英文药名：ADVATE(antihemophilic factor, human recombinant) kit

中文药名：抗血友病因子（重组）血浆/白蛋白乾粉注射剂

生产厂家：百特制药
药品介绍
长效型血友病药物ADVATE是一种重组人类凝血因子VIII注射剂，用于治疗血友病A
ADAVTE于2003年7月份在美国上市，当时作为抗血友因子，用于控制和预防血友病患者的出血。
ADVATE[抗血友病因子（重组）血浆/白蛋白]
静脉注射，冻干粉
活性成分：
重组人凝血因子VIII
性状：
本品为白色或类白色易碎粉末。按标示量加入本品所附的灭菌注射用水，配制后溶液应为澄清、无色、无异物的溶液。
适应症：
本品适用于甲型血友病（先天性凝血因子VIII缺乏）患者出血的治疗和预防。
剂型和规格
ADVATE是包含250，500，1000，1500，2000和3000 IU的单次使用小瓶可用。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ADVATE safely and effectively. See full prescribing information for ADVATE.
ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin Free Method]
For Intravenous Injection, Lyophilized Powder for Reconstitution
Initial U.S. Approval: 2003
RECENT MAJOR CHANGES
Adverse Reactions (6, 6.1, 6.2) 10/2009
INDICATIONS AND USAGE
ADVATE is an Antihemophilic Factor (Recombinant) indicated for:
Control and prevention of bleeding episodes in adults and children with Hemophilia A(1.1)
Perioperative management in adults and children with hemophilia A (1.2)
DOSAGE AND ADMINISTRATION
For intravenous use after reconstitution only (2)
Each vial of ADVATE contains the labeled amount of recombinant Factor VIII in international units (IU) (2)
The required dosage is determined using the following formulas:
Desired increment in Factor VIII concentration (IU/dL or % of normal)=[Total Dose (IU)/body weight (kg) × 2 [IU/dL]/[IU/kg]
OR Required Dose (IU) = body weight (kg) × Desired Factor VIII Rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL)
Frequency of intravenous injection of the reconstituted product is determined by the type of bleeding episode and the recommendation of the treating physician (2.1, 2.2)
DOSAGE FORMS AND STRENGTHS
ADVATE is available in single use vials containing 250, 500, 1000, 1500, 2000 and 3000 IU. (3)
CONTRAINDICATIONS
Known anaphylaxis to mouse or hamster protein or other constituents of the product.. (4)
WARNINGS AND PRECAUTIONS
Anaphylaxis and severe hypersensitivity reactions are possible. Should symptoms occur, treatment with ADVATE should be discontinued, and appropriate treatment should be administered (5.1)
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. (5.3)
Patients may develop hypersensitivity to mouse or hamster protein, which a present in trace amounts in the product. (5.2)
ADVERSE REACTIONS
The most serious adverse drug reactions are hypersensitivity reactions and Factor VIII inhibitors. (6.1)
The most common adverse drug reactions observed in ≥ 2% of patients are: Factor VIII inhibitors (observed predominantly in previously untreated patients (PUPs) and headache.(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
USE IN SPECIFIC POPULATIONS
Pregnancy: No human or animal data. Use only if clearly needed.(8.1)
Pediatric Use: Consider larger or more frequent doses to account for the observed differences in adjusted recovery and terminal half-life. Dose adjustment may be needed (8.4)).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling 
Revised: 08/2010
FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Control and Prevention of Bleeding Episodes

ADVATE is an antihemophilic factor (recombinant) indicated for control and prevention of bleeding episodes in adults and children with Hemophilia A.

1.2 Perioperative Management

ADVATE is indicated in the perioperative management in adults and children with Hemophilia A.

ADVATE is not indicated for the treatment of von Willebrand's disease.

2 DOSAGE AND ADMINISTRATION

For Intravenous Use After Reconstitution only

• Treatment with ADVATE should be initiated under the supervision of a physician experienced in the treatment of hemophilia A.
• Each vial of ADVATE has the recombinant Factor VIII potency in international units stated on the label. The expected in vivo peak increase in Factor VIII level expressed as IU/dL of plasma or percent normal can be estimated by multiplying the dose administered per kg body weight (IU/kg) by 2.
• The dosage and duration depend on the severity of Factor VIII deficiency, the location and extent of the bleeding, and the patient's clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes. [Control and Prevention of Bleeding Episodes (2.1) and Perioperative Management (2.2)]

The expected in vivo peak increase in Factor VIII level expressed as IU/dL (or % of normal) can be estimated using the following formulas:

IU/dL (or % of normal)=[Total Dose (IU)/body weight (kg)] × 2 [IU/dL]/[IU/kg]

OR

Dose (IU) = body weight (kg) × Desired Factor VIII Rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL)

Examples (assuming patient's baseline Factor VIII level is < 1% of normal):

1. A dose of 1750 IU ADVATE administered to a 70 kg patient should be expected to result in a peak post-infusion Factor VIII increase of 1750 IU × {[2 IU/dL]/[IU/kg]}/[70 kg] = 50 IU/dL (50% of normal).
2. A peak level of 70% is required in a 40 kg child. In this situation, the appropriate dose would be 40 kg × 70 IU/dL/{[2 IU/dL]/[IU/kg]} = 1400 IU.

The dose and frequency of administration should be based on the individual clinical response. Patients may vary in their pharmacokinetic (e.g. half-life, in vivo recovery) and clinical responses to ADVATE. Although you can estimate the dose by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests including serial Factor VIII activity assays be performed [see WARNINGS and PRECAUTIONS: Monitoring Laboratory Tests (5.4) and Pharmacokinetics (12.3)].

2.1 Control and Prevention of Bleeding Episodes

A guide for dosing in the treatment of bleeding episodes is provided in Table 1. The careful control of treatment dose is especially important in cases of life-threatening episodes.

Table 1 Guide to ADVATE Dosing for Treatment of Bleeding Episodes in Adults and Children

* Dose (IU/kg) = Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)
Degree of Hemorrhage Or Type of Bleeding Episodes	Required Peak Post-infusion Factor VIII Activity in the Blood (as % of Normal or IU/dL)	Dosage and Frequency Necessary to Maintain the Therapeutic Plasma Level
Minor Early hemarthrosis, mild muscle bleeding, or mild oral bleeding episode.	20-40	10-20 IU/kg* Repeat infusions every 12 to 24 hours (8 to 24 hours for patients under the age of 6) for one to three days until the bleeding episode is resolved (as indicated by relief of pain) or healing is achieved.
Moderate Moderate bleeding into muscles, bleeding into the oral cavity, definite hemarthroses, and known trauma.	30-60	15-30 IU per kg* Repeat infusions every 12 to 24 hours (8 to 24 hours for patients under the age of 6) for three days or more until the bleeding episode is resolved (as indicated by relief of pain) or healing is achieved.
Major Significant gastrointestinal bleeding, intracranial, intra-abdominal or intrathoracic bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces or iliopsoas sheath, Fractures, Head trauma.	60-100	Initial dose 30-50 IU per kg: Repeat dose 30-50 IU per kg every 8 to 24 hours (6 to 12 hours for patients under the age of 6) until resolution of the bleeding episode has occurred.

2.2 Peri-operative Management

A guide for dosing in perioperative management is provided in Table 2. The careful control of dose and duration of treatment is especially important in cases of major surgery or life-threatening bleeding episodes.

Table 2 Guide to ADVATE Dosing for Perioperative Management in Adults and Children

Type of Surgery	Required Peak Post-infusion Factor VIII Activity in the Blood (% of Normal or IU/dL)	Frequency of Infusion
* Dose (IU/kg) = Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL)
Minor Including tooth extraction	60-100	A single bolus infusion (30-50 IU/kg*) beginning within one hour of the operation. Optional additional dosing every 12 to 24 hours as needed to control bleeding. For dental procedures, adjunctive therapy may be considered.
Major Examples include intracranial, Intra-abdominal, or Intrathoracic surgery, joint replacement surgery	80-120 (pre- and post-operative)	Preoperative bolus infusion: 40-60 IU/kg*. Verify 100% activity has been achieved prior to surgery. Maintenance bolus infusion (40-60 IU/kg*) repeat infusions every 8 to 24 hours (6 to 24 hours for patients under the age of 6), depending on the desired level of Factor VIII and state of wound healing.

2.3 Instruction for Use

ADVATE is administered by intravenous (IV) injection after reconstitution. Patients should follow the specific reconstitution and administration procedures provided by their physicians.

For instructions, patients should follow the recommendations in the FDA-approved patient labeling.

Reconstitution, product administration, and handling of the administration set and needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted ADVATE in an appropriate container.

2.4 Preparation and Reconstitution:

The procedures below are provided as general guidelines for the reconstitution and administration of ADVATE. Always work on a clean surface and wash your hands before performing the following procedures.

1. Bring the ADVATE (dry factor concentrate) and Sterile Water for Injection, USP (diluent) to room temperature.
2. Remove caps from the factor concentrate and diluent vials.
3. Cleanse stoppers with germicidal solution, and allow to dry prior to use. Place the vials on a flat surface.
4. Open the BAXJECT II device package by peeling away the lid, without touching the inside (Figure A). Do not remove the device from the package.
5. Turn the package over. Press straight down to fully insert the clear plastic spike through the diluent vial stopper (Figure B).
6. Grip the BAXJECT II package at its edge and pull the package off the device (Figure C). Do not remove the blue cap from the BAXJECT II device. Do not touch the exposed white plastic spike.
7. Turn the system over, so that the diluent vial is on top. Quickly insert the white plastic spike fully into the ADVATE vial stopper by pushing straight down (Figure D). The vacuum will draw the diluent into the ADVATE vial.
8. Swirl gently until ADVATE is completely dissolved.

Do not refrigerate after reconstitution.

2.5 Administration

ADVATE is intended for intravenous use after reconstitution only.

• Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear and colorless in appearance. If not, do not use the solution and notify Baxter immediately.
• Administer ADVATE at room temperature not more than 3 hours after reconstitution.
• Plastic syringes must be used with this product, since proteins such as ADVATE tend to stick to the surface of glass syringes.

1. Use aseptic technique.
2. Remove the blue cap from the BAXJECT II device. Connect the syringe to the BAXJECT II device (Figure E). DO NOT INJECT AIR.
3. Turn the system upside down (factor concentrate vial now on top). Draw the factor concentrate into the syringe by pulling the plunger back slowly (Figure F).
4. Disconnect the syringe; attach a suitable needle and inject intravenously as instructed under Administration by Bolus Infusion.
5. If a patient is to receive more than one vial of ADVATE, the contents of multiple vials may be drawn into the same syringe. Please note that the BAXJECT II device is intended for use with a single vial of ADVATE and Sterile Water for Injection only, therefore reconstituting and withdrawing a second vial into the syringe requires a second BAXJECT II device.

Administration by bolus infusion

Administer a dose of ADVATE over a period of ≤ 5 minutes (maximum infusion rate, 10 mL/min). Determine the pulse rate before and during administration of ADVATE. Should a significant increase in pulse rate occur, reducing the rate of administration or temporarily halting the injection usually allows the symptoms to disappear promptly.

3 DOSAGE FORMS AND STRENGTHS

ADVATE is available as a lyophilized powder in single use glass vials containing nominally 250, 500, 1000, 1500, 2000 or 3000 International Units (IU).

Each vial of ADVATE is labeled with the recombinant antihemophilic factor (rAHF) activity expressed in IU per vial. This potency assignment employs a Factor VIII concentrate standard that is referenced to a WHO International Standard for Factor VIII concentrates, and is eva luated by appropriate methodology to ensure accuracy of the results.

4 CONTRAINDICATIONS

Known anaphylaxis to mouse or hamster protein or other constituents of the product.

5 WARNINGS AND PRECAUTIONS

5.1 General

The clinical response to ADVATE 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 ADVATE 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.

5.2 Anaphylaxis and Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis are possible and have been reported with ADVATE. Symptoms have manifested as dizziness, paresthesias, rash, flushing, face swelling, urticaria, dyspnea, and pruritis.[see PATIENT COUNSELING INFORMATION (17)]

ADVATE contains trace amounts of mouse immunoglobulin G (MuIgG; maximum of 0.1 ng.IU ADVATE) and hamster proteins (maximum of 1.5 ng/IU ADVATE.. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment.

5.3 Neutralizing Antibodies

Patients treated with AHF products should be carefully for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs). If expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures Factor VIII inhibitor concentration should be performed [see Monitoring Laboratory Tests (5.4)].

5.4 Monitoring Laboratory Tests

• Monitor plasma Factor VIII activity levels by the one-stage clotting assay to confirm the adequate Factor VIII levels have been achieved and maintained, when clinically indicated [see DOSAGE AND ADMINISTRATION (2)].
• Monitor for development of Factor VIII inhibitors. Perform the Bethesda assay to determine if Factor VIII inhibitor is present. If expected Factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of ADVATE. Use Bethesda Units (BU) to titer inhibitors.
• If the inhibitor is less than 10 BU per mL, the administration of additional Antihemophilic Factor concentrate may neutralize the inhibitor, and may permit an appropriate hemostatic response.
• Adequate hemostasis may not be achieved if inhibitor titers are above 10 BU per mL. The inhibitor titer may rise following ADVATE infusion as a result of an anamnestic response to Factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.

6 ADVERSE REACTIONS

The most serious adverse drug reactions (ADRs) seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments of Factor VIII..

The most common ADRs observed in clinical trials (frequency > 2% of subjects) were: Factor VIII inhibitor formation (observed predominantly in PUPs) and headache.(6.1)

6.1 Clinical Trial 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 clinical trials of another drug and may not reflect the rates observed in clinical practice.

ADVATE has been eva luated in five completed studies in previously treated patents (PTPs) and one ongoing study in PUPs with severe to moderately severe Hemophilia A (Factor VIII ≤ 2% of normal). A total of 234 subjects have been treated with ADVATE as of March 2006. Total exposure to ADVATE was 44,926 infusions. The median duration of participation per subject was 370.5 (range: 1 to 1,256) days and the median exposure to ADVATE per subject was 128.0 (range: 1 to 598) days.

There were 2,507 adverse events (AEs) reported in 215 subjects. None of the subjects withdrew from the studies due to adverse events. There were no deaths. Nineteen treated subjects reported no AEs during their participation. The most common AEs (product-related and unrelated, according to the investigator's opinion) occurring in at least 5% if subjects who received at least 1 ADVATE study infusion as shown in Table 3.

Table 3. Adverse Events Reported by > 5% Treated of Study Subject*

* Includes data from 234, treated subjects from 5 completed studies in PTPs, and 1 ongoing study in PUPs as of 27 March 2006. † MedDRA version 8.1 was used. ‡ This percent is calculated relative to 234, the total number of treated subjects.
MedDRA† System Organ Class	MedDRA Preferred Term	Number of Events	Number of Subjects	Percent‡ of Subjects
Ear and labyrinth disorders	Ear pain	17	14	6.0
Gastrointestinal disorders	Constipation	16	12	5.1
	Diarrhoea	48	34	14.5
	Nausea	25	19	8.1
	Vomiting	53	38	16.2
General disorders and administration site conditions	Influenza like illness	17	13	5.6
	Pain	21	18	7.7
	Pyrexia	173	76	32.5
Infections and infestations	Ear infections	40	25	10.7
	Influenza	22	18	7.7
	Nasopharyngitis	121	62	26.5
	Otitis media	12	12	5.1
	Sinusitis	21	14	6.0
	Upper respiratory tract infection	49	31	13.2
Injury, poisoning and procedural complications	Accident	41	20	8.5
	Fall	22	17	7.3
	Joint sprain	16	14	6.0
	Limb injury	141	44	18.8
	Procedural pain	16	12	5.1
Musculoskeletal and connective tissue disorders	Arthralgia	79	40	17.1
	Joint swelling	15	13	5.6
	Pain in extremity	22	15	6.4
Nervous system disorders	Headache	205	64	27.4
Respiratory, thoracic and mediastinal disorders	Cough	150	68	29.1
	Nasal congestion	64	33	14.1
	Pharyngolaryngeal pain	50	32	13.7
	Rhinorrhoea	40	25	10.7
Skin and subcutaneous tissue disorders	Rash	23	19	8.1

The majority of the events in Table 3 appear to have been related to trauma, intercurrent mild respiratory or gastrointestinal disease or well-described complications of hemophilia.

Fifty-six ADRs were reported in 27 subjects. Nearly all (53/56) were isolated events or occurred once in one subject with numerous subsequent infusions without reoccurrence. The most common ADRs with a frequency greater than or equal to 2% are shown in Table 4. Of all ADRs, none were reported in neonates, 16 were reported in infants, 7 were reported in children, 8 were reported in adolescents, and 25 were reported in adults.

Table 4. Summary of Most Common Adverse Drug Reactions (ADRs)* with a frequency ≥ 2%

* ADR = Adverse Drug Reaction = adverse events considered by the investigator to be at least possibly related to administration of the product. † The ADVATE clinical program included 234, treated subjects from 5 completed studies in PTPs, and 1 ongoing study in PUPs as of 27 March 2006. ‡ All 5 ADRs occurred in (PUPs) from an ongoing clinical study, and all were for the development of Factor VIII inhibitors with a titer ≥ 0.6 BU that were to be reported as a serious AE.
MedDRA System Organ Class	MedDRA Preferred Term	Number of Patients	ADR Rate (% Patients)†
Investigations	Anti-Factor VIII antibody positive	5‡	2.14%
Nervous System Disorders	Headache	5	2.14%

Immunogenicity

The development of Factor VIII inhibitors with the use of ADVATE was eva luated in clinical studies with pediatric PTPs (<6 years of age with >50 Factor VIII exposures) and PTPs (>10 years of age with >150 Factor VIII exposures). Of 198 subjects who were treated for at least 10 exposure days or on study for a minimum of 120 days, 1 adult developed a low-titer inhibitor (2.0 [BU] in the Bethesda assay) after 26 exposure days. Eight weeks later, the inhibitor was no longer detectable, and in vivo recovery was normal at 1 and 3 hours after infusion of another marketed recombinant Factor VIII concentrate. This single event results in a Factor VIII inhibitor frequency in PTPs of 0.51% (95% CI of 0.03 and 2.91% for the risk of any Factor VIII inhibitor development). No factor VIII inhibitors were detected in the 53 treated pediatric PTPs.

In clinical studies that enrolled previously untreated subjects (defined as having had up to 3 exposures to a Factor VIII product at the time of enrollment, 5 (20%) of 25 subjects who received ADVATE developed inhibitors to Factor VIII. Four patients developed high titer ( > 5 BU) and one patient developed low-titer inhibitors. Inhibitors were detected at a median of 11 exposure days (range 7 to 13 exposure days) to investigational product.

Immunogenicity was also eva luated by measuring the development of antibodies to heterologous proteins. 182 treated subjects were assessed for anti-chinese hamster ovary cell protein antibodies. Of these patients, 3 showed an upward trend in antibody titer over time and 4 showed repeated but transient elevations of antibodies. 182 treated subjects were assessed for muIgGl protein antibodies. Of these 10 showed an upward trend in anti-mu IgG antibody titer over time and 2 showed repeated but transient elevations of antibodies. Four subjects who demonstrated antibody elevations reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts. All of these subjects had numerous repeat exposures to the study product without recurrence of the events and a causal relationship between the antibody findings and these clinical events has not been established.

Of the 181 subjects who were treated and assessed for the presence of anti-human von Willebrand Factor (VWF) antibodies, none displayed laboratory evidence indicative of a positive serologic response.

6.2 Post Marketing Experience

The following adverse reactions have been identified during post approval use of ADVATE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Among patients treated with ADVATE, cases of serious allergic/hypersensitivity reactions including anaphylaxis have been reported and Factor VIII inhibitor formation (observed predominantly in PUPs).

Table 5 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms.

Table 5. Post-Marketing Experience

* These reactions and have been manifested by dizziness, paresthesias, rash, flushing, face swelling, urticaria, and/or pruritus.
Organ System [MedDRA Primary SOC]	Preferred Term
Immune System Disorders:	Anaphylactic reaction* Hypersensitivity*
Blood And Lymphatic System Disorders:	Factor VIII inhibition
General disorders and administration site conditions	Injection site reaction Chills Fatigue Malaise

7 DRUG INTERACTIONS

There are no known drug interactions reported with ADVATE. Drug interaction studies have not been performed.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with ADVATE. It is not known whether ADVATE can cause fetal harm when administered to a pregnant woman, or whether it can affect reproductive capacity. ADVATE should be given to a pregnant woman only if clearly needed.

8.2 Labor and Delivery

There are no adequate and well-controlled human studies that have investigated the effects of ADVATE during labor and delivery. ADVATE should be used only if clinically needed.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ADVATE is administered to a nursing woman. ADVATE should be given to nursing mothers only if clinically needed.

8.4 Pediatric Use

In comparison to adults, children present with higher Factor VIII clearance values and thus lower half-life and recovery of Factor VIII. This may be explained by differences in body composition and should be taken into account when dosing or following Factor VIII levels in the pediatric population. Larger or more frequent doses should be considered to account for the observed differences in adjusted recovery and terminal half-life Dose adjustment may be needed. [see Pharmacokinetics (12.3)].

8.5 Geriatric Use

Clinical studies of ADVATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects. Dose selection for a geriatric patient should be individualized.

10 OVERDOSAGE

No symptoms of overdose with ADVATE have been reported.

11 DESCRIPTION

ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] is a purified glycoprotein consisting of 2,332 amino acids that is synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line. In culture, the CHO cell line expresses recombinant antihemophilic factor (rAHF) into the cell culture medium. The rAHF is purified from the culture medium using a series of chromatography columns. The purification process includes an immunoaffinity chromatography step in which a monoclonal antibody directed against Factor VIII is employed to selectively isolate the rAHF from the medium. The cell culture and purification processes used in the manufacture of ADVATE employ no additives of human or animal origin. The production process includes a dedicated, viral inactivation solvent-detergent treatment step. The rAHF synthesized by the CHO cells has the same biological effects on clotting as Antihemophilic Factor (Human) [AHF (Human)]. Structurally the recombinant protein has a similar combination of heterogeneous heavy and light chains as found in AHF (Human).

ADVATE is formulated as a sterile, non-pyrogenic, white to off white powder for intravenous injection. ADVATE is available in single-dose vials that contain nominally 250, 500, 1000, 1500, 2000 and 3000 International Units (IU) per vial. When reconstituted with the appropriate volume of diluent, the product contains the following stabilizers in maximal amounts: 38 mg/mL mannitol, 10 mg/mL trehalose, 108 mEq/L sodium, 12 mM histidine, 12 mM Tris, 1.9 mM calcium, 0.15 mg/mL polysorbate-80, and 0.10 mg/mL glutathione. Von Willebrand Factor (vWF) is co-expressed with Factor VIII, and helps to stabilize it in culture. The final product contains no more than 2 ng vWF/IU rAHF, which will not have any clinically relevant effect in patients with von Willebrand's disease. The product contains no preservative.

Each vial of ADVATE is labeled with the rAHF activity expressed in IU per vial. Biological potency is determined by an in vitro assay, which employs a Factor VIII concentrate standard that is referenced to a World Health Organization (WHO) International Standard for Factor VIII concentrates. One IU, as defined by the World Health Organization standard for blood coagulation FVIII, human, is approximately equal to the level of FVIII activity found in 1 mL of fresh pooled human plasma. The specific activity of ADVATE is 4000 to 10000 IU per milligram of protein.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

ADVATE temporarily replaces the missing clotting Factor VIII that is needed for effective hemostasis.

12.2 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 ADVATE normalizes the aPTT over the effective dosing period.

12.3 Pharmacokinetics

A randomized, crossover pharmacokinetic study of ADVATE produced at Orth, Austria (test) and RECOMBINATE [Antihemophilic Factor (Recombinant)] (reference) was conducted in 56 non-bleeding subjects. The subjects received either of the products as an IV infusion (50 ± 5 IU/kg body weight) and there was a washout period of 72 hours to 4 weeks between the two infusions. The pharmacokinetic parameters were calculated from Factor VIII activity measurements in blood samples obtained up to 48 hours following each infusion. Pharmacokinetic parameters for adults for each study preparation in the per-protocol analysis are presented in Table 6.

Table 6. Pharmacokinetic Parameters for ADVATE and RECOMBINATE (Per-Protocol Analysis, Adult Subjects age > 16 years)

* 56 subjects were enrolled in the clinical study. The per protocol analysis included 30 patients (20 adults and 10 children). The PK parameters in the table are calculated for adult subjects only. † Area under the plasma Factor VIII concentration x time curve from 0 to 48 hours post-infusion ‡ Calculated as (Cmax – baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-infusion Factor VIII measurement
Parameter	RECOMBINATE		ADVATE
	N	Mean ± SD	N*	Mean ± SD
AUC0-48h (IU•h/dL)†	20	1638 ± 357	20	1644 ± 338
In vivo recovery (IU/dL/IU/kg)‡	20	2.74 ± 0.56	20	2.57 ± 0.53
Half-life (h)	20	11.16± 2.50	20	12.03 ± 4.15
Cmax (IU/dL)	20	136 ± 29	20	128 ± 28
MRT (h)	20	14.68 ± 3.82	20	15.81 ± 5.91
Vss (dL/kg)	20	0.43 ± 0.10	20	0.44 ± 0.10
CL (dL/kg/h)	20	0.03 ± 0.01	20	0.03 ± 0.01

The 90% confidence intervals for the ratios of the mean AUC(0-48h) and in vivo recovery values for the test and control products were within the pre-established limits of 0.80 and 1.25. In addition, in vivo recoveries at the onset of treatment and after 75 exposure days were compared for 62 subjects. Results of this analysis indicated no significant change in the in vivo recovery at the onset of treatment and after ≥ 75 exposure days.

See the description of the clinical study results for a discussion of the effect of long-term exposure on the pharmacokinetic properties of ADVATE [CLINICAL STUDIES (14.2 )].

In an interim analysis of data from 10 of 25 planned subjects in the Phase 2/3 surgery study, the target Factor VIII level was met or exceeded in all cases following a single loading dose ranging from 48.0 to 69.8 IU/kg.

Pharmacokinetic parameters calculated from interim pharmacokinetic data for 51 subjects ≤ 16 years of age (per-protocol analysis) are available for 0 neonates, 3 infants, 21 children, and 27 adolescents as shown in Table 7. The clearance of ADVATE in infants, children, older children, and adolescents was 26%, 23%, 42%, and 23% higher than adults (0.031 dL/hr/kg). The half-life of ADVATE in infants, children, older children, and adolescents was 27%, 15%, 10%, and 3% lower than adults (12.08 hours). Clinical significance of these differences is not known.

Table 7. Pharmacokinetic Parameters (Mean ± Sd) of ADVATE by Age Group (N = 51; Intent to Treat Analysis)

* Volume of distribution † Incremental recovery at Cmax
Parameters	Infants (N =3) (1 month to <2 yrs)	Children (N = 8 ) (2 - <5 yrs)	Older Children (N = 13) (5 - <12 yrs)	Adolescents (N =27) (12 - <16 yrs)
AUC (IU*hr/dL)	1385 ± 476	1545 ± 616	1282 ± 509	1447 ± 528
Cmax (IU/dL)	98.0 ± 10.5	104.6 ± 34.5	111.8 ± 25.7	113.3 ± 21.7
CL (dL/hr/kg)	0.039 ± 0.015	0.038 ± 0.016	0.044 ± 0.012	0.038 ± 0.012
Half-life (hrs)	8.86 ± 1.78	10.27 ± 1.94	10.89 ± 1.60	11.70 ± 3.72
Vd (dL/kg)*	0.43 ± 0.08	0.46 ± 0.12	0.54 ± 0.07	0.53 ± 0.08
Recovery† IU/dL/IU/kg	1.96 ± 0.21	2.05 ± 0.62	2.21 ± 0.44	2.26 ± 0.42

13 NONCLINICAL TOXICOLOGY

Single doses several fold higher than the recommended clinical dose (related to body weight) did not demonstrate any acute or toxic effect for ADVATE in laboratory animals (mouse, rat, rabbit, and dog). Multiple dose studies were not performed with ADVATE, but were preformed with the related product, RECOMBINATE and with formulation buffers of ADVATE.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with the active ingredient in ADVATE to assess its mutagenic or carcinogenic potential. The CHO cell line employed in the production of ADVATE is derived from that used in the biosynthesis of RECOMBINATE [Antihemophilic Factor (Recombinant)]. ADVATE has been shown to be comparable to RECOMBINATE with respect to its biochemical and physicochemical properties, as well as its non-clinical in vivo pharmacology.

RECOMBINATE was tested for mutagenicity at doses considerably exceeding plasma concentrations in vitro, and at doses up to ten times the expected maximal clinical dose in vivo. At that concentration, it did not cause reverse mutations, chromosomal aberrations, or an increase in micronuclei formation in bone marrow polychromatic erythrocytes. Studies in animals have not been performed to eva luate carcinogenic potential.

14 CLINICAL STUDIES

The pharmacokinetic properties of ADVATE were investigated at the beginning of treatment in a multicenter study of previously treated subjects, and at the end of treatment in a subset of subjects (N=13) who had completed at least 75 exposure days of treatment with ADVATE. Post-infusion levels and clearance of Factor VIII during the perioperative period were examined in an interim analysis of subjects enrolled in an ongoing surgery study. The pharmacokinetics of ADVATE were investigated in an interim analysis of a study of pediatric previously treated subjects < 6 years of age. [see USE IN SPECIAL POPULATIONS: Pediatric Use (8.4) and Clinical Pharmacology (12)].

14.1 Original Safety and Efficacy Study

In the safety and efficacy study, a global assessment of efficacy was rendered by the subject (for home treatment) or study site investigator (for treatment under medical supervision) using an ordinal scale of excellent, good, fair, or none, based on the quality of hemostasis achieved with ADVATE produced in the Orth facility for the treatment of each new bleeding episode. A total of 510 bleeding episodes were reported, with a mean (± SD) of 6.1 ± 8.2 bleeding episodes per subject. Of the 510 new bleeding episodes treated with ADVATE, 439 (86%) were rated excellent or good in their response to treatment, 61 (12%) were rated fair, 1 (0.2%) was rated as having no response, and for 9 (2%), the response to treatment was unknown. A total of 411 (81%) new bleeding episodes were managed with a single infusion, 62 (12%) required 2 infusions, 15 (3%) required 3 infusions, and 22 (4%) required 4 or more infusions of ADVATE for satisfactory resolution. A total of 162 (32%) new bleeding episodes occurred spontaneously, 228 (45%) were the result of antecedent trauma, and for 120 (24%) bleeding episodes, the etiology was unknown.

The rate of new bleeding episodes during the protocol-mandated 75 exposure day prophylactic regimen (≥ 25 IU/kg body weight 3-4 times per week) was calculated as a function of the etiology of bleeding episodes for 107 eva luable subjects (n = 274 new bleeding episodes). These rates are presented in Table 8.

Table 8. Rate of New Bleeding Episodes During Prophylaxis

* Etiology was indeterminate
Bleeding Episode Etiology	Mean (± SD) New Bleeding Episodes/Subject/Month
Spontaneous	0.34 ± 0.49
Post-traumatic	0.39 ± 0.46
Unknown*	0.33 ± 0.34
Overall	0.52 ± 0.71

In a post-hoc analysis, the overall rate of bleeding was correlated inversely with the degree of compliance with the prescribed prophylactic regimen. Subjects who infused less than 25 IU ADVATE per kg per dose for more than 20% of prophylactic infusions or administered less than 3 infusions per week for more than 20% of study weeks (n = 37) experienced a 2.3-fold higher rate of bleeding in comparison with subjects who complied with the prescribed prophylactic regimen at least 80% of the time and for ≥ 80% of doses (n = 70). These data should be interpreted with caution due to the non-randomized nature of the comparison.

14.2 Continuation Study

Additional safety and efficacy data were based on subjects who continued with treatment following participation in the safety and efficacy study. An interim analysis of efficacy from the continuation study was conducted for 27 of 82 enrolled subjects who self-administered ADVATE produced in Neuchâtel on a routine prophylactic regimen during a minimum period of 50 exposure days to ADVATE. New bleeding episodes were treated with ADVATE and the outcome of treatment was rated as excellent, good, fair, or none, based on the quality of hemostasis achieved. A total of 51 new bleeding episodes occurred in 13 of the 27 subjects being treated with ADVATE. By etiology, 53% of these bleeding events resulted from trauma and 27% occurred spontaneously; the other 20% had an undetermined etiology. The response to treatment with ADVATE for the majority (63%) of all new bleeding episodes was rated as excellent or good. 86% of the bleeding episodes resolved with only 1 infusion and an additional 6% were resolved by a second infusion. Thus, 92% of all bleeding episodes required 1 or 2 infusions of study product.

In vivo recoveries at the onset of treatment and after 75 exposure days were compared for 62 subjects. There were no significant differences between the in vivo recoveries at the onset of treatment and the in vivo recoveries after ≥ 75 exposure days.

14.3 Perioperative Management Study

An interim analysis of the hemostatic efficacy of ADVATE during the perioperative management of subjects undergoing surgical procedures was conducted for 10 of 25 planned subjects. Ten subjects underwent 10 surgical procedures while receiving ADVATE. Eight subjects received the test product by intermittent bolus infusion and 2 subjects received a combination of continuous and intermittent bolus infusion. Nine of the 10 subjects completed the study. Six of the surgical procedures were classified as major, and 4 were minor. Of the 6 major surgeries, 5 were for orthopedic complications of hemophilia. A brief description of each surgical procedure, along with study duration and study medication exposure, are presented in Table 9.

Table 9. Surgical Procedures, Study Duration, and Study Medication Exposure

* ADVATE was administered by continuous infusion for the first 48 hours post-operatively, following by bolus infusions for the remainder of study treatment.
Surgery Type	Days of Study	ADVATE Exposure days	Cumulative ADVATE Exposure (IU)
Total hip replacement	16	15	61,600
Knee joint replacement	22	18	76,060
Knee arthrodesis	24	22	66,080
Transposition of the left ulnar nerve	5	3	14,560
Insertion of Mediport	28	8*	46,893
Dental extraction	18	6	16,599
Left elbow synovectomy	43	32	102,180
Teeth extraction	2	2	10,350
Right knee arthroscopy, chondroplasty and synovectomy	13	10*	32,334
Wisdom teeth extraction	14	5	15,357

For each of the 10 subjects, intra- and post-operative quality of hemostasis achieved with ADVATE was assessed by the operating surgeon and study site investigator, respectively, using an ordinal scale of excellent, good, fair, or none. The same rating scale was used to eva luate control of hemorrhage from a surgical drain placed at the incision site in one subject. The quality of hemostasis achieved with ADVATE was rated as excellent or good for all assessments.

15. REFERENCES

1. Aledort L: Inhibitors in hemophilia patients: Current status and management. Am J Hematol 1994 47:208-217.
2. Kessler CM: An introduction to Factor VIII inhibitors: The detection and quantitation. Am J Med 1991 91 (Suppl 5A):1S-5S.
3. White II GC, Courter S, Bray GL, et al: A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. Thromb Haemost 1997 77:660-667.
4. Abshire TC, Brackmann H-H, Scharrer I, et al: Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy. Thromb Haemost 2000 83:811-816.
5. Lee CA, Owens D, Bray G, et al: Pharmacokinetics of recombinant factor VIII (Recombinate) using one-stage clotting and chromogenic factor VIII assay. Thromb Haemost 1999 82:1644-1647.
6. Manco-Johnson MJ, Abshire TC, Shapiro AD et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007; 357:603-5.
7. Ljung R, Aronis-Vournas S, Kurnik-Auberger K, et al. Treatment of children with haemophilia in Europe: a survey of 20 centres in 16 countries. Haemophilia. 2000; 6:619-24.
8. Löfqvist T, Nilsson IM, Berntorp E, Pettersson H. Haemophilia prophylaxis in young patients--a long-term follow-up. J Intern Med. 1997; 241:395-400.

16. HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

ADVATE [Antihemophilic factor (recombinant) plasma /Albumin Free Method] is available in single-dose vials that contain the following nominal product strengths:

Nominal Strength	Factor VIII Potency Range	NDC Number
250 IU per vial	200 – 400 IU/vial	NDC 0944-2941-10
500 IU per vial	401 – 800 IU/vial	NDC 0944-2942-10
1000 IU per vial	801 – 1200 IU/vial	NDC 0944-2943-10
1500 IU per vial	1201 – 1800 IU/vial	NDC 0944-2944-10
2000 IU per vial	1801 – 2400 IU/vial	NDC 0944-2945-10
3000 IU per vial	2401 – 3600 IU/vial	NDC 0944-2946-10

Actual Factor VIII activity in IU is stated on the label of each ADVATE carton and vial.

16.2 Storage and Handling

ADVATE is packaged with 5 mL of Sterile Water for Injection, USP, a BAXJECT II Needleless Transfer Device, one full prescribing physician insert, and one patient insert.

ADVATE should be refrigerated (2° - 8°C [36° - 46°F]) in powder form.

ADVATE may be stored at room temperature (up to 30°C [86°F]) for a period of up to 6 months not to exceed the expiration date.

The date that ADVATE is removed from refrigeration should be noted on the carton.

Do not use beyond the expiration date printed on the vial or six months after date noted on the carton, whichever is earlier. After storage at room temperature, the product must not be returned to the refrigerator. Avoid freezing to prevent damage to the diluent vial.

百特药物ADVATE欧洲SmPC更新获EMA批准
2013年7月23日,欧洲药品管理局（EMA）已批准了药物ADVATE（重组全长FVIII因子）的产品特性概要（SmPC）更新，纳入了IV期预防性研究的数据，使临床医师和患者能够更好地选择个性化的治疗方案。
现在，ADVATE在欧洲的SmPC药效学特性部分的更新内容包括了ADVATE IV期预防性研究的数据，该研究将标准的预防（prophylaxis）给药方案及药代动力学（PK）指导的预防给药方案与按需（on-demand）治疗方案进行了比较。PK指导的预防给药是基于每个患者个体对凝血因子的反应。在该项研究中，PK指导的给药方案为一些患者提供了每3天一个剂量的时间表选择。临床数据也表明，标准的预防给药方案及PK指导的预防给药方案在降低年出血率（ABR）方面具有同样的效果。
更重要的是，ADVATE SmPC为欧洲的临床医生和患者提供的已更新的药代动力学信息，能够更好地选择个性化的治疗方案。
ADVATE是一种全长重组FVIII产品，未添加任何血液添加剂，适用于A型血友病患者出血的治疗和预防，不适用于血管性血友病（von Willebrand disease，vWD）的治疗。目前该药已获全球59个国家批准。

欧盟批准ADVATE用于治疗6岁以下儿童Ａ型血友病
美国百特医疗用品公司（Baxter）日前宣布，欧盟批准其重组第八凝血因子（ADVATE）扩展适应证，用于治疗年龄在6岁以下的Ａ型血友病儿童患者。 　　
这项决定是在一项第三期临床研究的中期分析结果基础上作出的。这项研究吸收53名年龄小于6岁的血友病儿童患者参加，以评价该药物的药代动力学、安全性、疗效以及免疫原性。 　　
中期临床研究结果显示，92.4％的患者对该药具有优异／良好的出血控制应答。临床研究中未见与该药有关的不良反应事件。该药对成人和儿童的安全性以及疗效相同，但在两者体内的药代动力学稍有不同。该药疗效显著，耐受性良好，可用于预防和治疗Ａ型血友病儿童患者的出血症状。 该药于2004年3月获欧盟批准上市，为世界上第一个也是目前惟一一个在细胞培养、纯化以及最后的制剂过程中未添加人或动物血浆蛋白和白蛋白的第八凝血因子，从而避免了被这些蛋白所携带的病毒感染的危险。 　　
该药慎用于对第八因子制剂成份有过敏史或对大鼠或仓鼠蛋白过敏者，最常见的不良反应包括味觉障碍、头疼、眩晕以及脸红。