)
Early intervention has been shown to be efficacious in the treatment of mild to moderate joint, muscle and mucocutaneous bleeds. Two dosing regimens can be recommended:
1) Two to three injections of 90 µg per kg body weight administered at three-hour intervals.
If further treatment is required, one additional dose of 90 µg per kg body weight can be administered.
2) One single injection of 270 µg per kg body weight.
The duration of home therapy should not exceed 24 hours. Only after consultation with the haemophilia treatment centre can continued home treatment be considered.
There is no clinical experience with administration of a single dose of 270 µg per kg body weight in elderly patients.
Serious bleeding episodes
An initial dose of 90 µg per kg body weight is recommended and could be administered on the way to the hospital where the patient is usually treated. The following dose varies according to the type and severity of the haemorrhage. Dosing frequency should initially be every second hour until clinical improvement is observed. If continued therapy is indicated, the dose interval can then be increased to 3 hours for 1 - 2 days. Thereafter, the dose interval can be increased successively to every 4, 6, 8 or 12 hours for as long as treatment is judged as being indicated. A major bleeding episode may be treated for 2 - 3 weeks but can be extended beyond this if clinically warranted.
Invasive procedure/surgery
An initial dose of 90 µg per kg body weight should be given immediately before the intervention. The dose should be repeated after 2 hours and then at 2 - 3 hour intervals for the first 24 - 48 hours depending on the intervention performed and the clinical status of the patient. In major surgery, the dose should be continued at 2 - 4 hour intervals for 6 - 7 days. The dose interval may then be increased to 6 - 8 hours for another 2 weeks of treatment. Patients undergoing major surgery may be treated for up to 2 - 3 weeks until healing has occurred.
Acquired Haemophilia
Dose and dose interval
Eptacog alfa (activated) should be given as early as possible after the start of a bleeding episode. The recommended initial dose, administered by intravenous bolus injection, is 90 µg per kg body weight. Following the initial dose of Eptacog alfa (activated) further injections may be given if required. 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.
The initial dose interval should be 2 - 3 hours. Once haemostasis has been achieved, the dose interval can be increased successively to every 4, 6, 8 or 12 hours for as long as treatment is judged to be indicated.
Factor VII deficiency
Dose, dose range and dose interval
The recommended dose range in adults and children for treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures is 15 - 30 μg per kg body weight every 4 - 6 hours until haemostasis is achieved. Dose and frequency of injections should be adapted to each individual.
Paediatric population
Limited clinical experience in long term prophylaxis has been gathered in the paediatric population below 12 years of age, with a severe clinical phenotype.
Dose and frequency of injections for prophylaxis should be based on clinical response and adapted to each individual.
Glanzmann's thrombasthenia
Dose, dose range and dose interval
The recommended dose for treatment of bleeding episodes and for the prevention of bleeding in patients undergoing surgery or invasive procedures is 90 µg (range 80 - 120 µg) per kg body weight at intervals of two hours (1.5 - 2.5 hours). At least three doses should be administered to secure effective haemostasis. The recommended route of administration is bolus injection as lack of efficacy may appear in connection with continuous infusion.
For those patients who are not refractory, platelets is the first line treatment for Glanzmann's thrombasthenia.
Method of administration
Administer the solution as an intravenous bolus injection over 2 - 5 minutes.Monitoring of treatment - laboratory tests
There is no requirement for monitoring of Eptacog alfa (activated) therapy. Severity of bleeding condition and clinical response to Eptacog alfa (activated) administration must guide dosing requirements.
After administration of rFVIIa, prothrombin time (PT) and activated partial thromboplastin time (aPTT) have been shown to shorten, however no correlation has been demonstrated between PT and aPTT and clinical efficacy of rFVIIa.
The solvent of Eptacog alfa (activated) is provided in either a vial or in a pre-filled syringe. Not all presentations may be marketed. Handling procedures for both presentations are described below.
Powder in vial and solvent in vial:
Always use an aseptic technique.
Reconstitution
- Eptacog alfa (activated) powder and solvent vials should be at room temperature at reconstitution. Remove the plastic caps from the two vials. If the caps are loose or missing, do not use the vials. Clean the rubber stoppers on the vials with alcohol swabs and allow them to dry before use. Use a disposable syringe of an appropriate size and a vial adapter, transfer needle (20 - 26G) or other suitable device. If devices other than those supplied by Novo Nordisk are used, ensure the use of an adequate filter with a pore size of 25 micrometer.
- Attach the vial adapter to the solvent vial. If using a transfer needle, screw the transfer needle tightly onto the syringe.
- Pull the plunger to draw in a volume of air that is equal to the amount of solvent in the solvent vial (ml equals cc on the syringe).
- Screw the syringe tightly onto the vial adapter on the solvent vial. If using a transfer needle, insert the transfer needle into the rubber stopper of the solvent vial. Inject air into the vial by pushing the plunger until you feel a clear resistance.
- Hold the syringe with the solvent vial upside down. If using a transfer needle, make sure the transfer needle tip is in the solvent. Pull the plunger to draw the solvent into the syringe.
- Remove the empty solvent vial. If using a vial adapter, tip the syringe to remove it from the vial.
- Attach the syringe with the vial adapter or transfer needle to the powder vial. If using a transfer needle, make sure to penetrate the centre of the rubber stopper. Hold the syringe slightly tilted with the vial facing downwards. Push the plunger slowly to inject the solvent into the powder vial. Make sure not to aim the stream of solvent directly at the Eptacog alfa (activated) powder as this will cause foaming.
- Gently swirl the vial until all the powder is dissolved. Do not shake the vial as this will cause foaming.
Eptacog alfa (activated) reconstituted solution is colourless and should be inspected visually for particulate matter and discolouration prior to administration.
Do not store reconstituted Eptacog alfa (activated) in plastic syringes.
It is recommended to use Eptacog alfa (activated) immediately after reconstitution.
Administration
- Ensure that the plunger is pushed all the way in before turning the syringe upside down (it may have been pushed out by the pressure in the syringe). If using a transfer needle, make sure the transfer needle tip is in the solution. Hold the syringe with the vial upside down and pull the plunger to draw all the solution into the syringe.
- If using a vial adapter, unscrew the vial adapter with the empty vial. If using a transfer needle, remove the transfer needle from the vial, replace the transfer needle cap, and twist the transfer needle off the syringe.
- Eptacog alfa (activated) is now ready for injection. Locate a suitable site, and slowly inject Eptacog alfa (activated) into a vein over a period of 2 - 5 minutes without removing the needle from the injection site.
Safely dispose of the syringe, vials and any unused product. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Powder in vial and solvent in pre-filled syringe:
Always use an aseptic technique.
Reconstitution
- The Eptacog alfa (activated) powder vial and pre-filled syringe with solvent should be at room temperature at reconstitution. Remove the plastic cap from the vial. If the cap is loose or missing, do not use the vial. Wipe the rubber stopper on the vial with a sterile alcohol swab and allow it to dry for a few seconds before use. Do not touch the rubber stopper after wiping it.
- Remove the protective paper from the vial adapter. Do not take the vial adapter out of the protective cap. If the protective paper is not fully sealed or it is broken do not use the vial adapter. Turn over the protective cap, and snap the vial adapter onto the vial. Lightly squeeze the protective cap with the thumb and index finger. Remove the protective cap from the vial adapter.
- Screw the plunger rod clockwise into the plunger inside the pre-filled syringe until resistance is felt. Remove the syringe cap from the pre-filled syringe by bending it down until the perforation breaks. Do not touch the syringe tip under the syringe cap. If the syringe cap is loose or missing, do not use the pre-filled syringe.
- Screw the pre-filled syringe securely onto the vial adapter until resistance is felt. Hold the pre-filled syringe slightly tilted with the vial pointing downwards. Push the plunger rod to inject all the solvent into the vial. Keep the plunger rod pressed down and swirl the vial gently until all the powder is dissolved. Do not shake the vial as this will cause foaming.
If a larger dose is needed, repeat the procedure with additional vials, pre-filled syringes and vial adapters.
The Eptacog alfa (activated) reconstituted solution is colourless and should be inspected visually for particulate matter and discolouration prior to administration.
It is recommended to use Eptacog alfa (activated) immediately after reconstitution.
Administration
- 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 adapter with the vial.
- Eptacog alfa (activated) is now ready for injection. Locate a suitable site, and slowly inject Eptacog alfa (activated) into a vein over a period of 2 - 5 minutes without removing the needle from the injection site.
Safely dispose of the used materials. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
