What is BeneFIX?
Why should I prescribe BeneFIX for my patients with hemophilia B?
How is BeneFIX produced?
Why are Chinese hamster ovary (CHO) cells used to make BeneFIX?
Most cell-culture media contain proteins derived from humans and/or animals. Is this also the case for the medium used for the cells that produce BeneFIX?
What additional measures are taken for the viral safety of BeneFIX?
Stabilizers derived from human or plasma products are used in the final formulation of some recombinant products. Is this true for BeneFIX?
How closely does the BeneFIX molecule resemble factor IX purified from human plasma?
How is the purity of BeneFIX confirmed?
What is the specific activity of BeneFIX?
What are the half-life and recovery of BeneFIX after infusion into patients with hemophilia B?
How effective is BeneFIX in stopping bleeding episodes in patients with hemophilia B?
Has BeneFIX been used to successfully prevent bleeding in a surgical setting?
Has the development of inhibitors been a problem with BeneFIX?
What are common side effects of BeneFIX?
What are the guidelines for dosing BeneFIX?
What is the shelf life of BeneFIX?
How soon must BeneFIX be administered after reconstitution?

What is BeneFIX?
BeneFIX is a coagulation factor produced by recombinant DNA technology for use in therapy for factor IX deficiency, known as hemophilia B. BeneFIX is produced without blood or plasma products and is therefore inherently free from the risk of transmission of blood-borne pathogens, such as hepatitis and parvovirus B19.

Why should I prescribe BeneFIX for my patients with hemophilia B?
The most important reason to prescribe BeneFIX is that it has been proven to effectively control and prevent hemorrhagic episodes in patients with hemophilia B—including control and prevention in surgical settings—using a product that is inherently free from the risk of transmission of blood-borne pathogens.

How is BeneFIX produced?
BeneFIX is produced by a genetically engineered Chinese hamster ovary (CHO) cell line. Scientists at Wyeth identified and cloned the gene that directs the formation of factor IX. The cloned gene was inserted into the DNA of the CHO cell. As these genetically engineered CHO cells grow and multiply, they secrete factor IX protein into the cell-culture media. The factor IX is then purified from the cell-culture media through a chromatography-based purification process. This purified material is then lyophilized into vials containing 250, 500, or 1000 IUs.

Click here for manufacturing diagram

Why are Chinese hamster ovary (CHO) cells used to make BeneFIX?
CHO cells were chosen for the production of BeneFIX for several reasons. First, they can perform the posttranslational processing necessary for the secretion of a biologically active recombinant factor IX.¹¹ Second, CHO cells have been characterized extensively for over 45 years and have an established viral safety record.¹¹ Finally, there have been more than 100 million treatments with CHO-based pharmaceuticals, without a single reported case of viral transmission.^11,12

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Most cell-culture media contain proteins derived from humans and/or animals. Is this also the case for the medium used for the cells that produce BeneFIX?
No. The CHO cells that produce BeneFIX were adapted to grow in a state-of-the-art, completely defined, serum-free medium lacking any components derived from blood or plasma products (eg, human serum albumin, transferrin, bovine serum albumin, bovine insulin).¹ Moreover, purification of the BeneFIX produced by these cells does not involve the use of a monoclonal antibody step or the introduction of materials derived from blood or plasma products.¹

What additional measures are taken for the viral safety of BeneFIX?
To address the theoretical possibility of a virus entering the cell-culture process and not being detected, the purification process of BeneFIX comprises several steps with the capacity to remove potential viral contaminants. For example, a membrane filtration step that has the ability to retain molecules with apparent molecular weights of >70,000 (such as large proteins and viral particles) is included for additional viral safety.¹ The effectiveness of the purification process to remove potential viruses has been formally tested with the following model viruses: amphotropic murine leukemia virus (A-MuLV), bovine parvovirus (BPV), human herpes simplex virus (HSV), and reovirus type 3 (Reo-3). These model viruses represent a range of viral classes and sizes, and cover both enveloped and nonenveloped viruses. The purification steps evaluated provide significant (≥10 log₁₀) removal of each of the model viruses tested and thus offer a wide margin of viral safety to address the theoretical possibility of contamination.⁵

Stabilizers derived from human or plasma products are used in the final formulation of some recombinant products. Is this true for BeneFIX?
No blood or plasma products (eg, albumin) are required for the stabilization of BeneFIX.¹³ Only nonproteinaceous excipients are employed in the formulation of the BeneFIX product (ie, glycine, sucrose, L-histidine, and vegetable-derived polysorbate 80).¹

How closely does the BeneFIX molecule resemble factor IX purified from human plasma?
Many state-of-the-art biochemical and biophysical techniques have been used to compare BeneFIX to factor IX derived from human plasma. These analyses indicate that the primary amino acid sequence is identical to the Ala-148 allelic form of plasma-derived factor IX.¹⁴ In addition, the structure and function of BeneFIX were found to be similar to the plasma-derived molecule.¹⁴

How is the purity of BeneFIX confirmed?
Multiple independent and complementary affinity separation methods are used to purify and concentrate BeneFIX. Taken together, these steps produce a consistent product with high purity, structural integrity, and specific activity.

What is the specific activity of BeneFIX?
The specific activity of BeneFIX is ≥200 IU/mg.¹

What are the half-life and recovery of BeneFIX after infusion into patients with hemophilia B?
After single intravenous (IV) doses of 50 IU/kg of BeneFIX in 36 patients, each given as a 10-minute infusion, the mean increase in circulating factor IX activity was 0.8 ± 0.2 IU/dL per IU/kg infused (ranged from 0.4 to 1.4 IU/dL per IU/kg), and the mean biological half-life was 18.8 ± 5.4 hours (ranged from 11 to 36 hours).¹ In an 11-patient crossover study comparing the pharmacokinetics of BeneFIX to a high-purity plasma-derived product, the in vivo recovery with BeneFIX was 28% lower than the recovery with a highly purified plasma-derived factor IX product. There was no significant difference in biological half-life. In subsequent evaluations at 6 and 12 months, the pharmacokinetic parameter estimates did not change.

How effective is BeneFIX in stopping bleeding episodes in patients
with hemophilia B?
BeneFIX is indicated for the control and prevention of hemorrhagic episodes in patients with hemophilia B (congenital factor IX deficiency or Christmas disease), including control and prevention of bleeding in surgical settings. Clinical trials demonstrated that BeneFIX is effective in stopping bleeding episodes. In 56 patients with severe or moderate hemophilia B who received BeneFIX for on-demand control of bleeding episodes, 81% of the episodes were resolved after a single infusion.¹ Of all infusions used to treat these episodes, 88% were rated as providing an excellent or good clinical response.¹

Has BeneFIX been used to successfully prevent bleeding in a surgical setting?
In clinical trials, BeneFIX was used to treat 28 patients who underwent major and minor surgical procedures. These procedures included liver transplantation, hernia repair, orthopedic surgeries, and dental extractions.¹ Preoperative doses ranged from 25 to 155 IU/kg and postoperative doses from 30 to 169 IU/kg.¹⁵ Hemostasis was maintained throughout the surgical period; however, 1 patient required evacuation of a surgical wound site hematoma, and another patient who received BeneFIX after a tooth extraction required further surgical intervention due to oozing at the extraction site.¹

Has the development of inhibitors been a problem with BeneFIX?
Of 56 patients receiving BeneFIX, 1 previously treated patient discontinued therapy because of bleeding that was difficult to control; he did not have a detectable inhibitor.¹ Two of 54 previously untreated patients developed a high-titer inhibitor.¹

What are common side effects of BeneFIX?
BeneFIX is indicated for the control and prevention of hemorrhagic episodes in patients with hemophilia B (congenital factor IX deficiency or Christmas disease), including control and prevention of bleeding in surgical settings.

BeneFIX is not indicated for the treatment of other factor deficiencies (eg, factors II, VII, VIII and X) nor the treatment of hemophilia A patients with inhibitors to factor VIII, nor the reversal of coumarin-induced anticoagulation, nor the treatment of bleeding due to low levels of liver-dependent coagulation factors.

As with the intravenous administration of any protein product, common adverse reactions may include headache, fever, chills, flushing, nausea, vomiting, or tiredness. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported for all factor IX products. Patients should be informed of the early symptoms and signs of hypersensitivity reactions. Patients should discontinue use of the product and contact their health care provider immediately and/or seek emergency care if any hypersensitivity reactions occur. BeneFIX may be contraindicated in patients with a known history of hypersensitivity to hamster protein. The accompanying diluent vial may contain dry natural rubber that may cause hypersensitivity reactions in persons with known or possible latex sensitivity.

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What are the guidelines for dosing BeneFIX?¹
Dosage and duration of treatment for all factor IX products depend on the severity of the factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition, age, and recovery of factor IX. To ensure that the desired factor IX activity level has been achieved, precise monitoring using the factor IX activity assay is advised. Doses should be titrated using the factor IX activity and pharmacokinetic parameters (such as half-life and recovery), as well as taking the clinical situation into consideration in order to adjust the dose as appropriate.

In the clinical efficacy studies⁶, patients were initially administered the same dose previously used for plasma-derived factor IX. Even in the absence of a factor IX inhibitor, approximately half of the patients increased their dose of BeneFIX during these studies. Titrate the initial dose upward if necessary to achieve the desired clinical response. As with some plasma-derived factor IX products, patients at the low end of the observed factor IX recovery may require upward dosage adjustment to as much as 2 times the initial empirically calculated dose in order to achieve the intended rise in circulating factor IX activity.

In adult PTPs, on average, 1 IU of BeneFIX per kg body weight increased the circulating activity of factor IX by 0.8 ± 0.2 (ranged from 0.3 to 1.4) IU/dL. The method of dose estimation is illustrated in the following example:

 

Adult Patients
number of factor IX IU required (IU)	=	body weight (kg)	x	desired factor IX increase (% or IU/dL)	x	1.2 (IU/kg per IU/dL)

In pediatric patients (<15 years of age), on average, 1 IU of BeneFIX per kg body weight increased the circulating activity of factor IX by 0.7 ± 0.2 (ranged from 0.3 to 1.1) IU/dL.

The method of dose estimation is illustrated in the following example:

Pediatric Patients (<15 years)
number of factor IX IU required (IU)	=	body weight (kg)	x	desired factor IX increase (% or IU/dL)	x	1.4 (IU/kg per IU/dL)

      

What is the shelf life of BeneFIX?
BeneFIX should be stored under refrigeration at a temperature of 36º to 46ºF (2º to 8ºC). Prior to the expiration date, BeneFIX may be stored at room temperature (77ºF or 25ºC) for up to 6 months. Freezing should be avoided.

How soon must BeneFIX be administered after reconstitution?
Because BeneFIX does not contain a preservative, it should be used within 3 hours after reconstitution. BeneFIX should not be used after the expiration date on the label.

Indication
BeneFIX is indicated for the control and prevention of hemorrhagic episodes in patients with hemophilia B (congenital factor IX deficiency or Christmas disease), including control and prevention of bleeding in surgical settings. BeneFIX is not indicated for the treatment of other factor deficiencies (eg, factors II, VII, VIII and X) nor the treatment of hemophilia A patients with inhibitors to factor VIII, nor the reversal of coumarin-induced anticoagulation, nor the treatment of bleeding due to low levels of liver-dependent coagulation factors.

Important Safety Information

	•	As with the intravenous administration of any protein product, common adverse reactions may include headache, fever, chills, flushing, nausea, vomiting, or tiredness.
	•	BeneFIX may be contraindicated in patients with a known history of hypersensitivity to hamster protein.
	•	Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported for all factor IX products. Patients should be informed of the early symptoms and signs of hypersensitivity reactions. Patients should discontinue use of the product and contact their health care provider immediately and/or seek emergency care if any hypersensitivity reactions occur.

Please see BeneFIX Prescribing Information

The health information contained herein is provided for educational purposes only and is not meant to replace personal discussions between health care providers and patients. All decisions about patient care must be made with a health care provider who can assess the special needs of each individual patient.