COAGULATION FACTOR VIIA RECOMBINANT HUMAN: 952 Adverse Event Reports & Safety Profile

SEVENFACT [coagulation factor VIIa (recombinant)-jncw] is a sterile, white to off-white lyophilized powder in a single-dose vial containing either 1 mg, 2 mg or 5 mg of coagulation factor VIIa (recombinant)-jncw as the active ingredient. SEVENFACT is to be reconstituted with Sterile Water for Injection in a pre-filled syringe supplied with the product. The reconstituted product is a clear to slightly opaque solution of coagulation factor VIIa (recombinant)-jncw at a concentration of 1 mg of protein per mL with a pH of approximately 6.0. SEVENFACT is formulated with arginine, isoleucine, citrate, glycine, lysine and polysorbate 80. It does not contain any antimicrobial preservatives nor human or bovine plasma-derived proteins. The active ingredient in SEVENFACT, activated coagulation Factor VII, is a glycoprotein of 406 amino acids with a molecular weight of approximately 50 kilodaltons. The amino acid sequence of activated coagulation Factor VII is identical to that of human plasma-derived Factor VIIa. It is >99% pure with a nominal specific activity of 45,000 IU/mg of protein when tested against the World Health Organization international standard for human Factor VIIa activity. SEVENFACT is produced by recombinant DNA technology using genetically engineered rabbits into which the DNA coding sequence for human Factor VII has been introduced.

Human

Factor VII is expressed in the rabbit mammary gland and secreted into the milk. During purification and processing, Factor VII is enzymatically converted to activated Factor VII. The manufacturing process of SEVENFACT includes specific steps to reduce impurities. SEVENFACT may contain trace amounts of rabbit proteins. The purification process also includes steps that are validated to inactivate or remove viruses, such as Xenotropic murine leukemia virus (X-MuLV), bovine viral diarrhea virus (BVDV), Pseudorabies virus (PRV), Feline Calicivirus (FCV), and Porcine Parvovirus (PPV).

AND USAGE SEVENFACT is indicated for the treatment and control of bleeding episodes occurring in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors. Limitation s of Use: SEVENFACT is not indicated for the treatment of patients with congenital Factor VII deficiency. SEVENFACT is a coagulation factor VIIa concentrate indicated for the treatment and control of bleeding episodes occurring in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors ( 1 ). Limitation s of Use: SEVENFACT is not indicated for treatment of congenital factor VII deficiency.

AND ADMINISTRATION For i ntravenous u se after reconstitution only . Type of Bleeding Dosing Regimen Recommendation For Mild or Moderate bleeds 75 mcg/kg repeated every 3 hours until hemostasis is achieved or Initial dose of 225 mcg/kg. If hemostasis is not achieved within 9 hours, additional 75 mcg/kg doses may be administered every 3 hours as needed to achieve hemostasis For Severe bleeds 225 mcg/kg, followed if necessary 6 hours later with 75 mcg/kg every 2 hours Consider alternative treatments if successful control of bleeding does not occur within 24 hours of the first administration of SEVENFACT. The vial includes a rubber stopper under the plastic cap. The syringe plunger rod has a wide top end and threaded end. The pre-filled syringe with Water for Injection diluent has a plastic backstop, rubber stopper, syringe tip (luer lock top under syringe cap), and syringe cap. The SEVENFACT 1 mg and 2 mg vial adapter and SEVENFACT 5 mg vial adapter each contain a plastic cover, paper protective cover, and spike (under protective paper).

2.1 Dose For intravenous use after reconstitution only. Dose and duration of SEVENFACT depend on the location and severity of the bleeding, need for urgent hemostasis, frequency of administration, and known patient responsiveness to FVIIa-containing bypassing agents during prior bleeding events. Treatment with SEVENFACT should be initiated as soon as a bleeding event occurs. The dose, frequency, and duration of SEVENFACT therapy should be based on the patient’s clinical response and hemostasis evaluation. The use of laboratory assessment(s) of coagulation (PT/INR, aPTT, FVII:C) does not necessarily correlate with or predict the hemostatic effectiveness of SEVENFACT. Dose adjustment may be required if the patient has received other procoagulant therapies prior to treatment with SEVENFACT. Based on the clinical trial program for SEVENFACT, the recommended initial dose should be adjusted based on the criteria provided in Table 1.

Table

1 Dosing for Treatment and Control of Bleeding Type of Bleeding Dosing Regimen Recommendation Duration of Therapy Mild and Moderate Joint, superficial muscle, soft tissue and mucous membranes. 75 mcg/kg repeated every 3 hours until hemostasis is achieved or Initial dose of 225 mcg/kg. If hemostasis is not achieved within 9 hours, additional 75 mcg/kg doses may be administered every 3 hours as needed to achieve hemostasis. Consider alternative treatments if successful control of bleeding does not occur within 24 hours of the first administration of SEVENFACT. Continue therapy to support healing and prevent recurrent hemorrhage after hemostasis to maintain the hemostatic plug. The site and severity of bleeding should determine therapy duration.

Severe

Life or limb threatening hemorrhage, iliopsoas and deep muscle with neurovascular injury, retroperitoneum, intracranial, or gastrointestinal. Patients should seek immediate medical care if signs or symptoms of severe bleeding occur in the home setting. 225 mcg/kg initially, followed if necessary 6 hours later with 75 mcg/kg every 2 hours until hemostasis is achieved.

Subsequent

Dosing: After achieving hemostasis, base the decision for dosing on clinical assessment and the type of bleeding. Consider the risk of thrombosis with subsequent dosing after achieving hemostatic efficacy. Continue therapy to support healing and prevent recurrent hemorrhage. The site and severity of bleeding and the use of other procoagulant therapies should determine therapy duration.

2.2 Reconstitution Follow the procedures below for reconstitution of SEVENFACT. Calculate the amount of SEVENFACT required and select the appropriate SEVENFACT packages containing the matching pre-filled syringe of sterile Water for Injection, and the vial adapters. Reconstitute each vial with the pre-filled syringe provided with each vial of SEVENFACT. Overview of SEVENFACT P ackage : Figure 1 Vial with SEVENFACT L yophilized P owder Lyophilized Powder Drug Vial Figure 2 Syringe P lunger R od and P re-filled S yringe with Water for Injection D iluent Syringe Plunger Rod Pre-filled S yringe with Diluent Figure 3 SEVENFACT 1 mg and 2 mg V ial A dapter and SEVENFACT 5 mg V ial A dapter Vial Adapters* and Packaging 1 mg and 2 mg V ial A dapter 5 mg V ial A dapter * N ote : Each SEVENFACT kit will contain only one vial adapter. The instructions below serve as a general guideline for reconstitution of SEVENFACT. Reconstitution : Based on the prescribed dose, take out the number of SEVENFACT kits (each kit containing one vial of SEVENFACT powder and one pre-filled Water for Injection diluent syringe with one vial adapter for needleless reconstitution), an infusion set (not supplied in the kit) and an alcohol swab (not supplied in the kit). Check the expiration date on the side of the box(es) for the SEVENFACT kit(s). Always use aseptic technique. Wash your hands with soap and water and dry them using a clean towel or air dry. Take out the contents of one kit and one alcohol swab. Place items on a clean surface. Inspect all contents of the kit. Make sure each vial has a matching colored syringe. Bring SEVENFACT (lyophilized powder) and the specified pre-filled syringe (diluent) to room temperature. The specified volume of diluent corresponding to the amount of SEVENFACT is as follows: 1 mg (1000 micrograms) vial + 1.1 mL Water for Injection diluent in pre-filled syringe 2 mg (2000 micrograms) vial + 2.2 mL Water for Injection diluent in pre-filled syringe 5 mg (5000 micrograms) vial + 5.2 mL Water for Injection diluent in pre-filled syringe Remove the plastic cap from the SEVENFACT vials to expose the central portion of the rubber stopper. Cleanse the rubber stoppers with an alcohol swab and allow to dry prior to use. Peel back the protective paper from the vial adapter. Do not remove the vial adapter from the package. Place the SEVENFACT vial on a flat surface. While holding the vial adapter package, place the vial adapter over the SEVENFACT vial and press down firmly on the package until the vial adapter spike breaks through the rubber stopper. Lightly squeeze the plastic cover and lift up to remove it from the vial adapter. Note: the 5 mg vial adapter may not sit flat against the vial, but it is fully functional. Remove the syringe cap from the pre-filled syringe by holding the syringe body with one hand to unscrew the syringe cap (turn to the left). While holding the edges of the vial adapter, screw on the pre-filled syringe (turn to the right) a few turns until it starts to tighten. Insert the plunger rod into the syringe, then screw a few turns (turn to the right) so that the plunger rod is attached to the gray rubber stopper in the syringe. Push the plunger rod to slowly inject all the diluent into the vial. Keep the plunger rod pressed down and swirl the vial gently until the powder is dissolved. The reconstituted solution is clear to slightly opaque. All powder must be mixed with no particles floating in the liquid. Without withdrawing any drug back into the syringe, unscrew the syringe from the vial adapter (turn to the left) until it is completely detached. Withdraw the liquid drug from the vial(s), using an infusion syringe provided by the pharmacy; the syringe should be large enough to hold the prescribed dose. The reconstituted solution should be stored in the vial at room temperature, but can be stored between 36 o F to 86 o F (2 o C to 30 o C) for up to 4 hours after reconstitution. After reconstitution with the specified volume of diluent, each vial contains approximately 1 mg per mL SEVENFACT (1000 micrograms per mL).

2.3 Administration For Intravenous Use Only . Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is observed. Do not freeze reconstituted solution or store it in a syringe. SEVENFACT must be infused within 4 hours after reconstitution. SEVENFACT should be infused over 2 minutes or less as a bolus intravenous infusion. Do not mix with other infusion solutions. Any unused solution should be discarded 4 hours after reconstitution.

SEVENFACT is contraindicated in patients with: known allergy to rabbits or rabbit proteins. Exposure to SEVENFACT in these patients can result in severe hypersensitivity reaction. severe hypersensitivity reaction to SEVENFACT or any of its components. Exposure to SEVENFACT in these patients can result in severe hypersensitivity reaction. Known allergy to rabbits or rabbit proteins. Severe hypersensitivity reaction to SEVENFACT or any of its components ( 4 ).

REACTIONS The most common adverse reactions (incidence ≥1%) were headache, dizziness, infusion-site discomfort, infusion-site hematoma, infusion-related reaction, and fever ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact HEMA Biologics at 855-718-HEMA (4362) or FDA at 1-800-FDA-1088 or https://www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety database described in this section reflect exposure to SEVENFACT in two clinical studies, Study 1 and Study 2. A total of 42 patients with Hemophilia A or B with or without inhibitors received SEVENFACT: 27 patients in Study 1 at doses 75 mcg/kg and 225 mcg/kg and 15 patients in Study 2 at three escalating dose levels 25 mcg/kg, 75 mcg/kg and 225 mcg/kg <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . The most common adverse reactions (incidence ≥1%) reported in clinical trials for SEVENFACT were headache, dizziness, infusion-site discomfort, infusion-site hematoma, infusion-related reaction, and fever. Adverse reactions reported in the two clinical studies are shown in Table 2.

Table

2 Adverse Reactions Occurring in Clinical Studies Preferred Terms Number of Patient Adverse Reactions (% Incidence Rate)

Study

2 (N=15) Number of A dverse R eactions * Study 2 Number of Patient Adverse Reactions (% Incidence Rate)

Study

1 (N=27) Number of A dverse R eactions * Study 1 Infusion site discomfort - - 1 (4) 4 Infusion site hematoma - - 1 (4) 2 Dizziness 1 (7) 2 - - Headache 1 (7) 1 - - Body temperature increase - - 1 (4) 1 Infusion related reaction** 1 (7) 1 - - * Three patients experienced adverse reactions in Study 2 and two patients experienced adverse reactions in Study 1. ** Symptoms resolved without any intervention and did not recur with subsequent administration.

AND PRECAUTIONS Patients with hemophilia A or B with inhibitors who have other risk factors for thrombosis may be at increased risk of serious arterial and venous thrombotic events ( 5.1 ). Hypersensitivity reactions, including anaphylaxis, are possible with SEVENFACT. Should symptoms occur, patients should discontinue SEVENFACT and seek appropriate medical intervention ( 5.2 ).

5.1 Thrombosis Serious arterial and venous thrombosis can occur with coagulation factor VIIa containing products including SEVENFACT. The following patients may have increased risk of thrombosis with use of SEVENFACT: History of congenital or acquired hemophilia receiving concomitant treatment with aPCC/PCC (activated or non-activated prothrombin complex) or other hemostatic agents History of atherosclerotic disease, coronary artery disease, cerebrovascular disease, crush injury, septicemia, or thromboembolism. Monitor patients who receive SEVENFACT for the development of signs and symptoms of activation of the coagulation system or thrombosis. When there is laboratory confirmation of intravascular coagulation or presence of clinical thrombosis, reduce the dose of SEVENFACT or stop treatment, depending on the patient’s condition.

5.2 Hypersensitivity and Infusion-Related Reactions Hypersensitivity and infusion-related reactions including anaphylaxis can occur with coagulation factor VIIa containing products including SEVENFACT. Sign and symptoms may include hives, itching, rash, difficulty breathing, swelling around the mouth and throat, tightness of the chest, wheezing, dizziness or fainting, and low blood pressure. Patients with known IgE-based hypersensitivity to casein may be at higher risk of hypersensitivity reactions. In the event of hypersensitivity or infusion-related reactions, discontinue SEVENFACT and manage according to clinical practice guideline.

5.3 Neutralizing Antibodies Neutralizing antibodies may occur with the use of SEVENFACT. If treatment with SEVENFACT does not result in adequate hemostasis, then suspect development of neutralizing antibody as the possible cause and perform testing as clinically indicated. Neutralizing antibodies to other Factor VIIa-containing products have been observed in congenital Factor VII-deficient patients. SEVENFACT has not been studied in this patient population. [ See limitation of use statement under Indications and Usage ( 1 )] .

5.4 Laboratory Tests Laboratory coagulation parameters (PT/INR, aPTT, FVII:C) do not correlate with clinical response to SEVENFACT treatment.

INTERACTIONS Clinical experience with pharmacologic use of FVIIa-containing products indicates an elevated risk of serious thrombotic events when used simultaneously with activated prothrombin complex concentrates. Clinical experience with pharmacologic use of FVIIa-containing products indicates an elevated risk of serious thrombotic events when used simultaneously with activated prothrombin complex concentrates ( 7 ).