XYNTHA 1000 IU

Xyntha LPD WC TC 08 Sep 20

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Xyntha

®

Moroctocog alfa

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

Clinically Relevant Nonmedicinal Ingredients

Intravenous

Infusion

Available as 250, 500,

1000, or 2000 IU in

single-use vials.

Polysorbate 80 (0.4 mg/vial or

prefilled dual-chamber

syringe

), Sucrose (12 mg/vial or

prefilled dual-

chamber syringe

), L-Histidine (6 mg/vial or

prefilled

dual-chamber syringe

), Calcium Chloride Dihydrate

(1 mg/vial or

prefilled dual-chamber syringe

), Sodium

Chloride (72 mg/vial or

prefilled dual-chamber

syringe

) [after reconstitution with diluent].

Xyntha

®

is prepared by a modified process that eliminates any exogenous human- or animal-derived

protein in the cell culture process, purification, or final formulation. The purification process uses a

series of chromatography steps, one of which is based on affinity chromatography using a synthetic

peptide affinity ligand. The process also includes a solvent-detergent viral inactivation step and a

virus-retaining nanofiltration step.

The labeled potency of Xyntha

®

is based on the European Pharmacopoeial chromogenic substrate

assay, in which the Pfizer In-House Recombinant Factor VIII Potency Reference Standard has been

calibrated to the WHO 7

International Standard using the one-stage clotting assay. This method

of potency assignment is intended to harmonize Xyntha

®

with clinical monitoring using a one-

stage

clotting assay.

INDICATIONS AND CLINICAL USE

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII

deficiency).

Geriatrics (≥ 65 years of age):

Clinical studies of Xyntha

®

did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects. Other reported clinical

experience has not identified differences in responses between the elderly and younger patients. As

with any patient receiving Xyntha

®

, dose selection for an elderly patient should be individualized.

Pediatrics:

Xyntha

®

is appropriate for use in children of all ages, including newborns.

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CONTRAINDICATIONS

Xyntha

®

may be contraindicated in patients with a known hypersensitivity to any of the

constituents

of the preparation.

Xyntha

®

has not been studied in patients with a known history of hypersensitivity to hamster

proteins and may be contraindicated in these patients.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Anaphylaxis and severe hypersensitivity reactions are possible as with any intravenous

protein product. Should such reactions occur, treatment with the product should be

discontinued and appropriate treatment should be administered.

Development of activity-neutralizing antibodies has been detected in patients receiving

factor VIII-containing products. If expected plasma factor VIII activity levels are not

attained, or if bleeding is not controlled with an appropriate dose, an assay that measures

factor VIII inhibitor concentration should be performed.

General

It is recommended that, whenever possible, every time that Xyntha

®

is administered to patients the

lot number of the product is documented.

Effects on Ability to Drive and Use Machines

No studies on the ability to drive and use machines have been performed.

Carcinogenesis and Mutagenesis

Xyntha

®

has been shown to be nonmutagenic in the mouse micronucleus assay. No other

mutagenicity studies and no investigations on carcinogenesis, impairment of fertility or fetal

development have been conducted.

Drug-Drug Interactions

No formal drug interaction studies have been conducted with Xyntha

®

. No interactions with other

medicinal products are known.

Immune

The occurrence of neutralizing antibodies (inhibitors) is well known in patients receiving

factor VIII-containing products. Inhibitors most commonly occur early in the treatment course of

previously untreated patients, but have also been observed in patients who have previously received

large amounts of factor VIII products. All patients using coagulation factor VIII products,

including Xyntha

®

, should be monitored periodically for the development of factor VIII inhibitors.

In addition, 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. In patients with factor VIII inhibitors, factor VIII therapy may not be effective

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and other therapeutic options should be considered. Management of such patients should be

directed by physicians with experience in the care of patients with hemophilia.

Sensitivity/Resistance

As with any intravenous protein product, 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.

If allergic or anaphylactic reactions occur, administration of Xyntha

®

should be stopped

immediately, and appropriate medical management should be given, which may include treatment

for shock. Patients should be advised to discontinue use of the product and contact their

hemophilia physicians and/or seek immediate emergency care, depending on the type and severity

of the reaction, if any of these symptoms occur.

Special Populations

Pregnancy and Lactation:

No animal reproduction and lactation studies have been conducted with Xyntha

®

. Based on the rare

occurrence of hemophilia A in women, experience regarding the use of factor VIII during

pregnancy is not available

.

Xyntha

®

should be administered to pregnant and lactating women only

the benefit outweighs the risk.

Pediatric:

Xyntha

®

is appropriate for use in children of all ages, including newborns.

Safety and efficacy studies have been performed both in previously treated children and adolescents

(N=98, ages 7-18 years) and in previously untreated neonates, infants, and children (N=101, ages 0-

52 months). An additional ongoing clinical study is evaluating the use of Xyntha

®

previously

treated subjects under 6 years of age with moderately severe to severe hemophilia A.

Geriatrics (≥ 65 years of age):

Clinical studies of Xyntha

®

did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects. Other reported clinical

experience with factor VIII products has not identified differences in responses between the elderly

and younger patients. As with any patient receiving Xyntha

®

, dose selection for an elderly patient

should be individualized.

ADVERSE REACTIONS

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Body System

Table 1: Adverse Reactions for Body System

Adverse Reactions

Frequency per Infusion

Blood and lymphatic system disorders

Rare (

0.01% and

<

0.1%)

Factor VIII inhibition

Body as a whole

Rare (

0.01% and

<

0.1%)

Asthenia, pyrexia

Very Rare (<0.01%)

Chills, Cold sensation

Cardiac disorders

Very Rare (<0.01%)

Angina pectoris, tachycardia

Nervous system disorders

Very Rare (<0.01%)

Dizziness, perspiration increased, somnolence,

flushing, neuropathy

Uncommon (

0.1% and

<

Headache

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Body System

Table 1: Adverse Reactions for Body System (Cont'd)

Adverse Reactions

Frequency per Infusion

Metabolism and nutrition disorders

Very Rare (<0.01%)

Hypotension, palpitations, anorexia, increased amino

transferase, CPK increased

Musculoskeletal disorders

Rare (

0.01% and

<

0.1%)

Myalgia

Vascular disorders

Rare (

0.01% and

<

0.1%)

Vasodilation

Very Rare (<0.01%)

Bleeding/hematoma, thrombophlebitis

Respiratory, thoracic and mediastinal

disorders

Very Rare (<0.01%)

Coughing, dyspnea

Gastrointestinal disorders

Rare (

0.01% and

<

0.1%)

Diarrhea, nausea, Vomiting

Very Rare (<0.01%)

Abdominal pain

Hepato-biliary disorders

Very Rare (<0.01%)

Increased bilirubin

Skin

Rare (

0.01% and

<

0.1%)

Hives

Very Rare (<0.01%)

Pruritis, rash, urticaria

Special senses

Very Rare (<0.01%)

Taste perversion (altered taste)

General disorders and administration

site disorders

Very Rare (<0.01%)

Injection site reaction, permanent venous access

catheter complications, injection site inflammation,

injections site pain

This table reports the frequency of factor VIII inhibitors per infusion. The incidence of factor VIII inhibitors

per patient is described in the individual study narratives below.

The most frequently reported treatment-emergent adverse reaction was headache. Most adverse

reactions reported were considered mild or moderate in severity.

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In addition, as with any intravenous protein product, allergic type hypersensitivity reactions are

possible. Manifestations of hypersensitivity reactions may include hives, generalized urticaria,

tightness of the chest, wheezing, hypotension, and anaphylaxis.

Patients with hemophilia A may develop neutralizing antibodies (inhibitors) to factor VIII. If such

inhibitors occur, the condition may manifest itself as an insufficient clinical response or an

unexpectedly low yield of plasma factor VIII activity. In such cases, it is recommended that a

specialized hemophilia center be contacted.

Reports of lack of effect, mainly in prophylaxis patients, have been received during the clinical

trials and post-marketing setting. The lack of effect and/or low factor VIII recovery has been

reported in patients with inhibitors but also in patients who had no evidence of inhibitors. The lack

of effect has been described as bleeding into target joints, bleeding into new joints, other bleeding

or a subjective feeling by the patient of a new onset bleeding. In order to ensure an adequate

therapeutic response, it is important TO INDIVIDUALLY TITRATE AND MONITOR each

patient’s dose of Xyntha

®

, particularly when initiating treatment with Xyntha

®

(see WARNINGS

AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

If any reaction takes place that is thought to be related to the administration of Xyntha

®

, the rate of

infusion should be decreased or the infusion stopped, as dictated by the response of the patient.

In a clinical trial, 32 out of 101 (32%) previously untreated patients treated with Xyntha

®

manufactured by the previous process developed inhibitors: 16 out of 101 (16%) with a titer

>

Bethesda Units (BU) and 16 out of 101 (16%) with a titer

5 BU. The median number of exposure

days prior to inhibitor development in these patients was 12 days (range 3-49 days). Of the 16

high-responder patients, 15 received immune tolerance (IT) treatment. Eleven (11) of the high

responders had a titer of <0.6 BU at their latest available test after IT. In addition, IT treatment was

started in 10 of the 16 low titer (

5 BU) patients, 9 of whom had titer

<

0.6 BU for their latest value.

Therefore, IT had an overall efficacy of 80% (20/25), 73% for high-responders and 90% for low-

responders. Five (5) of the 6 remaining low-responder patients who did not receive IT also had a

titer

<

0.6 BU for their latest value.

In a clinical trial of Xyntha

®

manufactured by the previous process, one of 113 (0.9%) previously

heavily treated patients who were evaluated for efficacy in bleeding episodes developed a high-titer

inhibitor. Inhibitor development in this patient occurred in the same time frame as the development

of monoclonal gammopathy of uncertain significance. The patient was noted initially at a local

laboratory to have a treatment-emergent low-titer inhibitor at 98 exposure days, which was

confirmed at 2 BU at the central laboratory at 113 exposure days. After 18 months on continued

treatment with Xyntha

®

, the inhibitor level rose to nearly 13 BU and a bleeding episode failed to

respond to Xyntha

®

treatment.

In a pivotal phase 3 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

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of Xyntha

®

, resulting in a total of 6775 infusions. In this study, the incidence of FVIII inhibitors

Xyntha

®

was the primary safety endpoint. Two patients with low-titer, transient inhibitors were

observed in these 94 patients (2.1%). In a Bayesian statistical analysis, results from this study were

used to update PTP results from prior supporting studies of Xyntha

®

. This Bayesian analysis

indicates that the population (true) inhibitor rate for Xyntha

®

was below a predefined acceptable

value of 4.4%; the estimate of the 95% upper limit of the true inhibitor rate was 4.07%.

There have been spontaneous post-marketing reports of high-titer inhibitors developing in

previously treated patients.

Twenty of 113 (18%) previously treated patients (PTPs) had an increase in anti-CHO (Chinese

hamster ovary, the cell line which is the source of factor VIII for Xyntha

®

) antibody titer, without

any apparent clinical effect.

DRUG INTERACTIONS

No interactions with other medicinal products are known.

DOSAGE AND ADMINISTRATION

Treatment with Xyntha

®

should be initiated under the supervision of a physician experienced in

treatment of hemophilia A.

Xyntha

®

is appropriate for use in adults and children, including newborns.

Dosage and duration of treatment depend on the severity of the factor VIII deficiency, the location

and extent of bleeding, and the patient’s clinical condition. Individual patients may vary in their

response to factor VIII, achieving different levels of

in vivo

recovery and demonstrating different

half-lives. Doses administered should be titrated to the patient’s clinical response. In the presence

of an inhibitor, higher doses or appropriate alternative treatment may be required. Dosage

adjustment for patients with renal or hepatic impairment has not been studied in clinical trials.

The number of units of factor VIII administered is expressed in International Units (IU), which are

related to the current World Health Organization (WHO) international standard for factor VIII

activity. Factor VIII activity in plasma is expressed either as a percentage (relative to normal

human plasma) or in IU (relative to an International Standard for factor VIII in plasma).

One IU of factor VIII activity corresponds approximately to the quantity of factor VIII in one ml of

normal human plasma. The calculation of the required dosage of factor VIII is based upon the

empirical finding that, on average, 1 IU of factor VIII per kg body weight raises the plasma factor

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VIII activity by 2 IU/dl. The required dosage is determined using the following formula:

Required units = body weight (kg) x desired factor VIII rise (IU/dL or % of normal) x 0.5

(IU/kg per IU/dL)

Clinical data support the use of the one-stage clotting assay for monitoring Xyntha

®

therapy.

The labeled potency of Xyntha

®

is based on the European Pharmacopoeia chromogenic substrate

assay in which the Pfizer In-House Recombinant Factor VIII Potency Reference Standard has been

calibrated using a one-stage clotting assay. This method of potency assignment is intended to

harmonize Xyntha

®

with clinical monitoring using a one-stage clotting assay.

Precise monitoring of the replacement therapy by means of plasma factor VIII activity assay should

be considered, particularly for surgical intervention.

Dosing for Bleeding and Surgery:

In the case of the following hemorrhagic events, consideration should be given to maintaining the

factor VIII activity at or above the plasma levels (in % of normal or in IU/dL) for the indicated

period, as outlined in the following table.

Table 2: Maintenance of Factor VIII Activity for Various Hemorrhagic Events

Type of Hemorrhage

Factor VIII

Level Required (% or

IU/dl)

Frequency of Doses (h)/

Duration of Therapy (d)

Minor

Early hemarthrosis,

superficial muscle or

soft tissue and oral

bleeds

20-40

Repeat every 12 to 24 hours as necessary

until resolved. At least 1 day, depending

upon the severity of the hemorrhage.

Moderate

Hemorrhages into

muscles. Mild head

trauma capitus.

Minor operations

including tooth

extraction.

Hemorrhages into the

oral cavity.

30-60

Repeat infusion every 12 - 24 hours for 3

- 4 days or until adequate hemostasis is

achieved. For tooth extraction a single

infusion plus oral antifibrinolytic therapy

within 1 hour may be sufficient.

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Major

Gastrointestinal

bleeding.

Intracranial, intra-

abdominal or

intrathoracic

hemorrhages.

Fractures.

Major operations.

60-100

Repeat infusion every 8 - 24 hours until

threat is resolved or in the case of

surgery, until adequate local hemostasis

is achieved, then continue therapy for at

least another 7 days.

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Dosage for Prophylaxis

Xyntha

®

has been administered prophylactically in a pivotal clinical trial in adolescent and adult

previously treated patients at a dose of 30 + 5 IU/kg given 3 times weekly.

Inhibitors

Patients using factor VIII replacement therapy 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. In patients with factor VIII inhibitors, factor VIII therapy may not be effective

and other therapeutic options should be considered. Management of such patients should be

directed by physicians with experience in the care of patients with hemophilia.

Administration

Patients should follow the specific reconstitution and administration procedures provided by

their physicians. For instructions, patients should follow the recommendations in the below

Administration and Reconstitution sections. The procedures below are provided as general

guidelines for the reconstitution and administration of Xyntha®.

Additional instructions are provided after Infusion section that detail the use of a Xyntha®

vial.

Parenteral drug products should be inspected visually for particulate matter and discoloration

prior to administration, whenever solution and container permit.

Xyntha Vial Kit:

Xyntha

®

is administered by I.V. infusion after reconstitution of the lyophilized powder with the

supplied pre-filled diluent (0.9% Sodium Chloride solution) syringe.

Reconstitution

Always wash your hands before performing the following procedures. Use germ-free methods

during the preparation procedures.

All components used in the mixing and injection of Xyntha

®

should be used as soon as possible

after

opening their sterile containers to minimize unnecessary exposure to room air.

Xyntha

®

Vial Kit:

Use only the materials provided in the Xyntha

®

kit for dissolving the Xyntha

®

powder with the

sodium chloride diluent.

Xyntha

®

is administered by intravenous injection after dissolving with the supplied diluent (0.9%

sodium chloride) in the pre-filled syringe.

Note: If you use more than one vial of Xyntha

®

per injection, each vial should be dissolved

according to the following instructions. The empty syringe should be removed, leaving the vial

adapter in place, and a separate large luer lock syringe may be used to draw back the dissolved

contents of each vial. Do not detach the diluent syringes or the large luer lock syringe until you are

ready to attach the large luer lock syringe to the next vial adapter.