Included as part of the PRECAUTIONS section.

Anaphylaxis and Severe Hypersensitivity Reactions

Allergic type hypersensitivity reactions are possible. Patients should be informed of the early signs or symptoms of hypersensitivity reactions [including hives (rash with itching), generalized urticaria, tightness of the chest, wheezing, and hypotension] and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physicians if these symptoms occur.

Neutralizing Antibodies

The occurrence of neutralizing antibodies (inhibitors) is well known in the treatment of patients with hemophilia A. Inhibitors have been detected in patients receiving factor VIII-containing products. Inhibitors are common in previously untreated patients^4,5,6 and have been observed in previously treated patients on factor VIII products.^{7,8,9,10,11,12} Patients using coagulation factor VIII products, including XYNTHA, should be monitored for the development of factor VIII inhibitors. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. If detected, inhibitors should be titered in Bethesda Units (BU).

Formation of Antibodies to Hamster Protein

XYNTHA contains trace amounts of hamster proteins. Patients treated with this product could develop hypersensitivity to these non-human mammalian proteins.

Monitoring: Laboratory Tests

When clinically indicated, patients should have plasma factor VIII activity levels monitored by the one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and are maintained. [see DOSAGE AND ADMINISTRATION]

It is recommended that individual factor VIII values for recovery and, if clinically indicated, other pharmacokinetic characteristics be used to guide dosing and administration.

Patient counseling Information

Allergic-type Hypersensitivity Reactions

Allergic-type hypersensitivity reactions are possible. Patients should be informed of the early signs of hypersensitivity reactions [including hives (rash with itching), generalized urticaria, tightness of the chest, wheezing, hypotension] and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physicians if these symptoms occur.

Neutralizing Antibodies (Inhibitors)

Patients should be advised to contact their physician or treatment facility for further treatment and/or assessment, if they experience a lack of a clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor.

Pregnancy

Female patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Nursing

Patients should be advised to notify their physician if they are breastfeeding.

Usage While Traveling

Based on their current regimen, individuals with hemophilia using XYNTHA should be advised to bring an adequate supply of XYNTHA for anticipated treatment when traveling. Patients should be advised to consult with their healthcare professional prior to travel.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Pregnancy Category C

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.

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.

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.

REFERENCES

4.   Ehrenforth S, Kreuz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in hemophiliacs. Lancet. 1992;339:594-598.

5.   Lusher J, Arkin S, Abildgaard CF, Schwartz RS, the Kogenate PUP Study Group. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med. 1993;328:453-459.

6.   Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood. 1994;83(9):2428-2435.

7.   Kessler C, Sachse K. Factor VIII:C inhibitor associated with monoclonal-antibody purified FVIII concentrate. Lancet. 1990;335:1403.

8.   Schwartz RS, Abildgaard CF, Aledort LM, et al. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med. 1990;323:1800-1805.

9.   White GC II, Courter S, Bray GL, et al. A multicenter study of recombinant factor VIII (recombinate) in previously treated patients with hemophilia A. Thromb Haemost. 1997;77(4):660-667.

10. Gruppo R, Chen H, Schroth P, et al. Safety and immunogenicity of recombinant factor VIII (Recombinate) in previously untreated patients: A 7.3 year update. Haemophilia. 1998;4:228 (Abstract No. 291, XXIII Congress of the WFH, The Hague).

11. Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A patients - a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia. 1999;5:145-154.

12. Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinant human antihemophilic Factor VIII is safe and efficacious for treatment of hemophilia A in home therapy: Results of a multicenter, international, clinical investigation. Thromb Haemost. 2000;83(6):811-816.

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