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, Lyophiliz

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

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.

For Intravenous Use After Reconstitution only

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):

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)].

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.

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.

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.

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.

Do not refrigerate after reconstitution.

ADVATE is intended for intravenous use after reconstitution only.

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.

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.

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

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.

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.

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) ].

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)

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.

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.

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.

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.

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

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.

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.

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.

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) ].

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.

No symptoms of overdose with ADVATE have been reported.

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.

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

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.

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.

The 90% confidence intervals for the ratios of the mean AUC 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.