4.1. Therapeutic indications

NovoSeven 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 past or present refractoriness to platelet transfusions, or where platelets are not readily available.

Severe postpartum haemorrhage

NovoSeven is indicated for the treatment of severe postpartum haemorrhage when uterotonics are insufficient to achieve haemostasis.

4.2. Posology and method of administration

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

In the management of severe postpartum haemorrhage, appropriate multidisciplinary expertise should be consulted. In addition to obstetricians, this includes anaesthesiologists, critical care specialists and/or haematologists. Standard management practices should remain implemented, based on the individual patient's requirements. Maintenance of adequate fibrinogen concentration and platelet count is recommended in order to optimise the benefit of NovoSeven treatment.

Posology

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

Dose

NovoSeven 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 NovoSeven 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 (see section 5.2).

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

NovoSeven 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 NovoSeven 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 (see section 5.1).

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.

Severe postpartum haemorrhage

Dose range and dose interval

The recommended dose range for the treatment of bleeding is 60 – 90 µg per kg body weight administered by intravenous bolus injection. Peak coagulant activity can be expected at 10 minutes. A second dose can be administered based on clinical response of the individual patient.

It is recommended that in case of insufficient haemostatic response, a second dose can be administered after 30 minutes.

Method of administration

For instructions on reconstitution of the medicinal product before administration, see section 6.6. Administer the solution as an intravenous bolus injection over 2 – 5 minutes.

Monitoring of treatment – laboratory tests

There is no requirement for monitoring of NovoSeven therapy. Severity of bleeding condition and clinical response to NovoSeven 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.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse, hamster or bovine protein.

4.4. Special warnings and precautions for use

In pathological conditions in which tissue factor may be expressed more extensively than considered normal, there may be a risk of development of thrombotic events or induction of Disseminated Intravascular Coagulation (DIC) in association with NovoSeven 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 NovoSeven to patients with a history of coronary heart disease, to patients with liver disease, to post-operative patients, to pregnant or peripartum women, to neonates, or to patients at risk of thromboembolic events or DIC. In each of these situations, the potential benefit of treatment with NovoSeven should be weighed against the risk of these complications.

In severe postpartum haemorrhage and pregnancy, the clinical conditions (delivery, severe haemorrhage, transfusion, DIC, surgery/invasive procedures and coagulopathy) are known contributing factors to the thromboembolic risk; and in particular venous thromboembolic risk associated with the administration of NovoSeven (see section 4.8).

As recombinant coagulation factor VIIa NovoSeven 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 NovoSeven.

Factor VII deficient patients should be monitored for prothrombin time and factor VII coagulant activity before and after administration of NovoSeven. 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 NovoSeven during surgery but the risk of thrombosis in factor VII deficient patients treated with NovoSeven is unknown (see section 5.1).

Sodium content

The medicinal product contains less than 1 mmol sodium (23 mg) per injection, indicating that it is essentially 'sodium free'.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

4.5. Interaction with other medicinal products and other forms of interaction

The risk of a potential interaction between NovoSeven and coagulation factor concentrates is unknown. Simultaneous use of prothrombin complex concentrates, activated or not, should be avoided.

Antifibrinolytics have been reported to reduce blood loss in association with surgery in haemophilia patients, especially in orthopaedic surgery and surgery in regions rich in fibrinolytic activity, such as the oral cavity. Antifibrinolytics are also used to reduce blood loss in women with postpartum haemorrhage. Experience with concomitant administration of anti-fibrinolytics and rFVIIa treatment is, however, limited.

Based on a non-clinical study (see section 5.3) it is not recommended to combine rFVIIa and rFXIII. There are no clinical data available on interaction between rFVIIa and rFXIII.

4.6. Fertility, pregnancy and lactation

Pregnancy

As a precautionary measure, it is preferable to avoid use of NovoSeven during pregnancy. Data on a limited number of exposed pregnancies within approved indications indicate no adverse effects of rFVIIa 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 (see section 5.3).

Breast-feeding

It is unknown whether rFVIIa is excreted in human breast milk. The excretion of rFVIIa in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with NovoSeven should be made taking into account the benefit of breast-feeding to the child and the benefit of NovoSeven therapy to the woman.

Fertility

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

4.7. Effects on ability to drive and use machines

No studies on the effect on the ability to drive and use machines have been performed.

4.8. Undesirable effects

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 include venous thromboembolic events (uncommon: ≥ 1/1,000 to < 1/100) and arterial thromboembolic events (rare: ≥ 1/10,000 to < 1/1,000).

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 (see section 4.4)

- Related laboratory findings, including elevated levels of D-dimmer and decreased levels of AT (see section 4.4)

- 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 (see sections 4.3 and 4.4)

- 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. It is important that the dosage regimen of NovoSeven is compliant with the recommended dosage as stated in section 4.2.

Description of selected adverse reactions

Inhibitory antibody formation

In post-marketing experience, there have been no reports of inhibitory antibodies against NovoSeven or FVII in patients with haemophilia A or B. Development of inhibitory antibodies to NovoSeven 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 NovoSeven 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 NovoSeven, were present. Patients with factor VII deficiency treated with NovoSeven should be monitored for factor VII antibodies (see section 4.4).

Thromboembolic events - arterial and venous

When NovoSeven 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 NovoSeven 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 NovoSeven have not been established outside the approved indications and therefore NovoSeven 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.

Women with severe postpartum haemorrhage

In an open-label randomised clinical trial, venous thromboembolic events were reported in 2 of 51 patients treated with a single dose of NovoSeven (median dose 58 µg/kg) and none of 33 patients not treated with NovoSeven; no arterial thromboembolic events were reported in either group.

In 4 non-interventional studies, venous thromboembolic events were reported in 3 of 358 (0.8%) patients treated with NovoSeven (median dose range 63-105 µg/kg) and arterial thromboembolic events were reported in 1 (0.3%) patient treated with NovoSeven.

For known contributing factors to thromboembolic risk associated with pregnancy and severe postpartum haemorrhage, see section 4.4.

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Dose limiting toxicities of NovoSeven 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 NovoSeven 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.