Xyntha

The active ingredient in XYNTHA, Antihemophilic Factor (Recombinant), is a recombinant antihemophilic factor (rAHF), also called coagulation factor VIII, which is produced by recombinant DNA technology. It is secreted by a genetically engineered Chinese hamster ovary (CHO) cell line. The cell line is grown in a chemically defined cell culture medium that contains recombinant insulin, but does not contain any materials derived from human or animal credits.

The rAHF in XYNTHA is a purified glycoprotein, with an approximate molecular mass of 170 kDa consisting of 1,438 amino acids, which does not contain the B-domain.13 The amino acid sequence of the rAHF is comparable to the 90 + 80 kDa form of human coagulation factor VIII.

The purification process uses a series of chromatography steps, one of which is based on affinity chromatography using a patented synthetic peptide affinity ligand.14 The process also includes a solvent-detergent viral inactivation step and a virus-retaining nanofiltration step.

The potency expressed in International Units (IU) is determined using the chromogenic assay of the European Pharmacopoeia. The Wyeth manufacturing reference standard for potency has been calibrated against the World Health Organization (WHO) International Standard for factor VIII activity using the one-stage clotting assay. The specific activity of XYNTHA is 5,500 to 9,900 IU per milligram of protein.

XYNTHA is formulated as a sterile, nonpyrogenic, no preservative, lyophilized powder preparation for intravenous injection. Each singleuse vial contains nominally 250, 500, 1000, or 2000 IU of XYNTHA. Upon reconstitution, the product is a clear to slightly opalescent, colorless solution that contains sodium chloride, sucrose, L-histidine, calcium chloride, and polysorbate 80.

REFERENCES

13. Sandberg H, Almstedt A, Brandt J, Castro VM, Gray E, Holmquist L, et al. Structural and Functional Characterization of B-Domain Deleted Recombinant Factor VIII. Sem Hematol. 2001;38 (Suppl. 4):4–12.

14. Kelley BD, Tannatt M, Magnusson R, Hagelberg S. Development and Validation of an Affinity Chromatography Step Using a Peptide Ligand for cGMP Production of Factor VIII. Biotechnol Bioeng. 2004;87(3):400–412.

Included as part of the PRECAUTIONS section.

Mechanism Of Action

XYNTHA temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.

Pharmacodynamics

The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. Treatment with XYNTHA normalizes the aPTT over the effective dosing period.

Pharmacokinetics

The pharmacokinetic parameters of XYNTHA in 30 previously treated adult patients (PTP) 12 to 60 years old, who received a single infusion of 50 IU/kg XYNTHA are summarized in Table 3.

In addition, 25 of the same subjects later received a single infusion of 50 IU/kg of XYNTHA for a 6-month follow-up pharmacokinetic study. The parameters were comparable between baseline and 6 months, indicating no time-dependent changes in the pharmacokinetics of XYNTHA.

In a separate study, 8 of 30 subjects at least 12 years old with hemophilia A undergoing elective major surgery received a single 50 IU/kg infusion of XYNTHA. The pharmacokinetic parameters in these subjects are also summarized in Table 3.

Table 3: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated Patients with Hemophilia A after Single 50 IU/kg Dose

Table 4 shows the pharmacokinetic parameters of nine children; four aged 14 or 15 years of age, who are also included in the summary for the adults above, along with five children aged 3.7–5.8 years after single 50 IU/kg doses of XYNTHA. Compared to adults, the half-life of XYNTHA is shorter in children and the clearance (based on per kg body weight) is approximately 40% higher in children.

Table 4: Mean ± SD XYNTHA Pharmacokinetic Parameters in Previously Treated Pediatric Patients with Hemophilia A after Single 50 IU/kg Dose

Animal Toxicology And/Or Pharmacology

Preclinical studies evaluating XYNTHA in hemophilia A dogs without inhibitors demonstrated safe and effective restoration of hemostasis. XYNTHA demonstrated a toxicological profile that was similar to the toxicological profile observed with the predecessor product. Toxicity associated with XYNTHA was primarily associated with anti-FVIII neutralizing antibody generation first detectable at 15 days of repeat dosing in high (approximately 735 IU/kg/day) level-dosed, non-human primates.

Clinical Studies

In an open label safety and efficacy study (n=94), subjects received XYNTHA in a routine prophylaxis treatment regimen with on-demand treatment administered as clinically indicated. All 94 subjects were treated with at least one dose and all are included in the intent-to-treat (ITT) population. All subjects had been previously treated (previously treated patients or PTPs) with factor VIII. Eighty-nine (89) subjects accrued ≥ 50 exposure days (EDs). Median age for the 94 treated subjects was 24 years (mean 27.7 and range 12–60 years). All subjects had ≥ 150 previous exposure days with baseline FVIII activity level of ≤ 2%.

Of the 94 subjects enrolled in this study, 30 evaluable subjects participated in a randomized crossover pharmacokinetics study. Twenty-five (25/30) of these subjects with FVIII:C ≤ 1% completed both the first (PK1) and the second (PK2) pharmacokinetic assessments [see CLINICAL PHARMACOLOGY].16

For routine prophylaxis, XYNTHA was administered at a dose of 30 ± 5 IU/kg 3 times a week with provisions for dose escalation based on pre-specified criteria. Seven dose escalations were prescribed for 6 subjects during the course of the study. Forty-three subjects (43/94 or 45.7%) reported no bleeding while on routine prophylaxis. The median annualized bleeding rate (ABR) for all bleeding episodes was 1.9 (mean 3.9, range 0–42.1).

Fifty-three subjects (53/94) received XYNTHA on-demand treatment for a total of 187 bleeding episodes. Seven of these bleeding episodes occurred in subjects prior to switching to a prophylaxis treatment regimen. One hundred ten of 180 bleeds (110/180 or 61.1%) occurred ≤ 48 hours after the last dose and 38.9% (70/180 bleeds) occurred > 48 hours after the last dose. The majority of bleeds reported to occur ≤ 48 hours after the last prophylaxis dose were traumatic (64/110 bleeds or 58.2%). Forty-two bleeds (42/70 or 60%) reported to occur > 48 hours after the last prophylaxis dose were spontaneous. The on-demand treatment dosing regimen was determined by the investigator. The median dose for on-demand treatment was 30.6 IU/kg (range 6.4 to 74.4 IU/kg).

The majority of bleeding episodes (173/187 or 92.5%) resolved with 1 or 2 infusions (Table 5). Subjects rated the outcomes of infusions on a pre-specified four (4) point hemostatic efficacy scale. One hundred thirty-two of 187 bleeding episodes (132/187 or 70.6%) treated with XYNTHA were rated excellent or good in their response to initial treatment, 45 (24.1%) were rated moderate. Five (2.7%) were rated no response, and 5 (2.7%) were not rated.

Table 5: Summary of Response to Infusions to Treat New Bleeding Episode by Number of Infusions Needed for Resolution

In an open-label study (n=30) for surgical prophylaxis in subjects with hemophilia A, XYNTHA was administered to 25 efficacy-evaluable PTPs with severe or moderately severe (FVIII:C ≤ 2%) hemophilia A undergoing major surgical procedures (11 total knee replacements, 1 hip replacement, 5 synovectomies, 1 left ulnar nerve transposition release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 revision and debridement of the knee after a total knee replacement, 1 hip arthroplasty revision, 1 stapes replacement, 1 ankle arthrodesis, and 1 pseudotumor excision).17

The results of the hemostatic efficacy ratings for these subjects are presented in Table 6. Investigator's ratings of efficacy at the end of surgery and at the end of the initial postoperative period were “excellent” or “good” for all assessments. Intraoperative blood loss was reported as “normal” or “absent” for all subjects. Thirteen of the subjects (13/25 or 52%) had blood loss in the postoperative period. The postoperative blood loss was rated as “normal” for ten of these cases while three cases were rated “abnormal” (1 due to hemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL blood loss after hip replacement surgery, and 1 after an elbow synovectomy where the blood loss could not be measured by the investigator).

Table 6: Summary of Hemostatic Efficacy

REFERENCES

1. Nilsson IM, Berntorp EE and Freiburghaus C. Treatment of patients with factor VIII and IX inhibitors. Thromb Haemost. 1993;70(1):56–59.

3. Juhlin F. Stability and Compatibility of Reconstituted Recombinant Factor VIII SQ, 250 IU/ml, in a System for Continuous Infusion. Pharmacia Document 9610224, 1996.

15. Mann KG and Ziedens KB. Overview of Hemostasis. In: Lee CA, Berntorp EE and Hoots WK, eds. Textbook of Hemophilia. USA, Blackwell Publishing; 2005:1–4.

16. Recht M, Nemes L, Matysiak M et al. Clinical Evaluation of Moroctocog Alfa (AF-CC), a New Generation of B-Domain Deleted Recombinant Factor VIII (BDDrFVIII) for Treatment of Haemophilia A: Demonstration of Safety, Efficacy and Pharmacokinetic Equivalence to Full-length Recombinant Factor VIII. Haemophilia 2009; 1–12.

17. Windyga J, Rusen L, Gruppo R, et al. BDDrFVIII (Moroctocog alfa [AF-CC]) for surgical haemostasis in patients with haemophilia A: results of a pivotal study. Haemophilia. 2010 Sep 1;16(5):731-9.

Xyntha is part of the drug class:

• Blood coagulation factors

Antihemophilic factor (AHF) injection is used to treat and prevent serious bleeding episodes in patients with a bleeding problem called hemophilia A. The bleeding episode may be related to an injury (trauma) or a surgical procedure. AHF is a protein that is produced naturally in the body. It helps the blood form clots to stop bleeding and prevents bleeding problems from happening as often.

Hemophilia A, also called classical hemophilia, is a condition where the body does not make enough AHF. If you do not have enough AHF and you become injured, your blood will not form clots properly. You might bleed into and damage your muscles and joints. AHF injection is given to increase the levels of AHF in the blood.

There are several different types of AHF. They are made from human blood or artificially by a man-made process (recombinant). AHF made from human blood has been treated and is not likely to contain harmful viruses, such as hepatitis B, hepatitis C, or human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). The man-made AHF products do not contain these viruses.

This medicine is available only with your doctor's prescription.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Allergic side effects may rarely happen.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Call the doctor right away if the normal dose does not work as well.
• Talk with the doctor before you travel. You will need to bring enough of Xyntha for use during travel.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

All products:

• If this medicine is given at home, store unopened containers at room temperature or in the refrigerator. Do not freeze.
• Store in original container.
• If stored at room temperature, make a note of the date it was placed at room temperature.
• Protect from light.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Xyntha:

• If stored at room temperature, return Xyntha vials to the refrigerator after 3 months or throw away any unused part. You may return vials to the refrigerator only 1 time.

Xyntha Solofuse:

• If stored at room temperature, throw away any unused vials after 3 months or after the expiration date, whichever comes first.
• Do not put Xyntha back in the refrigerator after it has been stored at room temperature.

None known.

Pregnancy

Animal reproduction studies have not been conducted with Xyntha Antihemophilic Factor (Recombinant), Plasma/Albumin-Free. It is also not known whether Xyntha can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Xyntha should be given to a pregnant woman only if clinically indicated.

Labor and Delivery

There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Xyntha should be used only if clinically indicated.

Nursing Mothers

It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Xyntha is administered to nursing mothers. Xyntha should be given to nursing mothers only if clinically indicated.

Pediatric Use

A study of Xyntha in previously treated patients less than 6 years of age is currently ongoing.

Pharmacokinetics of Xyntha was studied in 7 previously treated patients 12-16 years of age. Pharmacokinetic parameters in these patients were similar to those obtained for adults after a dose of 50 IU/kg. For these 7 patients, the mean (± SD) Cmax and AUC∞ were 1.09 ± 0.21 IU/mL and 11.5 ± 5.2 IU∙h/mL, respectively. The mean clearance and plasma half‑life values were 5.23 ± 2.36 mL/h/kg and 8.03 ± 2.44 hours (range 3.52 – 10.6 hours), respectively. The mean K‑value and in vivo recoveries were 2.18 ± 0.41 IU/dL per IU/kg and 112 ± 23%, respectively.

Geriatric Use

Clinical studies of Xyntha did not include subjects aged 65 and over. In general, dose selection for an elderly patient should be individualized.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with Xyntha to assess its mutagenic or carcinogenic potential. Xyntha has been shown to be comparable to the predecessor product with respect to its biochemical and physicochemical properties, as well as its non-clinical in vivo pharmacology and toxicology. By inference, predecessor product and Xyntha would be expected to have equivalent mutagenic and carcinogenic potential. The predecessor product has been shown to be nongenotoxic in the mouse micronucleus assay. No studies have been conducted in animals to assess impairment of fertility or fetal development.

Animal Toxicology and/or Pharmacology

Preclinical studies evaluating Xyntha in hemophilia A dogs without inhibitors demonstrated safe and effective restoration of hemostasis. Xyntha demonstrated a toxicological profile that was similar to the toxicological profile observed with the predecessor product. Toxicity associated with Xyntha was primarily associated with anti-FVIII neutralizing antibody generation first detectable at 15 days of repeat dosing in high (approximately 735 IU/kg/day) level-dosed, non-human primates.