Niastase Product Monograph

SUMMARY PRODUCT INFORMATION

DESCRIPTION

NiaStase^® (eptacog alfa, activated) contains activated recombinant human blood coagulation Factor VII (rFVIIa) (eptacog alfa, activated). Recombinant Factor VII is a vitamin K-dependent glycoprotein consisting of 406 amino acids (MW approximately 50 K Dalton), which is structurally similar to human plasma-derived Factor VIIa.

INDICATIONS AND CLINICAL USE

NiaStase^® (eptacog alfa, activated) is indicated:

• in hemophilia A/B patients with inhibitors to FVIII or FIX, respectively, for the treatment of bleeding episodes (including treatment and prevention of those occurring during and after surgery).

Based on the data obtained so far with NiaStase^® in the treatment of hemophilia patients with inhibitors, the apparent lack of anamnestic response during and after exposure to NiaStase^® makes it suitable for use in all inhibitor patients.

CONTRAINDICATIONS

Known hypersensitivity to the active substance, the excipients, or to mouse, hamster or bovine protein may be a contraindication to the use of NiaStase^®.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

• Both arterial and venous thromboembolic adverse events have been reported after treatment with NiaStase^®, mostly in patients with predisposing concurrent risk factors. (See General under WARNINGS AND PRECAUTIONS; Pharmacodynamics, under ACTION AND CLINICAL PHARMACOLOGY; ADVERSE REACTIONS).
• Patients with inherent Factor VII deficiency may have pre-existing or may develop anti-Factor VII antibodies during therapy with NiaStase^®. The clinical significance of these antibodies is unknown. See ADVERSE REACTIONS section.

General

The extent of the risk of thrombotic adverse events after treatment with NiaStase^® (eptacog alfa, activated) in patients with hemophilia and inhibitors is not known, but is considered to be low.

Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with aPCCs/PCCs (activated or non-activated prothrombin complex concentrates) may have an increased risk of developing thrombotic events due to their underlying condition or concomitant treatment. Because the risk of thromboembolic complications, caution should be exercised when administering NiaStase^® to patients with a history of coronary heart disease, to patients with liver disease, to patients immobilised 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 NiaStase^® should be weighed against the risk of these complications.

Clinical studies in non hemophilia patients indicated an increased risk of arterial thromboembolic adverse events with the use of NiaStase^® including myocardial infarction, myocardial ischemia, cerebral infarction and cerebral ischemia.

Patients who receive NiaStase^® should be kept under close observation for signs and symptoms of unfavourable activation of the coagulation system or thrombosis. When there is laboratory confirmation of intravascular coagulation or presence of clinical thrombosis, the rFVIIa dosage should be reduced or treatment stopped, depending on the patient's symptoms.

Patients self-administering NiaStase^® at home should be instructed not to exceed three doses. The duration of the ambulatory treatment should not exceed 24 hours. Patients should seek medical attention if bleeding is not controlled or if any unusual symptoms are experienced.

Patients receiving NiaStase^® should be directed in its appropriate use and informed of the benefits and risks associated with treatment. If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient, and patients should be thoroughly instructed in the importance of proper disposal and cautioned against reuse of syringes and needles.

Hypersensitivity and anaphylaxis reactions have rarely been reported with the use of NiaStase^®. Initial treatment with NiaStase^® would always be under medical supervision, where emergency treatment for anaphylaxis can be rapidly applied. Patients should be monitored and warned about the early signs of hypersensitivity reactions and anaphylaxis, and asked to contact a physician if needed.

As recombinant coagulation factor VIIa, NiaStase^®, 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 i.v. antihistamines 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.

A special package insert 'Consumer Information' for patients who self-administer NiaStase^® in a home setting is provided in each package. Also provided in the same package are instructions entitled, 'Health Professional Information'.

Carcinogenesis and Mutagenesis

No chronic carcinogenicity studies have been performed with NiaStase^®. Two mutagenicity studies have given no indication of carcinogenic potential for NiaStase^®. See TOXICOLOGY.

Special Populations

Pregnant Women:

As a precautionary measure it is preferable to avoid the use of NiaStase^® during pregnancy. Data on a limited number of exposed pregnancies indicate no adverse effects of rFVIIa on pregnancy or on the health of the fetus/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/fetal development, parturition or postnatal development (see TOXICOLOGY).

In patients receiving NiaStase^® during delivery or post partum, thrombotic events such as myocardial infarction, pulmonary embolism, deep venous thrombosis, retinal artery occlusion, or cerebral ischemia were observed. In this period, patients are at increased risk for thrombotic complications. It is not known to which extent rFVIIa contributes to the occurrence of these events. No specific preventive actions can be recommended.

Nursing Women:

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 NiaStase^® should be made taking into account the benefit of breast-feeding to the child and the benefit of NiaStase^® therapy to the woman.

Pediatric Patients (birth to 16 years of age):

Evidence for the safety and effectiveness of NiaStase^® has been obtained in the age groups up to adolescence (up to 16 years of age). When dosed on a body weight basis, the efficacy and safety of NiaStase^® appear to be comparable in adult and pediatric patients. Available clinical trials and post marketing data show a faster clearance of FVII in children. However, the data are insufficient to support the recommendation of higher doses in children. See also PART II - CLINICAL TRIALS.

Geriatric Patients (≥ 65 years of age):

Clinical studies in hemophilia did not enrol geriatric patients.

Monitoring and Laboratory Tests

It should be noted that the therapeutic range of NiaStase^® for hemostasis has not been identified in tests for prothrombin time (PT), aPTT, and plasma FVII clotting activity (FVII:C). For these reasons, coagulation parameters should be used only as an adjunct to the evaluation of clinical hemostasis to monitor the effectiveness and treatment schedule of NiaStase^® in patients.

Monitoring the effectiveness of therapy, the need for additional doses of NiaStase^® or a change to alternative therapy should be based on the changes in the clinical parameters of pain, swelling and joint mobility compared to baseline or, if following improvement in any of the above parameters; symptoms of a rebleed are present.

There is no requirement for monitoring of NiaStase^® therapy. Severity of bleeding condition and clinical response to NiaStase^® administration must guide dosing requirements.

After administration of NiaStase^®, 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 NiaStase^®.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most serious adverse drug reactions observed in patient receiving NiaStase^® (eptacog alfa, activated) are thrombotic events, however the extent of the risk of thrombotic adverse events after treatment with NiaStase^® in individuals with hemophilia and inhibitors is considered to be low.

The most common adverse drug reactions observed for the labelled indication of NiaStase^® are pyrexia, injection site reaction, headache, hypertension, hypotension, nausea, vomiting, pain, oedema and rash. See WARNINGS AND PRECAUTIONS.

Patients who receive NiaStase^® should be kept under close observation for signs and symptoms of unfavourable activation of the coagulation system or thrombosis.

Clinical Trial Adverse Drug Reactions in the Hemophiliac Population

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

During clinical studies in 298 hemophilia A/B patients with inhibitors involving 1,939 bleeding episodes, there were 182 adverse reactions that were possibly related or of unknown relationship to NiaStase^®. Of these, there were 21 serious adverse reactions that were possibly related or of

unknown relation to treatment reported in 14 patients, and included 6 deaths. During the clinical program, 4 episodes of clinical or laboratory evidence of DIC were documented in hemophilia patients with inhibitors.

In the clinical studies, thrombogenicity has been associated rarely with the use of NiaStase^® (11 events out of 1,939 treatment episodes for an incidence of <1%). Thrombosis was reported in two of the 298 patients with hemophilia.

In 175 surgical procedures with NiaStase^®, three thrombotic events occurred - one thrombosis, one episode of phlebitis and one patient with a large abscess and sepsis died of DIC. In the clinical testing program, isolated cases of antibody development have been reported in FVII deficient patients after treatment with NiaStase^®.

No severe allergic reactions have occurred in hemophilia patients receiving NiaStase^®. Additionally, the potential for development of antibodies towards NiaStase^® has been followed in hemophilia A/B patients and in none of these cases have antibodies towards NiaStase^® or other potentially antigenic components of the drug product (BHK-cell protein, murine IgG, or bovine serum) been detected.

In a clinical study comparing the safety and efficacy of NiaStase^® when administered through bolus injection versus continuous infusion to hemophiliacs with inhibitors during and after surgery, seven of 24 patients had serious adverse events (4 for bolus injection, 3 for continuous infusion). There were 4 serious adverse events which were considered probably or possibly related to rFVIIa treatment (2 events of decreased therapeutic response in each treatment arm). No deaths occurred during the study period.

Table 1 – Adverse events that were reported in ≥ 1% of NiaStase^® Treatment Episodes and were considered to be possibly related to NiaStase^® administration.

Less Common Clinical Trial Adverse Drug Reactions (< 1%)

Gastrointestinal: < 1 %

Liver and biliary: < 1 %

Metabolic and Endocrine: < 1 %

Respiratory: < 1 %

Urinary: < 1 %

Application Site: < 1 %

Resistance mechanism: < 1 %

Other: < 1 %

Abnormal Hematologic and Clinical Chemistry Findings

Table 2 – Coagulation Parameter Shifts in Hemophilia A/B Patients with Inhibitors

* Refers to potential clinically significant shift during the study. A shift to D-dimer values higher than the normal range may be clinically significant, while a shift to fibrinogen and platelet values lower than normal range may be clinically significant.

Table 3 – Clinical Chemistry Parameter Shifts in Hemophilia A/B Patients with Inhibitors

* Refers to potential clinically significant shift during the study. Increases to values above the normal range in alkaline phosphatase, ALT, AST and LDH may indicate changes in liver function, while increase in creatine may indicate renal function changes.

Post-Market Adverse Drug Reactions

The following post-marketing adverse drug reactions are reported voluntarily from a population of uncertain size; hence, it is not possible to estimate their frequency or establish a causal relationship to exposure.

Based on post-marketing experience adverse drug reactions are rare (< 1 per 1,000 standard doses). When analyzed by system organ classes, the reporting rates of adverse drug reactions during the post-marketing period, including both serious and non-serious reactions, are as indicated in the table below:

Table 4 - Reporting Rates of Post-marketing Adverse Drug Reactions

Adverse Drug Reaction Reporting and Re-Issuance of the Product Monograph

Healthcare providers are encouraged to report Adverse Drug Reactions associated with normal use of these and all drug products to Health Canada’s Health Product Safety Information Division at 1-866-234-2345. The Product Monograph will be re-issued in the event of serious safety concerns previously unidentified or at such time as the sponsor provides the additional data in support of the product’s clinical benefit.

DRUG INTERACTIONS

Serious Drug Interactions

• NiaStase^® (eptacog alfa, activated) should not be mixed with infusion solutions or be given in a drip.
• Simultaneous use of prothrombin complex concentrates, activated or not, should be avoided.

Overview

The risk of a potential interaction between NiaStase^® and coagulation factor concentrates is unknown.

Anti-fibrinolytics have been reported to reduce blood loss in association with surgery in hemophilia patients, especially in orthopaedic surgery and surgery in regions rich in fibrinolytic

activity, such as the oral cavity. Experience with concomitant administration of anti-fibrinolytics and NiaStase^® treatment is, however, limited.

Drug-Drug Interactions

Interactions with other drugs have not been established.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Changes in D-Dimer, Fibrinogen, Platelets, Alkaline Phosphatase, ALT, AST, LDH and Creatine were seen in clinical trials. See ADVERSE REACTIONS – Abnormal Hematologic and Clinical Chemistry Findings.

DOSAGE AND ADMINISTRATION

Dosing Considerations

• Treatment should be initiated under the supervision of a physician experienced in the treatment of hemophilia and/or bleeding disorders.
• Hemostasis evaluation should be used to determine the effectiveness of NiaStase^® (eptacog alfa, activated) and to provide a basis for modification of the NiaStase^® treatment schedule.

• NiaStase^® should be given as early as possible after the start of a bleeding episode.

  Following the initial dose of NiaStase^® 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.

• In hereditary severe FVII-deficient patients, replacement therapy with NiaStase^® in doses of

  15 to 30 µg/kg at 4 to 6 hour intervals has been shown to significantly shorten or normalize prothrombin time. However, no correlation has been demonstrated between PT and aPTT and clinical efficacy of NiaStase^®.

Recommended Dose and Dosage Adjustment

NiaStase^® is intended for intravenous bolus administration only. The recommended dose range, dose, frequency, and duration of NiaStase^® administration as a single agent are outlined below. Coagulation parameters should not be used to evaluate NiaStase^® effectiveness.

NiaStase^® Dosage

* Doses between 35 and 120 µg/kg have been used successfully in clinical trials for hemophilia A or B patients with inhibitors, and both the dose and administration interval may be adjusted based on the severity of the bleeding and degree of hemostasis achieved.

Reconstitution:

Reconstitution should be performed using the following procedures.

• Always use aseptic technique.

• Bring NiaStase^® (white, lyophilized powder) and the specified volume of diluent (Sterile

  Water for Injection, USP - without preservative) to room temperature, but not above 37°C (98.6°F).

• The specified volume of diluent corresponding to the amount of NiaStase^® is as follows:

Parenteral Products:

* Commercially available Sterile Water for Injection, without preservatives.

• Remove caps from NiaStase^® vial and diluent vial to expose the central portion of the rubber stoppers. Cleanse the rubber stoppers with an alcohol swab and allow to dry prior to use.
• Draw back the plunger of a sterile syringe (attached to a sterile needle) and admit air into the syringe.
• Inject the air into the vial containing Sterile Water for Injection (diluent).
• Withdraw the diluent and inject it into the NiaStase^® vial through the centre of the rubber stopper (the NiaStase^® vial does not contain vacuum).
• Gently swirl the NiaStase^® vial until all the material is dissolved. The reconstituted solution is colourless. Do not shake the vial, as this will cause ‘foaming’.

After reconstitution with the appropriate volume of diluent each vial contains 30 KIU/mL (0.6 mg/mL).

Administration

Administration should take place immediately or at least within 3 hours after reconstitution. Any unused solution should be discarded. Do not store reconstituted NiaStase^® in syringes. NiaStase^® is intended for intravenous bolus injection only and should not be mixed with infusion solutions or be given in a drip. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever the solution and container permit. Administration should be performed using the following procedures.

• Always use an aseptic technique.
• Draw back the plunger of the sterile syringe (attached to the sterile transfer needle) and admit air into the syringe.
• Insert the needle into the vial of reconstituted NiaStase^®. Inject the air into the vial and then withdraw the reconstituted material into the syringe.
• Remove and discard the transfer needle from the syringe; attach a suitable intravenous injection needle and administer.

OVERDOSAGE

Dose limiting toxicities of NiaStase^® (eptacog alfa, activated) have not been investigated in clinical trials.

The following are examples of accidental overdose. One hemophilia B patient (16 years of age, 68 kg) received a single dose of 352 μg/kg, and one hemophilia A patient (2 years of age, 14.6 kg) received doses ranging from 246 μg/kg to 986 μg/kg on five consecutive days. There were no reported complications in either case. One newborn female congenital FVII-deficient patient (7 weeks of age, 3 kg) received one dose of 800 μg/kg and 8 doses of 400 μg/kg and subsequently developed antibodies to FVII. No thrombotic complications as a result of the overdosages were reported.

A Factor VII deficient male (83 years of age, 111.1 kg) received two doses of 324 µg/kg (10-20 times the recommended dose) and experienced a thrombotic event (occipital stroke). In addition, the development of antibodies against NiaStase^® and FVII, has been associated with overdose in patients with factor VII deficiency.

In addition, 16 normal volunteers in a dose escalation study received doses up to 320 µg/kg without serious adverse reactions.

The recommended dose schedule should not be intentionally increased, even in the case of lack of effect, due to the absence of information on the additional risk that may be incurred.

ACTION AND CLINICAL PHARMACOLOGY

Pharmacodynamics

NiaStase^® (eptacog alfa, activated), when complexed with tissue factor at the site of injury, activates coagulation Factor X (to Factor Xa), as well as coagulation Factor IX (to Factor IXa). Factor Xa then converts prothrombin to thrombin. Thrombin leads to the activation of platelets and factors V and VIII at the site of injury and to the formation of the hemostatic plug by converting fibrinogen into fibrin. Pharmacological doses of NiaStase^® 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. Accordingly, the pharmacodynamic effect of factor VIIa gives rise to an increased local formation of factor Xa, thrombin and fibrin. Because NiaStase^® can activate Factor X independent of Factor VIII and IX activity, it can be used for the management of bleeding episodes and surgery in patients with inhibitors to coagulation Factors VIII or IX.

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.

Pharmacokinetics

Single-dose pharmacokinetic studies of NiaStase^® (17.5, 35, and 70 µg/kg) exhibited linear kinetics. FVII clotting activities were measured in plasma drawn prior to and during a 24-hour period after NiaStase^® administration.

NiaStase^® is distributed into a volume corresponding to 2 to 3 times the plasma volume. The median apparent volumes of distribution at steady state and at elimination were 106 and 122 mL/kg in non-bleeding hemophiliacs and 103 and 121 mL/kg in bleeding hemophiliacs, respectively. Median clearance was 31 mL/kg/h in hemophiliacs who were not bleeding and 33 mL/kg/h in hemophiliacs during bleeding episodes. The elimination of NiaStase^® was described by mean residence time and half-life (t½). In non-bleeding hemophiliacs, the median mean residence time was 3.4 hours and the median t½ was 2.9 hours. Compared with these results, elimination appeared faster in bleeding episodes, where the median mean residence time was 3 hours, and the median t½ was 2.3 hours. The median, in vivo plasma recovery was 46% in non-bleeding episodes and 43% in bleeding episodes.

STORAGE AND STABILITY

Temperature:

Store under refrigeration (2° to 8°C).

Do not freeze.

Do not store reconstituted NiaStase^® (eptacog alfa, activated) in syringes.

Light:

Store in original package in order to protect from light.

Other:

The vials should not be used after the expiration date. NiaStase^® should not be mixed with infusion solutions or given in a drip.

SPECIAL HANDLING INSTRUCTIONS

Each vial of reconstituted NiaStase^® (eptacog alfa, activated) should be used within 3 hours.

Table 5 – Recommended Storage Period and Conditions for NiaStase^®

* Chemical and physical stability has been demonstrated after reconstitution for 24 hours at 25°C. From a microbiological perspective, each vial of reconstituted NiaStase^® should be used within 3 hours.

DOSAGE FORMS, COMPOSITION AND PACKAGING

NiaStase^® (eptacog alfa, activated) is supplied as a white, lyophilized powder in single-use vials. There is one vial per package. The amount in milligrams and kilo-international units is stated on the label as follows:

• 1.2 mg per vial (60 KIU/vial)
• 2.4 mg per vial (120 KIU/vial)
• 4.8 mg per vial (240 KIU/vial)

The following non-medicinal ingredients are found in NiaStase^®:

• sodium chloride (3 mg/mL)
• calcium chloride dihydrate (1.5 mg/mL)
• glycylglycine (1.3 mg/mL)
• polysorbate 80 (0.1 mg/mL)
• mannitol (30 mg/mL)

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: eptacog alfa (activated)

Chemical name: activated recombinant coagulation factor VII

Molecular formula

and molecular mass: C₁₉₈₂H₃₀₅₄N₅₆₀O₆₁₈S₂₈, approximately 50 KD

Structural formula: A polypeptide consisting of 406 amino acids. rFVIIa is the two chain form of rFVII generated by a cleavage of the peptide bond between amino acids in position 152 and 153. The two chains are held together by a single disulphide bridge.

The molecule is glycosylated at the amino acids in position 52, 60,

145 and 322, and γ-carboxylated in the Glu-residues (partial γ-carboxylation in position 35).

Physicochemical properties:

Description: The powder for injection is a white lyophile, and the reconstituted preparation is a colourless solution.

Isoelectric Point: At pH 6.0-6.7

1 KIU equals 1000 International Units (IU).

Product Characteristics

Human FVII was cloned and expressed in baby hamster kidney (BHK) cells.

Recombinant Factor VII is secreted from BHK cells and converted to the active form (Recombinant Factor VIIa) during the purification process. NiaStase^® (eptacog alfa, activated) is structurally similar to human plasma-derived Factor VIIa.

Production of NiaStase^® via recombinant DNA technology eliminates the risks of transmission of human blood-borne pathogens such as HIV, hepatitis viruses and parvovirus.

CLINICAL TRIALS

Five adequate and well-controlled studies (see Table 6) and several supporting studies have provided substantial evidence for the efficacy of NiaStase^® (eptacog alfa, activated). In these trials hemophilia patients with inhibitors were treated with NiaStase^® for several types of bleeding episodes and for hemostasis during surgical procedures. The efficacy rates of NiaStase^® are shown in Table 8.

These efficacy results are consistent with results obtained in supporting clinical studies (see Table 7) with NiaStase^®.

Using the FVIIa assay, the pharmacokinetic properties of NiaStase^®were studied in 12 paediatric and 5 adult patients. Dose proportionality was established 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 per kg body weight). Mean clearance was approximately 50% higher in paediatric patients relative to adults (78 versus 53 mL kg^-1 h^-1), whereas the mean terminal half life was determined to 2.3 hours in both groups. Mean volume of distribution at steady state was 196 mL kg^-1 in paediatric patients versus 159 mL kg^-1 in adults.

Study demographics and trial design

Table 6 – Hemophilia A/B Patients with Inhibitors in Adequate and Well-Controlled Clinical Studies

Table 7 – Hemophilia A/B Patients with Inhibitors in Supporting Studies of Efficacy

Table 8 – Efficacy rates with NiaStase^®

DETAILED PHARMACOLOGY

A hemophilia rat model is not available. In this species, the direct effect of eptacog alfa, activated (rFVIIa) on bleeding was studied in warfarin-treated rats in a rat tail bleeding test. Warfarin treatment results in low levels of the vitamin K-dependent coagulation factors such as Factor II (prothrombin) and X which are essential for the effect of FVIIa. The effect of rFVIIa on prothrombin time in rat plasma was determined, where thromboplastin was prepared from rat brain. Similar tests were conducted in rabbits. The hemostatic effect of rFVIIa was studied in hemophiliac dogs, which are considered the standard model.

• The increased bleeding time in warfarin-treated rats was completely normalized by rFVIIa

  195 µg/kg and partially normalized by 39 µg/kg. This was associated with normalization of prothrombin time, and a modest reduction of activated partial thromboplastin time.

• In warfarin-treated rats, rFVIIa 13 or 40 µg/kg almost normalized prothrombin time;

  shortening of activated partial thromboplastin time was modest. Similar results were obtained in rabbits.

• rFVIIa corrects the hemostatic defect in hemophilia A and B dogs both when given as prevention, i.e. before the onset of bleeding, and when given as treatment of ongoing bleeding (45-155 µg/kg, single dose).

A study in rabbits examining coagulation following administration of 78 to 780 µg/kg NiaStase^® (eptacog alfa, activated) alone, 50 U/kg of an activated prothrombin complex concentrate (aPCC) alone, or a combination of NiaStase^® and the aPCC was performed. The results demonstrated decreased platelets and fibrinogen and increased activated partial thromboplastin time (aPTT) subsequent to a PCC administration and no effect following NiaStase^® administration. Administration of 50 U/kg aPCC and then 78 µg/kg NiaStase^® within 5 minutes demonstrated a trend towards increased coagulation factor consumption effects beyond those levels observed with aPCC administration alone. During the clinical program, 4 episodes of clinical or laboratory evidence of DIC were documented in hemophilia patients with inhibitors.

A study in rabbits examining coagulation following administration of 100 µg/kg NiaStase^® in combination with tranexamic acid demonstrated no interaction effect on coagulation parameters.

TOXICOLOGY

Carcinogenesis and Mutagenesis

The clastogenic activity of NiaStase^® (eptacog alfa, activated) was evaluated in both in vitro studies (i.e. cultured human lymphocytes) and in vivo studies (i.e. mouse micronucleus test). Neither of these studies indicated clastogenic activity of NiaStase^®. Gene mutation studies (e.g. Ames test) have not been performed with NiaStase^®.

Preclinical reproductive studies in male and female rats with dose ranges of 0.33-6.0 mg/kg/day had no effect on mating performance, fertility or litter characteristics.

Acute toxicity

• No drug-related effects were seen in mice at doses of 0.24 to 3.9 mg/kg. In other studies, mice treated at 0.69 to 14.8 mg/kg showed decreased activity, unsteady gait, convulsions, and laboured respiration.
• At 15.6 mg/kg in mice, clinical signs were seen on day of dosing only; they included laboured and rapid respiration, ptosis, piloerection, decreased rectal temperature, decreased activity. There were some deaths, in some cases preceded by convulsions.
• Histopathology of mice revealed edema at the injection site (treated and controls), the presence of occlusions or fibrin emboli of the large vessels of the lungs caused by intravascular coagulation.
• No drug-related toxicity in rats at doses of up to 15.6 mg/kg. Discolouration of the injection site seen at the higher doses.

Long Term Toxicity

Table 9 – Long Term Toxicity Studies in Animals

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