Coagulation factor IX

Get emergency medical help if you have any of these signs of an allergic reaction: hives; wheezing, tightness in your chest, difficult breathing, fast heartbeats, blue lips, feeling like you might pass out; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• swelling in your feet or ankles, weight gain, loss of appetite;
• fever or chills;
• continued bleeding after treatment;
• new or worsened bleeding; or
• signs of excessive blood clotting--sudden numbness or weakness (especially on one side of the body), slurred speech, problems with vision or balance, chest pain, coughing up blood, or pain, swelling, warmth and redness in one or both legs.

Common side effects may include:

• nausea;
• headache;
• dizziness;
• altered sense of taste;
• mild skin rash; or
• pain, stinging, or other irritation where the medicine was injected.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Coagulation Factor IX (Human), Mononine® (coagulation factor ix human) , is a sterile, stable, lyophilized concentrate of Factor IX prepared from pooled human plasma and is intended for use in therapy of Factor IX deficiency, known as Hemophilia B or Christmas disease. Mononine® (coagulation factor ix human) is purified of extraneous plasma-derived proteins, including Factors II, VII and X, by use of immunoaffinity chromatography. A murine monoclonal antibody to Factor IX is used as an affinity ligand to isolate Factor IX from the source material. Factor IX is then dissociated from the mon-oclonal antibody, recovered, purified further, formulated and provided as a sterile, lyophilized powder. The immunoaffinity protocol utilized results in a highly pure Factor IX preparation. It shows predominantly a single component by SDS polyacrylamide electrophoretic evaluation and has a specific activity of not less than 190 Factor IX units per mg total protein.

All Source Plasma used in the manufacture of this product was tested by FDA-licensed Nucleic Acid Tests (NAT) for HCV and HIV-1 and found to be nonreactive (negative).

An investigational NAT for HBV was also performed on all Source Plasma used in the manufacture of this product and found to be nonreactive (negative). The aim of the HBV test is to detect low levels of viral mate-rial, however, the significance of a nonreactive (negative) result has not been established.

This concentrate has been processed by monoclonal antibody immunoaffinity chromatography during its manufacture, which has been shown to be capable of reducing the risk of viral transmission. Additionally, a chemical treatment protocol and two sequential ultrafiltration steps used in its manufacture have also been shown to be capable of significant virus reductions. However, no procedure has been shown to be totally effective in removing the risk of viral infectivity from coagulation factor concentrates (see CLINICAL PHARMACOLOGY and WARNINGS).

Mononine® (coagulation factor ix human) is a highly purified preparation of Factor IX. When stored as directed, it will maintain its labeled potency for the period indicated on the container label.

Each vial contains the labeled amount of Factor IX activity expressed in International Units (IU). One IU represents the activity of Factor IX present in 1 mL of normal, pooled plasma. When reconstituted as recommended, the resulting solution is a clear, colorless, isotonic preparation of neutral pH, containing approximately 100 times the Factor IX potency found in an equal volume of plasma. Each mL of the reconstituted concentrate contains approximately 100 IU of Factor IX and non-detectable levels of Factors II, VII and X ( < 0.0025 IU per Factor IX unit using standard coagulation assays). Each vial also contains histidine (approx. 10mM), sodium chloride (approx. 0.066M), mannitol (approx. 3%) and polysorbate 80 (approx. 0.0075%). Hydrochloric acid and/or sodium hydroxide may have been used to adjust pH. Mononine® (coagulation factor ix human) also contains trace amounts ( ≤ 50 ng mouse protein/100 Factor IX activity units) of the murine monoclonal antibody used in its purification (see CLINICAL PHARMACOLOGY).

Mononine (coagulation factor ix human) ® is to be administered only intravenously.

Dosage Forms, Composition And Packaging

IDELVION, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is a preservative free, sterile, non-pyrogenic, lyophilized powder to be reconstituted with Sterile Water for Injection (SWFI) for intravenous injection. IDELVION is available in single-use vials containing actual FIX activity printed on the vial label and product carton, expressed in International Units (IU). Each vial contains nominally 250 IU, 500 IU, 1000 IU, or 2000 IU of IDELVION and must be reconstituted with the respective supplied volume of SWFI (diluent) listed in Table 7:

Table 7: Reconstitution Diluent Volume

The IDELVION package consists of 2 boxes.

The “Product box” contains one single-use product vial containing lyophilized Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP) and one vial of Sterile Water for Injection (Diluent).

The “Device box” contains one Mix2Vial® filter transfer set, one syringe, one infusion set and a plaster (non-sterile).

After reconstitution of the lyophilized powder, all dosage strengths yield a clear, yellow to colorless solution. The concentrations of excipients based on the presentation are summarized in Table 8.

Table 8: Excipients within each nominal composition of IDELVION following reconstitution with WFI

Storage And Stability

• Store at +2 °C to +25° C. Do not freeze.
• The shelf life of IDELVION is up to 24 months for 250 IU and 500 IU or 36 months for 1000 IU and 2000 IU. Do not use beyond the expiration date on the IDELVION carton and vial labels.
• Store vial in original carton to protect from light.

Product after reconstitution: the product administration should begin promptly or within 3 hours.

CSL Behring Canada, Inc. Revised: Jan 2016

Common adverse reactions observed in > 1% of subjects in clinical studies were dysgeusia, pain in extremity, and positive furin antibody test.

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 clinical practice.

During clinical development, in a combined trial, 99 male previously treated patients (PTPs; exposed to a factor IX-containing product for ≥ 150 days) received at least one infusion of RIXUBIS as part of either on-demand treatment of bleeding episodes, perioperative management of major and minor surgical, dental, or other invasive procedures, routine prophylaxis, or pharmacokinetic evaluation of RIXUBIS. Eleven subjects (11.1%) were < 6 years of age, 12 (12.1%) were 6 to < 12 years of age, 3 (3%) were adolescents (12 to < 16 years of age), and 73 (73.7%) were adults (16 years of age and older). The subjects received a total of 14,018 infusions with a median of 163 infusions of RIXUBIS (range 8 to 327 infusions), for a median of 156 exposure days (range 8 to 316 days).

A total of 337 adverse events were reported in 80 (80.8%) of the 99 subjects. Adverse reactions that occurred in > 1% of subjects are shown in Table 3.

Table 3 : Summary of Adverse Reactions

All 99 subjects were monitored for inhibitory and binding antibodies to factor IX, and binding antibodies to CHO protein and furin, at the following time points: at screening, at 72 hours following the first infusion of RIXUBIS and the commercial recombinant factor IX product in the crossover portion of the pharmacokinetic trial, after 5 and 13 weeks following first exposure to RIXUBIS, and thereafter every 3 months. Antibodies against furin were tested by an in-house enzyme-linked immunosorbent assay (ELISA). A titer of 1:20 or 1:40 was considered to be indeterminate for the above validated assay, as these titers were too low to be verified by the confirmatory assay.

No subjects developed neutralizing antibodies to factor IX. Low-titer, non-neutralizing antibodies against factor IX were observed in 21 (21.2%) subjects at one or more time points. Three of these 21 subjects were found to have these antibodies at screening, prior to receiving RIXUBIS. Six of the 21 subjects were pediatric (2 subjects in < 6 years of age cohort, 4 subjects in 6 to < 12 years age cohort). No clinical adverse findings were observed in any of these 21 subjects.

Nineteen subjects (19.2%) had signals for antibodies against furin (indeterminate specificity). Five of these 19 subjects expressed signals for antibodies at screening, prior to RIXUBIS treatment. One subject had an antibody signal after treatment with the comparator product and prior to RIXUBIS treatment. Two additional subjects had a positive titer of 1:80 that was not present when checked at a later time point and therefore considered transient. Two of the 19 subjects were pediatric (6 to < 12 years age cohort). All post-treatment antibody titer increases in these two pediatric subjects were < 2 dilution steps and therefore considered unrelated to treatment. No clinical adverse findings were observed in any of these 19 subjects.

In a trial of 500 normal volunteers, using the same assay as in the clinical trial, 7% had titers of 1:20 or 1:40 and 1.2% had higher titers ranging from 1:80 to 1:320. These antibodies are thought to be part of a natural immune system response. To date, these antibodies have not been associated with any clinical adverse findings.

The detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

There was no clinical evidence of thromboembolic complications in any of the subjects. Out-of-range values for thrombogenicity markers (thrombin-antithrombin III, prothrombin fragment 1.2, and D-dimer), determined during the pharmacokinetic portion of the combined trial, did not reveal any pattern indicative of clinically relevant thrombogenicity with either RIXUBIS or a comparator factor IX-containing product.

Post-marketing Experience

Because the following reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity (including symptoms such as dyspnea, pruritus)

Urticaria, rash

The following class adverse reactions have been seen with another recombinant factor IX: inadequate factor IX recovery, inhibitor development, anaphylaxis, angioedema, hypotension, and thrombosis.

Included as part of the PRECAUTIONS section.

You should tell your healthcare provider if you:

• Have or have had any medical problems
• Take any medicines, including prescription and non-prescription medicines, such as over-the-counter medicines, supplements, or herbal remedies
• Have any allergies, including allergies to hamsters
• Are breastfeeding. It is not known if coagulation factor IX passes into your milk and if it can harm your baby.
• Are pregnant or planning to become pregnant. It is not known if coagulation factor IX may harm your baby.
• Have been told that you have inhibitors to factor IX (because coagulation factor IX may not work for you).

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• how you respond to this medication
• the severity of your factor IX deficiency
• your weight

Do not use this medication if you have ever had an allergic reaction to a clotting factor medication, or if you are allergic to hamster proteins.

Before using this medication, tell your doctor if you are allergic to latex rubber, or if you have:

• liver disease;
• coronary artery disease (hardening of the arteries); or
• history of stroke or heart attack.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether coagulation factor IX passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Contact your doctor if you miss a dose of this medication.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.