2.1 Dosage

• Measurement of INR prior to treatment and close to the time of dosing is important because coagulation factors may be unstable in patients with need for an urgent surgery and other invasive procedures.
• Individualize BALFAXAR dosing based on the patient’s current pre-dose International Normalized Ratio (INR) value, and body weight (see Table 1 ).
• The actual potency per vial of Factor IX is stated on the carton. The potencies of Factors II, VII, IX and X, Proteins C and S are indicated as ranges.
• Administer Vitamin K concurrently to patients receiving BALFAXAR. Vitamin K is administered to maintain Vitamin K-dependent clotting factor levels once the effects of BALFAXAR have diminished.
• The safety and effectiveness of repeat dosing have not been established and it is not recommended.
• Dose ranging within pre-treatment INR groups has not been studied in randomized clinical trials of BALFAXAR.

* Dosing is based on body weight. Dose based on actual potency is stated on the vial, which will vary from 20-32 Factor IX units/mL after reconstitution. The actual potency for a 500 unit vial ranges from 400-640 units/vial. The actual potency for a 1000 unit vial ranges from 800-1280 units/vial.

† Units refer to International Units.

‡ Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg, maximum dose should not be exceeded.

Example dosing calculation for 80 kg patient:

For example, an 80 kg patient with a baseline of INR of 5.0, the dose would be 2,800 Factor IX units of BALFAXAR, calculated as follows based on INR range of 4-6, see Table 1 :

35 units of Factor IX/kg x 80 kg = 2,800 units of Factor IX required*

* For a vial with an actual potency of 30 units/mL Factor IX, 93 mL would be given (2,800 U/30 U per mL = 93 mL).

Monitor INR and clinical response during and after treatment. In clinical trials, BALFAXAR decreased the INR to ≤1.5 within 30 minutes in most subjects. The relationship between this or other INR values and clinical hemostasis in patients has not been established [see Clinical Studies ( 14 )] .

2.2 Preparation and Reconstitution

BALFAXAR is provided with a transfer device (Nextaro ® ) for reconstitution of the lyophilized powder in diluent (sterile Water for Injection (sWFI)).

BALFAXAR is for single dose only. Do not re-use any of the components.

Inspect all components for physical integrity prior to use. Do not use products or components that appear damaged or broken.

Reconstitute BALFAXAR using aseptic technique for the procedure described below.

The product reconstitutes quickly (1 to 5 minutes) at room temperature (20°C to 25°C; 68°F to 77°F). As BALFAXAR contains no preservatives, the solution should be administered immediately after reconstitution, or within 8 hours, provided sterility is maintained. The reconstituted solution can be stored for up to 8 hours at room temperature (20°C to 25°C; 68°F to 77°F).

Instructions for Reconstitution:

Figure 1	1. Ensure that the lyophilized powder and diluent vials are at room temperature (20°C to 25°C, 68°F to 77°F). This temperature should be maintained during reconstitution. 2. Remove the flip caps from the lyophilized powder and diluent vials and disinfect the rubber stoppers with an alcohol swab and allow to dry. 3. Open the transfer device package by peeling off the lid ( Figure 1 ). To maintain sterility, do not remove the transfer device from the blister package and do not touch the spike.
Figure 2	4. Place the diluent vial on an even, clean surface and hold it firmly. Without removing the blister package, place the blue part of the transfer device on top of the diluent vial and press straight and firmly down until it snaps into place ( Figure 2 ). Do not twist while attaching.
Figure 3	5. While holding onto the diluent vial, carefully remove the blister package from the transfer device by pulling vertically upwards. Make sure to leave the transfer device attached firmly to the diluent vial ( Figure 3 ).
Figure 4	6. Place the lyophilized powder vial on an even, clean surface and hold it firmly. Take the diluent vial with the attached transfer device and turn it upside down. Place the white part of the transfer device connector on top of the powder vial and press firmly down until it snaps into place ( Figure 4 ). Do not twist while attaching. The diluent will flow automatically into the powder vial. Note: The transfer device must be attached to the diluent vial first and then to the lyophilized powder vial. Otherwise, loss of vacuum occurs, and transfer of the diluent does not take place. If diluent is not completely transferred to the lyophilized powder vial during this process, contact your Octapharma representative.
Figure 5	7. With both vials still attached, gently swirl the product vial until the product is fully dissolved. To avoid foam formation, do not shake the vial. BALFAXAR dissolves quickly at room temperature (20°C to 25°C; 68°F to 77°F) and is a clear solution that may be colorless to slightly blue. Unscrew the transfer device counterclockwise into two parts ( Figure 5 ). Do not touch the luer lock connector. 8. Dispose of the empty diluent vial together with the blue part of the transfer device.

Reconstituted products should be inspected visually for particulate matter. Do not use solutions that are cloudy or have deposits.

If the lyophilized powder fails to dissolve completely or an aggregate is formed, do not use the preparation.

After reconstitution, administration should begin promptly or within 8 hours, provided sterility is maintained.

If the same patient is to receive more than one vial, you may pool the contents of multiple vials, provided sterility is maintained. Use a separate unused transfer device for the reconstitution of each product vial.

2.3 Administration

BALFAXAR is for intravenous use after reconstitution only.

Do not mix with other medicinal products; administer through a separate infusion line. The infusion line may be flushed with normal saline before and after administration of BALFAXAR.

Instructions for Infusion:

Figure 6	1. Attach a syringe to the luer lock outlet on the white part of the transfer device (Figure 6).
Figure 7	2. Turn the vial upside down and draw the solution into the syringe ( Figure 7 ).
Figure 8	3. Once the solution has been transferred, firmly hold the barrel of the syringe (keeping the syringe plunger facing down) and remove the syringe from the transfer device ( Figure 8 ). 4. Dispose of the white part of the transfer device together with the empty vial. 5.Attach a suitable administration set to the luer adapter of the syringe. 6.Disinfect the intended injection site appropriately. 7.Administer by intravenous infusion at a rate of 0.12 mL/kg/min (~3 units/kg/min), up to a maximum rate of 8.4 mL/min (~210 units/min). No blood should enter the syringe due to the risk of fibrin clot formation.

Any unused product or waste material should be disposed of immediately in accordance with local requirements.

5.1 Hypersensitivity Reactions

If severe allergic or anaphylactic-type reactions occur, immediately discontinue administration of BALFAXAR and initiate appropriate treatment. Therapeutic measures depend on the type and severity of the undesirable effect.

5.2 Thromboembolic Risk/Complications

There is a risk of thrombosis or disseminated intravascular coagulation when patients with acquired deficiency are treated with human prothrombin complex. [ 1 ] Patients given human prothrombin complex should be observed closely for signs or symptoms of disseminated intravascular coagulation or thrombosis. Because of the risk of thromboembolic complications, monitoring of signs and symptoms should be exercised when administering human prothrombin complex to patients with a history of coronary heart disease, patients with liver disease, or to patients at risk of thromboembolic events or disseminated intravascular coagulation. The potential benefit of treatment should be weighed against the risk of complications. BALFAXAR may not be suitable in patients with thrombotic or thromboembolic events in the prior 3 months, as it has not been studied in these patients. Resumption of anticoagulation should be carefully considered following administration of BALFAXAR and vitamin K once the risk of thromboembolic events outweighs the risk of bleeding.

5.3 Transmissible Infectious Agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses.

Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents e.g., viruses, the vCJD agent, and theoretically, CJD agent, cannot be completely eliminated. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV). The measures taken may be of limited value against non-enveloped viruses such as hepatitis A virus (HAV) and human parvovirus B19 (B19V).

B19V infections may be serious for pregnant women (fetal infection) and for individuals with immunodeficiency or increased erythropoiesis, e.g., hemolytic anemia.

All suspected infections thought by a physician to have been possibly transmitted by this product should be reported by the physician or other healthcare provider to Octapharma USA Inc. at 1-866-766-4860.

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.

In a prospective, randomized, controlled, double-blind, multicenter non-inferiority trial, 208 subjects who required reversal of vitamin K antagonist induced anticoagulation due to the need for urgent surgery were enrolled; 105 received BALFAXAR and 103 Kcentra. Subjects ranged in age from 31 years to 92 years. Adverse reactions for BALFAXAR and the comparator are described below.

Adverse Reactions

The most common adverse reactions observed in ≥ 3% subjects receiving BALFAXAR were procedural pain, wound complications, asthenia, anemia, dysuria, procedural vomiting and catheter site related reaction.

In the post-surgical setting, serious adverse reactions in BALFAXAR treatment arm included cerebral infarction, and pulmonary embolism as well as hemorrhage, acute respiratory failure, shock, subdural hemorrhage. One subject experienced one serious adverse reaction, unstable angina assessed as related to BALFAXAR.

Adverse reactions are summarized for BALFAXAR and Kcentra in the following table:

Deaths

There were a total of four deaths (3.8%) in the BALFAXAR group between 22 and 45 days post surgery, with one (1%) additional death occurring on day 47 just after completion of the study reporting period and one (1%) death in the Kcentra group 10 days after treatment. No deaths were considered to be related to study treatment.

Thromboembolic Events

There were three subjects (2.9%) with BALFAXAR who experienced four thromboembolic events in the randomized controlled trial in urgent surgery; cerebral infarction, pulmonary embolism, unstable angina and myocardial ischemia. The number of thromboembolic adverse reactions assessed as at least possibly related to study treatment was one (1%) with BALFAXAR (unstable angina). There were no thromboembolic events observed in the Kcentra treatment arm.

The following serious adverse reactions are described below and/or elsewhere in the labeling:

• Hypersensitivity Reactions [ see Warnings and Precautions ( 5.1 ) ]
• Arterial and venous thromboembolic complications [ see Boxed Warning and Warning s and Precautions ( 5.2 ) ]
• Possible Transmission of Infectious Agents [ see Warnings and Precautions ( 5.3 ) ]

6.2 Postmarketing Experience

Because post-marketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

The following adverse reactions have been reported during postmarketing use of BALFAXAR outside the US since 2003:

To report SUSPECTED ADVERSE REACTIONS, contact Octapharma USA Inc. at 1-866-766-4860 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy

Risk Summary

There are no data with BALFAXAR use in pregnancy to inform on drug-associated risk. Animal reproduction studies have not been conducted with BALFAXAR. It is not known whether BALFAXAR can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the excretion of BALFAXAR in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BALFAXAR and any potential adverse effects on the breastfed child from BALFAXAR or from the underlying maternal condition.

8.4 Pediatric Use

The efficacy and safety of BALFAXAR have not been evaluated in pediatric patients.

8.5 Geriatric Use

Of the total number of subjects (105) with need for an urgent surgery/invasive procedure treated with BALFAXAR to reverse VKA anticoagulation, 59% were 65 years old or greater and 20% were 75 years old or greater. There is no evidence to suggest that BALFAXAR use in the geriatric population is associated with differences in safety or effectiveness.

12.1 Mechanism of Action

The administration of BALFAXAR provides a rapid increase in plasma levels of the vitamin K-dependent coagulation factors (FII, FVII, FIX, FX) and antithrombotic proteins C and S. Together they are referred to/known as the prothrombin complex. [ 2 ; 3 ] BALFAXAR can temporarily correct the coagulation defect of patients with deficiency of one or several of these factors.

12.2 Pharmacodynamics

In the randomized controlled trial in urgent surgery, the INR was determined at varying time points after the end of infusion. The median INR was 3.0 prior to the infusion and dropped to a median value of 1.30 by the 30-minute time point after the end of infusion. After 24 hours it was 1.25 in the BALFAXAR group (see Table 5 ).

The relationship between these or other INR values and clinical hemostasis in patients has not been established [see Clinical Studies ( 14 )].

12.3 Pharmacokinetics

Since BALFAXAR is given intravenously, bioavailability is proportional to the dose administered. BALFAXAR is distributed, metabolized, and excreted in the same manner as the endogenous proteins (see Table 6 ).

Note: Values reported as geometric mean/geometric SDs (range), except for t max which is reported as median (min-max)

*Mean values SD (due to zero values, the geometric mean could not be calculated)

**The incremental recovery is defined as the rise in the plasma concentrations (%) achieved with 1 IU BALFAXAR/kg BW.

***The absolute recovery is defined as the rise in the plasma concentrations (%) achieved by the dose.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of BALFAXAR or studies to determine the effects of BALFAXAR on genotoxicity or fertility have not been performed.