ASH Clinical News November 2015 | Page 24

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Brief Summary
See package insert for full Prescribing Information. For further product information and current
package insert, please visit XYNTHA.com or call Pfizer Inc toll-free at 1-800-879-3477.
INDICATIONS AND USAGE
Control and Prevention of Bleeding Episodes in Patients with Hemophilia A
XYNTHA Antihemophilic Factor (Recombinant) is indicated in adults and children with
hemophilia A (congenital factor VIII deficiency or classic hemophilia) for control and prevention
of bleeding episodes. XYNTHA does not contain von Willebrand factor, and therefore is not
indicated in patients with von Willebrand’s disease.
Perioperative Management in Patients with Hemophilia A
XYNTHA Antihemophilic Factor (Recombinant) is indicated in adults and children with
hemophilia A for perioperative management.
DOSAGE FORMS AND STRENGTHS
XYNTHA is supplied as a white to off-white freeze-dried powder in the following dosages:
250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU.
CONTRAINDICATIONS
Do not use in patients who have manifested life-threatening immediate hypersensitivity
reactions, including anaphylaxis, to the product or its components, including hamster proteins.
WARNINGS AND PRECAUTIONS
General—The clinical response to XYNTHA may vary. If bleeding is not controlled with the
recommended dose, the plasma level of factor VIII should be determined and a sufficient dose
of XYNTHA should be administered to achieve a satisfactory clinical response. If the patient’s
plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the
expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and
appropriate testing performed.
Hypersensitivity Reactions—Allergic type hypersensitivity reactions, including anaphylaxis,
are possible with XYNTHA. Inform patients of the early signs or symptoms of hypersensitivity
reactions (including hives [rash with itching], generalized urticaria, chest tightness, wheezing,
and hypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occur
and administer appropriate emergency treatment.

Neutralizing Antibodies—Inhibitors have been reported following administration of
XYNTHA. Monitor patients for the development of factor VIII inhibitors by appropriate clinical
observations and labora tory tests. If expected factor VIII activity plasma levels are not attained,
or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor
VIII inhibitor concentration to determine if a factor VIII inhibitor is present.
Monitoring: Laboratory Tests—Monitor plasma factor VIII activity levels by the one-stage
clotting assay to confirm that adequate factor VIII levels have been achieved and are maintained,
when clinically indicated [see Dosage and Administration in full Prescribing Information].
It is recommended that individual factor VIII values for recovery and, if clinically indicated,
other pharmacokinetic characteristics be used to guide dosing and administration.
Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII
inhibitor is present when expected factor VIII activity plasma levels are not attained, or when
bleeding is not controlled with the expected dose of XYNTHA.
Use Bethesda Units (BU) to titer inhibitors.
ADVERSE REACTIONS
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 clinical practice.
XYNTHA was evaluated in five clinical studies (N=155), four completed studies with adult and
pediatric PTPs and one ongoing study in pediatric PTPs <6 years of age.
Study 1 is a pivotal phase 3 (safety and efficacy) study in which previously treated patients
(PTPs) with hemophilia A received XYNTHA for routine prophylaxis and on-demand treatment,
94 subjects received at least one dose of XYNTHA, resulting in a total of 6,775 infusions [see
Clinical Studies in full Prescribing Information]. Study 2 (surgery) is an open-label, single-arm
study of 30 evaluable PTPs with severe or moderately severe hemophilia A (factor VIII activity in
plasma [FVIII:C] ≤2%) who required elective major surgery and were planned to receive XYNTHA
replacement therapy for at least 6 days post-surgery. All subjects received at least one dose of
XYNTHA, resulting in 1,161 infusions [see Clinical Studies in full Prescribing Information].
Across all studies, safety was evaluated in 48 previously treated pediatric patients <16 years of age
(28 children, <6 years of age and 20 adolescents, 12 to <16 years of age). A total of 7,150 infusions
of XYNTHA were administered with a median dose per infusion of 29 IU/kg (min, max: 9,108 IU/kg).
Across all studies, the most common adverse reactions (≥10%) with XYNTHA in adult and
pediatric PTPs were headache (26% of subjects), arthralgia (25%), pyrexia (21%), cough (11%).
Other adverse reactions reported in ≥5% of subjects were: diarrhea (8%), vomiting (7%),
asthenia (7%), and nausea (6%).
Immunogenicity
There is a potential for immunogenicity with therapeutic proteins. The development of factor
VIII inhibitors with XYNTHA was evaluated in 144 adult and pediatric PTPs with at least 50 EDs.
Laboratory-based assessments for FVIII inhibitor (partial Nijmegen modification of the Bethesda
inhibitor assay) were conducted in the clinical studies. The criterion for a positive FVIII test result
was ≥0.6 BU/mL. Across all studies, 3 subjects developed factor VIII inhibitors (2.1%).

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In a Bayesian statistical analysis, results from this study were used to update PTP results from a
prior supporting study using XYNTHA manufactured at the initial facility, where one de novo and
two recurrent inhibitors were observed in 110 subjects, and the experience with predecessor
product (1 inhibitor in 113 subjects). This Bayesian analysis indicates that the population (true)
inhibitor rate for XYNTHA, the estimate of the 95% upper limit of the true inhibitor rate, was 4.17%.
None of the PTPs developed anti-CHO (Chinese hamster ovary) or anti-TN8.2 antibodies. One
PTP developed anti-FVIII antibodies, but this subject did not develop an inhibitor.
In the surgery study, one low titer persistent inhibitor and one transient false-positive inhibitor
were reported. In this study, one surgical subject developed anti-CHO cell antibodies with no
associated allergic reaction. One subject developed anti-FVIII antibodies, but this subject did not
develop an inhibitor.
Across all studies, safety was evaluated in 40 previously treated pediatric patients <16 years of
age with at least 50 EDs (25 children, <6 years of age and 15 adolescents, 12 to <16 years of
age). Of these, one pediatric subject developed an inhibitor.
DRUG INTERACTIONS—None known.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C - Animal reproduction studies have not been conducted with XYNTHA. It is 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—In comparison to the pharmacokinetic parameters reported in adults, children have
shorter half-lives, larger volumes of distribution and lower recovery of factor VIII after XYNTHA
administration. The clearance (based on per kg body weight) is approximately 40% higher in
children. Higher or more frequent doses may be required to account for the observed differences
in pharmacokinetic parameters [see Clinical Pharmacology in full Prescribing Information].
In the completed open label safety and efficacy study of XYNTHA (n=94), 17 adolescent
subjects 12 to <16 years of age with severe or moderately severe hemophilia A (FVIII:C ≤2%),
who were previously treated with at l east 150 EDs to FVIII products, received XYNTHA for ondemand and follow-up treatment. The median dose per infusion was 47 IU/kg (min-max: 24-74)
and the median exposure per subject was 6 days (min-max: 1-26).
Additional data are available from a safety and efficacy study of XYNTHA in children <6 years
of age with moderately severe or severe hemophilia A (FVIII:C ≤2%) and with at least 20 prior
EDs to FVIII products. In this study subjects received XYNTHA for on-demand and follow-up
treatment of bleeding episodes. The median dose per infusion was 28 IU/kg and the median
exposure per subject was 16 days.
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.
STORAGE AND HANDLING
XYNTHA Vials
Product as Packaged for Sale - Store XYNTHA vials under refrigeration at a temperature of
2° to 8°C (36° to 46°F) for up to 36 months from the date of manufacture until the expiration
date stated on the label. XYNTHA vials may also be stored at room temperature not to
exceed 25°C (77°F) for up to 3 months, until the expiration date. After room temperature
storage, XYNTHA vials can be returned to the refrigerator until the expiration date. Do not
store XYNTHA vials at room temperature and return it to the refrigerator more than once.
The starting date at room temperature storage should be clearly recorded. The patient should
write in the space provided on the outer carton. At the end of the 3-month period, the product
must be used immediately, discarded, or returned to refrigerated storage. The diluent syringe
may be stored at 2° to 25°C (36° to 77°F).
XYNTHA Solofuse
Product as Packaged for Sale - Store XYNTHA Solofuse under refrigeration at a temperature of
2° to 8°C (36° to 46°F) for up to 36 months from the date of manufacture until the expiration
date stated on the label. Within the expiration date, XYNTHA Solofuse may also be stored at
room temperature not to exceed 25°C (77°F) for up to 3 months.
The starting date at room temperature storage should be clearly recorded in the space provided
on the outer carton. At the end of the 3-month period, XYNTHA Solofuse must not be put back
into the refrigerator, but must be used immediately or discarded.
Do not use XYNTHA Solofuse after the expiration date stated on the label or after 3 months
when stored at room temperature, whichever is earlier.
Do not freeze, to prevent damage to XYNTHA Solofuse.
During storage, avoid prolonged exposure of XYNTHA Solofuse to light.
Product After Reconstitution - Administer XYNTHA within 3 hours after reconstitution or after
removal of the grey rubber tip cap from XYNTHA Solofuse. The reconstituted solution may be
stored at room temperature prior to administration.
This brief summary is based on the Xyntha ® [Antihemophilic Factor (Recombinant)] Prescribing
Information LAB-0516-5.0, revised 10/14, and LAB-0500-9.0, revised 10/14.

December 2014

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Formation of Antibodies to Hamster Protein—XYNTHA contains trace amounts of hamster
proteins. Patients treated with this product may develop hypersensitivity to these non-human
mammalian proteins.

The clinical studies for XYNTHA examined 124 subjects (94 for bleeding and 30 for surgery) who
had previously been treated with factor VIII (PTPs). In the safety and efficacy study, two subjects
with inhibitors were observed in 89 subjects (2.2%) who completed ≥50 exposure days.