What is ReFacto?
What is the indication for ReFacto?
What are the contraindications for ReFacto?

Adverse Events
What are common adverse events with ReFacto?

ReFacto: Product Characteristics
What are the important product characteristics of ReFacto?

Manufacturing ReFacto
How is ReFacto produced?
How closely does the factor VIII molecule of ReFacto resemble factor VIII purified from human plasma?
Is ReFacto consistent from one lot to the next?
Who is Wyeth?

Purification Process
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 ReFacto?
What measures are taken to increase the viral safety of ReFacto and the purity of the product?
Stabilizers derived from human or plasma proteins are used in the final formulations of some recombinant products. Is this true for ReFacto?

Pharmacokinetics
What are the half-life and recovery of ReFacto?

Clinical Experience
How extensive is the clinical experience with ReFacto?

Clinical Efficacy
How effective is ReFacto in stopping bleeding episodes in patients with hemophilia A?
What is the efficacy of ReFacto in surgical procedures?
How was prophylaxis evaluated in ReFacto clinical studies?

Incidence of Inhibitor Formation
Has the development of inhibitors been evaluated with ReFacto?

Dosage and Monitoring
How do I dose ReFacto?
How is ReFacto supplied?
How is ReFacto monitored in patients?

Administration and Storage
How is ReFacto administered?
What are the storage requirements for ReFacto? How long does it remain stable after it is reconstituted?

What is ReFacto?
ReFacto is a recombinant B-domain-deleted factor VIII with an albumin-free final formulation.^16* ReFacto works by replacing factor VIII in people with hemophilia A, enabling their blood to clot.

*The Chinese hamster ovary cell line used to produce ReFacto is grown in culture medium that contains human serum albumin. Following purification, the albumin concentration is below the detection limit of the assay.

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What is the indication for ReFacto?
ReFacto is indicated for the control and prevention of hemorrhagic episodes and for surgical prophylaxis and for short-term routine prophylaxis to reduce the frequency of spontaneous bleeding episodes in patients with hemophilia A. The effect of regular routine prophylaxis on long-term morbidity and mortality is unknown.

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What are the contraindications for ReFacto?
The remote possibility exists for hypersensitivity to non-human mammalian proteins. Known hypersensitivity to mouse or hamster proteins may be a contraindication to the use of ReFacto.

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Adverse Events

What are common adverse events with ReFacto?
As with the intravenous administration of any protein product, adverse reactions may include headache, fever, chills, flushing, nausea, vomiting, tiredness, or symptoms of allergic reactions.

Please see Important Safety Information and Prescribing Information for ReFacto.

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ReFacto: Product Characteristics

What are the important product characteristics of ReFacto?
ReFacto has an albumin-free final formulation for enhanced viral safety.† Human serum albumin (HSA) is used in cell culture only; no albumin is added during purification or to the final formulation,¹⁶ thus decreasing the risk of contamination by blood-borne viruses.¹⁶ This state-of-the-art manufacturing process results in a final formulation in which more than 99% of the protein is factor VIII versus less than 1% of the protein in other recombinant factor VIII products that are stabilized with HSA.^16-21

ReFacto is also the only factor VIII approved for short-term routine prophylaxis^16-20. The effect of regular routine prophylaxis on long-term morbidity and mortality is unknown. In clinical trials, previously treated patients undergoing prophylaxis with ReFacto had an almost fourfold reduction in bleeding episodes.¹⁶‡

In ReFacto, the nonessential B-domain of the factor VIII molecule has been removed, resulting in a smaller molecule.⁴⁴ The functional characteristics of ReFacto are comparable to those of endogenous factor VIII.¹⁶

Additionally, ReFacto offers dosing convenience because it is one of the only recombinant factor VIII products available in a 2000 IU vial. The small volume of reconstituted product (4 mL per vial) means that ReFacto offers the lowest volume of reconstituted product for high-dose infusions, such as 2000 IU and 4000 IU.^3-6,16-18

†The Chinese hamster ovary cell line used to produce ReFacto is grown in culture medium that contains human serum albumin. Following purification, the albumin concentration is below the detection limit of the assay.

‡These nonrandomized trial results should be interpreted with caution, as the investigators exercised their own discretion in deciding when and in whom prophylaxis was to be initiated and terminated.

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Manufacturing ReFacto

How is ReFacto produced?

1. Human gene for factor VIII isolated
2. The portion of the factor VIII gene encoding the B-domain is deleted
3. B-domain-deleted recombinant factor VIII (BDDrFVIII) gene inserted into production cell (Chinese hamster ovary cells)
4. Production cells grown in culture media that contain small amounts of human serum albumin
5. Production cells frozen and stored
6. Production cells taken from cell bank and thawed
7. Production cells grow inside bioreactors with human serum albumin in the culture medium
8. ReFacto is filtered away from production cells and then purified and concentrated by a chromatography step
9. ReFacto is processed through a solvent-detergent viral inactivation step
10. ReFacto is processed through monoclonal antibody purification and 3 more chromatography steps
11. ReFacto is then freeze-dried and packaged, and no albumin is added to the final product

Using recombinant technology, the gene for human factor VIII is identified, the B-domain deleted, and the gene inserted into special production cells (Chinese hamster ovary [CHO] cells).¹⁶ Once the gene is inserted into the CHO cells (through a process known as "recombination"), it "instructs" the cells to begin producing factor VIII. As the CHO cells grow and multiply, they produce recombinant factor VIII protein that ultimately becomes ReFacto.¹⁶

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How closely does the factor VIII molecule of ReFacto resemble factor VIII purified from human plasma?
Most of the factor VIII N-linked glycosylation sites are in the B-domain; therefore, the heterogeneity and structural complexity of the ReFacto molecule are greatly reduced. The functional characteristics of ReFacto are comparable to those of endogenous factor VIII (eg, binding kinetics to von Willebrand factor).¹⁶

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Is ReFacto consistent from one lot to the next?
One of the main advantages of recombinant technology is its ability to produce a consistent product with each subsequent lot. Manufacturing runs have produced ReFacto with specific activity within a consistent range. Additional analyses using peptide mapping, carbohydrate fingerprinting, and other characterization and purity measurements have demonstrated the lot-to-lot consistency of ReFacto.¹⁶

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Who is Wyeth?
Wyeth is one of the world's largest research-driven pharmaceutical and health care products companies. It is a leader in the discovery, development, manufacturing, and marketing of pharmaceuticals, vaccines, biotechnology products, and nonprescription medicines that improve the quality of life for people worldwide. The Company's major divisions include Wyeth Pharmaceuticals and Wyeth Consumer Healthcare.

For more than 2 decades, Wyeth divisions have pioneered the creation of recombinant products for people with hemophilia, leading to the introduction of the first commercially available recombinant factor VIII and factor IX products.

Wyeth also offers education, support programs, and assistance for people with hemophilia and their families. And, as part of its strong focus on research and community support, the Company participates in many hemophilia research projects, scientific meetings, and patient advocacy organizations.

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Purification Process

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 ReFacto?
The Chinese hamster ovary cells that produce ReFacto have been specifically adapted to grow in a medium devoid of any animal-derived protein; the medium does, however, have human serum albumin.¹⁶ Following purification, the albumin concentration is below the detection limit of the assay.

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What measures are taken to increase the viral safety of ReFacto and the purity of the product?
ReFacto uses the following multitiered approach to minimize the possibility of contamination by blood-borne pathogens.^26,27

• Manufactured through recombinant technology
• Use of well-characterized Chinese hamster ovary host cells that have been shown to be free of infectious agents
• Extensive testing of production cell line for the presence of microbial and viral contamination, including adventitious viruses and retroviruses
• Routine testing of production cultures for a wide spectrum of potential adventitious viral agents
• Five chromatography steps and a solvent-detergent step that has the capacity to inactivate lipid-enveloped viruses
• Final formulation that does not contain blood or plasma proteins

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Stabilizers derived from human or plasma proteins are used in the final formulations of some recombinant products. Is this true for ReFacto?
No human serum albumin is used in the final formulation of ReFacto. The final formulation contains sodium chloride, sucrose, l-histidine, calcium chloride, and polysorbate 80.¹⁶

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Pharmacokinetics

What are the half-life and recovery of ReFacto?
The half-life and recovery of ReFacto were determined to be comparable to results reported for a plasma-derived factor VIII product.^16,34 In a crossover pharmacokinetic study of 18 previously treated patients (PTPs), the circulating mean half-life of ReFacto was 14.8 ± 5.6 hours. Mean recovery was 118 ± 17% and mean incremental recovery was 2.4 ± 0.4 IU/dL per IU/kg. The circulating mean half-life of the plasma-derived factor VIII product was 13.7± 3.7 hours. Mean recovery was 111 ±14% and incremental recovery was 2.3 ± 0.3 IU/dL per IU/kg.³⁴

The half-life and recovery of ReFacto were also determined to be equivalent to results reported for a full-length recombinant factor VIII product. In a crossover pharmacokinetic study of 17 PTPs, the circulating mean half-life of ReFacto was 13.0 ± 3.1 hours; the mean elimination half-life of the full-length recombinant factor VIII product was 13.6 ± 3.8 hours. Mean recovery of ReFacto was 104 ± 15.5% and mean incremental recovery was 2.23 ± 0.33 IU/dL per IU/kg; mean recovery of the full-length recombinant factor VIII was 110.4 ± 25.3% and mean incremental recovery was 2.35 ± 0.50 IU/dL per IU/kg.⁵⁴

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Clinical Experience

How extensive is the clinical experience with ReFacto?
ReFacto has been studied for more than 6 years at multiple centers in the United States and Europe.^22,23 More than 80,000 infusions have been administered to more than 200 patients for hemorrhages, prophylaxis, and surgery, for a total surpassing 130 million units.^22,23

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Clinical Efficacy

How effective is ReFacto in stopping bleeding episodes in patients with hemophilia A?
ReFacto is indicated for the control and prevention of hemorrhagic episodes and for surgical prophylaxis and for short-term routine prophylaxis to reduce the frequency of spontaneous bleeding episodes in patients with hemophilia A. Clinical trials demonstrated that ReFacto is effective in stopping bleeding episodes. In 113 previously treated patients (PTPs), 73% of bleeding episodes were treated successfully with 1 infusion, and 88% within 2 infusions; hemostatic efficacy was described as "excellent" or "good" by patients or caregivers in 95% of episodes rated.** In 101 previously untreated patients (PUPs), 85% of episodes resolved within 2 infusions, and response was "excellent" or "good" in 94% of episodes rated.^16,22,23**

** Rated at first infusion. 4% of PTP episodes and 4% of PUP episodes were not rated.

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What is the efficacy of ReFacto in surgical procedures?
ReFacto has been successfully used in 39 patients undergoing 51 surgical procedures, including orthopedic surgeries as well as other major and minor procedures.¹⁶

Hemostasis was rated as "excellent" or "good" by the surgeon and treating physician in 99.6% (494/496) of assessments. Treatment with ReFacto was judged as "very useful" or "useful" in 98% (47/48) of procedures at discharge. (One procedure was not rated.)^16,21

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How was prophylaxis evaluated in ReFacto clinical studies?
ReFacto has been studied in short-term routine prophylaxis, and it is the only factor VIII approved for this indication.^{16-20 ||} In uncontrolled clinical trials, 64 previously treated patients were treated on a prophylaxis regimen.¹⁶

The mean number of breakthrough bleeding episodes during prophylaxis periods was nearly four times less than during on-demand periods in the 64 patients undergoing prophylaxis (10 and 37, respectively).¹⁶ These nonrandomized trial results should be interpreted with caution, as the investigators exercised their own discretion in deciding when and in whom prophylaxis was to be initiated and terminated.

^||The effect of regular routine prophylaxis on long-term morbidity and mortality is unknown.

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Incidence of Inhibitor Formation

Has the development of inhibitors been evaluated with ReFacto?
Yes. During 5 years of clinical study, only 1 of 113 (0.9%) previously treated patients developed an inhibitor after 99 exposure days in the study.¹⁶

In a study of previously untreated patients, 32 of 101 (32%) patients developed inhibitors; 16 (50%) of the 32 patients had high titers (>5 BU).¹⁶ Inhibitors subsequently disappeared (less than 0.6 BU/mL) in 15 of the patients who developed inhibitors. At the most recent sampling, there were detectable inhibitors in 15 patients, indicating a prevalence of 15%.

These incidences of inhibitor formation in clinical trials are similar to those reported for other factor VIII products.¹⁶

Low-titer inhibitors are common PUPs and in PTPs on factor VIII products, as are high-titer inhibitors in PUPs. High-titer inhibitors, which are generally rare in previously treated patients, have been reported post-marketing in PTPs on ReFacto.

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Dosage and Monitoring

How do I dose ReFacto?
Dosage and duration of treatment with ReFacto depend on the severity of the factor VIII deficiency, the location and extent of the bleeding, and the patient's clinical condition. Please see the Dosing and Administration section of the Prescribing Information for complete information. Doses administered should be titrated to the patient's clinical response.¹⁶

The calculation of the required dose of ReFacto can be based on the empirical finding that 1 IU of factor VIII per kilogram of body weight is expected, on average, to increase the circulating level of factor VIII by approximately 2 IU/dL per IU/kg administered.¹⁶

The following formula provides a guide to empirical dosage calculations:
Required units = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)

In the presence of an inhibitor, higher doses may be required.¹⁶

For short-term routine prophylaxis to prevent or reduce the frequency of spontaneous musculoskeletal hemorrhage, ReFacto should be given at least twice a week. In some cases, especially in those of pediatric patients, shorter dosage intervals or higher doses may be necessary.¹⁶

Once again, ReFacto offers dosing convenience because of its broad range of vial sizes, including the first 2000 IU vial. In addition, the small volume of reconstituted product (4 mL per vial) means that ReFacto offers the lowest volume of reconstituted product for high-dose infusions, such as 2000 IU and 4000 IU.^16-20,48

When switching to ReFacto, it is important to individually titrate and monitor each patient's dose to ensure an adequate therapeutic response.¹⁶

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How is ReFacto supplied?
Each ReFacto carton holds a single-use vial containing either 250, 500, 1000, or 2000 IU of product; a prefilled diluent syringe; a vial adapter; a sterile infusion set; and 2 alcohol swabs.

ReFacto introduced the convenience device called R2 (Rapid Reconstitution) in November 2004. Click here to obtain more information about the R2 Kit and how it is supplied.

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How is ReFacto monitored in patients?
The chromogenic substrate assay forms the basis for the potency labeling for ReFacto. Either the chromogenic substrate assay or the one-stage clotting assay for the factor VIII activity levels may be used; however, results of the one-stage clotting assay are lower than those obtained with the chromogenic substrate assay.¹⁶

The ReFacto Laboratory Standard^TM was created for use as a calibrated reference for coagulation assays monitoring factor VIII activity levels with either the one-stage clotting or chromogenic substrate assay in patients receiving ReFacto.³⁷

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Administration and Storage

How is ReFacto administered?
ReFacto is administered by intravenous infusion after reconstitution with sterile diluent. For ease of reconstitution and administration, ReFacto requires only 4 mL of diluent for all vial potencies.¹⁶

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What are the storage requirements for ReFacto? How long does it remain stable after it is reconstituted?
ReFacto should be stored under refrigeration (2°C to 8°C, or 36°F to 46°F).

ReFacto also may be stored at room temperature (not to exceed 25°C, or 77°F) for up to 3 months.

Prolonged exposure of the ReFacto vial to light should be avoided during storage. Freezing should be avoided to prevent damage to the diluent vial.

Because ReFacto does not contain a preservative, it should be administered within 3 hours after reconstitution.

ReFacto should not be used after the expiration date on the label.

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Indication
ReFacto is indicated for the control and prevention of hemorrhagic episodes and for surgical prophylaxis and for short-term routine prophylaxis to reduce the frequency of spontaneous bleeding episodes in patients with hemophilia A. The effect of regular routine prophylaxis on long-term morbidity and mortality is unknown.

Important Safety Information

	•	As with the intravenous administration of any protein product, adverse reactions may include headache, fever, chills, flushing, nausea, vomiting, tiredness, or symptoms of allergic reactions.
	•	The remote possibility exists for hypersensitivity to non-human mammalian proteins. Known hypersensitivity to mouse or hamster proteins may be a contraindication to the use of ReFacto.
	•	Allergic reactions such as hives, itching, difficulty breathing, rapid heart rate, light-headedness and anaphylaxis have been reported for all factor VIII products. Patients should discontinue use of the product and contact their health care provider immediately and/or seek emergency care if any of these symptoms occur.

Please see ReFacto 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.