Drug: Advate

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 CHO cell line. In culture, the CHO cell line expresses 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 human Antihemophilic Factor [hAHF]. 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. When reconstituted with the provided Sterile Water for Injection, USP, the product contains the following stabilizers and excipients in targeted amounts: Table 5 : Approximate Concentration of Stabilizer and Excipient after Reconstitution
Stabilizer and Excipient 5 mL Reconstitution (for 250, 500, 1000, 1500, 2000, 3000, 4000 IU) Target 2 mL Reconstitution (for 250, 500, 1000, 1500 IU) Target Tris (hydroxymethyl) aminomethane 10 mM 25 mM Calcium Chloride 1.7 mM 4.2 mM Mannitol 3.2% (w/v) 8% (w/v) Sodium Chloride 90mM 225 mM α, α-Trehalose 0.8% (w/v) 2% (w/v) Histidine 10 mM 25 mM Glutathione (Reduced) 0.08 mg/mL 0.2 mg/mL Polysorbate 80 0.01% (w/v) 0.025% (w/v) ADVATE is available in single-dose vials that contain nominally 250, 500, 1000, 1500, 2000, 3000 or 4000 International Units (IU) per vial. The product contains the following stabilizers and excipients: mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and glutathione. VWF is coexpressed 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 disease. The product contains no preservative. Each vial of ADVATE is labeled with the rAHF activity expressed in International Units per vial. Biological potency is determined by an in vitro assay, which employs a Factor VIII concentrate standard that is referenced to a WHO International Standard for Factor VIII concentrates. One International Unit, as defined by the WHO standard for blood coagulation Factor VIII, human, is approximately equal to the level of Factor VIII activity found in 1 mL of fresh pooled human plasma. The specific activity of ADVATE is 4000 to 10000 International Units per milligram of protein. Last reviewed on RxList: 4/4/2014
This monograph has been modified to include the generic and brand name in many instances.

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The serious adverse drug reactions (ADRs) seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to Factor VIII. The most common ADRs observed in clinical trials (frequency ≥ 10% of subjects) were pyrexia, headache, cough, nasopharyngitis, vomiting, arthralgia, limb injury. 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 evaluated in five completed studies in previously treated patients (PTPs) and one ongoing study in previously untreated patients (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 number of exposure days to ADVATE per subject was 128.0 (range: 1 to 598).3 The summary of adverse reactions (ADRs) with a frequency ≥ 5% (defined as adverse events occurring within 24 hours of infusion or any event causally related occurring within study period) is shown in Table 3. No subject was withdrawn from a study due to an ADR. There were no deaths in any of the clinical studies. Table 3: Summary of Adverse Reactions (ADRs)a with a Frequency ≥ 5% in 234 Treated Subjectsb
MedDRAc System Organ Class MedDRA Preferred Term Number of ADRs Number of Subjects Percent of Subjects General disorders and administration site conditions Pyrexia 78 50 21 Nervous system disorders Headache 104 49 21 Respiratory, thoracic and mediastinal disorders Cough 75 44 19 Infections and infestations Nasopharyngitis 61 40 17 Gastrointestinal disorders Vomiting 35 27 12 Musculoskeletal and connective tissue disorders Arthralgia 44 27 12 Injury, poisoning and procedural complications Limb injury 55 24 10 Infections and infestations Upper respiratory tract infection 24 20 9 Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain 23 20 9 Respiratory, thoracic and mediastinal disorders Nasal congestion 24 19 8 Gastrointestinal disorders Diarrhea 24 18 8 Gastrointestinal disorders Nausea 21 17 8 General disorders and administration site conditions Pair 19 17 8 Skin and subcutaneous tissue disorders Rash 16 13 6 Infections and infestations Ear infection 16 12 5 Injury, poisoning and procedural complications Procedural pain 16 12 5 Respiratory, thoracic and mediastinal disorders Rhinorrhea 15 12 5 a ADRs are defined as all Adverse Events that occurred (a) within 24 hours after being infused with investigational product or (b) all Adverse Events assessed related or possibly related to investigational product or (c) Adverse Events for which the investigator's or sponsor's opinion of causality was missing or indeterminate.
b 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.
c MedDRA version 8.1 was used. Immunogenicity The development of Factor VIII inhibitors with the use of ADVATE was evaluated 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 0.03 to 2.91% for the risk of any Factor VIII inhibitor development).3,4 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.3 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 also was evaluated by measuring the development of antibodies to heterologous proteins. 182 treated subjects were assessed for anti-Chinese hamster ovary (CHO) 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 muIgG protein antibodies. Of these, 10 showed an upward trend in anti-muIgG 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. 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 4 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms. Table 4: Post-Marketing Experience
Organ System [MedDRA Primary SOC] Preferred Term Immune system disorders Anaphylactic reactiona Hypersensitivitya Blood and lymphatic system disorders Factor VIII inhibition General disorders and administration site conditions Injection site reaction Chills Fatigue/Malaise Chest discomfort/pain Less-than-expected therapeutic effect a These reactions have been manifested by dizziness, paresthesias, rash, flushing, face swelling, urticaria, and/or pruritus. Read the Advate ([antihemophilic factor (recombinant), plasma/albumin-free method] for intravenous injection) Side Effects Center for a complete guide to possible side effectsLearn More »

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For Intravenous Use After Reconstitution Only
  • Initiate treatment with ADVATE 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 of treatment 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. [See Control and Prevention of Bleeding Episodes and Perioperative Management]
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)] x 2 [IU/dL]/[IU/kg] OR Dose (International Unit) = body weight (kg) x Desired Factor VIII Rise (IU/dL or % of normal) x 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 x {[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 x 70 IU/dL/{[2 IU/dL]/[IU/kg]} = 1400 IU.
Base the dose and frequency 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, whenever possible, perform appropriate laboratory tests including serial Factor VIII activity assays. [See WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY] 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 bleeding episodes. Table 1: ADVATE Dosing for Treatment of Bleeding Episodes in Adults and Children
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 International Units per kga
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 International Units per kga
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 International Units per kga
Repeat dose 30-50 International Units 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. a Dose (IU/kg) = Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL) Perioperative 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. Table 2: 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 Minor
Including tooth extraction 60-100 A single bolus infusion (30-50 International Units/kga) 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 International Units/ kga. Verify 100% activity has been achieved prior to surgery. Maintenance bolus infusion (40-60 International Units/kga) 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. a Dose (IU/kg) = Desired Factor VIII Rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL) Routine Prophylaxis For prevention of bleeding episodes, doses between 20 to 40 International Units of Factor VIII per kg body weight every other day (3 to 4 times weekly) may be utilized. Alternatively, an every third day dosing regimen targeted to maintain FVIII trough levels ≥ 1% may be employed. Adjust dose based on the patient's clinical response.1,2 Instruction For Use Administer ADVATE by intravenous (IV) injection after reconstitution. Ask patients to follow the specific preparation and administration procedures provided by their physicians. For instructions, ask patients to follow the recommendations in the FDA-approved patient labeling. [See FDA-approved patient labeling] Perform reconstitution, product administration, and handling of the administration set and needles 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. Preparation And Reconstitution The procedures below are provided as general guidelines for the preparation and reconstitution 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.
Figure A, B, C and D
Administration ADVATE is 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 within 3 hours of reconstitution.
  • Use plastic syringes with this product because proteins in the product 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. 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, USP only; therefore, reconstituting and withdrawing a second vial into the syringe requires a second BAXJECT II device.
  5. Administer 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.
Figure E and F

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There are no known drug interactions reported with ADVATE. Drug interaction studies have not been performed. REFERENCES 3. Shapiro A, Gruppo R, Pabinger I et al. Integrated analysis of safety and efficacy of a plasma- and albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A. Expert Opin Biol Ther 2009 9:273-283. Last reviewed on RxList: 4/4/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Control And Prevention Of Bleeding Episodes ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] is an Antihemophilic Factor (Recombinant) indicated for control and prevention of bleeding episodes in adults and children (0-16 years) with Hemophilia A. Perioperative Management ADVATE is indicated in the perioperative management in adults and children (0-16 years) with Hemophilia A. Routine Prophylaxis ADVATE is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children (0-16 years) with Hemophilia A. ADVATE is not indicated for the treatment of von Willebrand disease.

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Known anaphylaxis to mouse or hamster protein or other constituents of the product. Last reviewed on RxList: 4/4/2014
This monograph has been modified to include the generic and brand name in many instances.

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No symptoms of overdose with ADVATE have been reported.

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Dosage Forms And Strengths ADVATE with 5 mL of Sterile Water for Injection, USP is available as a lyophilized powder in single-use glass vials containing nominally 250, 500, 1000, 1500, 2000, 3000 or 4000 International Units (IU). ADVATE with 2 mL of Sterile Water for Injection, USP is available as a lyophilized powder in single-use glass vials containing nominally 250, 500, 1000 or 1500 IU. Reconstitute using Sterile Water for Injection, USP (sWFI) provided in the kit. Each vial of ADVATE is labeled with the recombinant Antihemophilic Factor (rAHF) activity expressed in International Units per vial. This potency assignment employs a Factor VIII concentrate standard that is referenced to a WHO (World Health Organization) International Standard for Factor VIII concentrates and is evaluated by appropriate methodology to ensure accuracy of the results. ADVATE is available in single-dose vials that contain the following nominal product strengths: Nominal Strength Factor VIII Potency Range NDC (Includes 5 mL sWFI Diluent) NDC (Includes 2 mL sWFI Diluent) 250 IU 200-400 IU per vial 0944-2960-10 0944-2921-02 500 IU 401-800 IU per vial 0944-2961-10 0944-2922-02 1000 IU 801-1200 IU per vial 0944-2962-10 0944-2923-02 1500 IU 1201-1800 IU per vial 0944-2963-10 0944-2924-02 2000 IU 1801-2400 IU per vial 0944-2964-10   3000 IU 2401-3600 IU per vial 0944-2965-10   4000 IU 3601-4800 IU per vial 0944-2948-10   Actual Factor VIII activity in International Units is stated on the label of each ADVATE carton and vial. Storage And Handling ADVATE is packaged with 5 mL or 2 mL of Sterile Water for Injection, USP, a BAXJECT II Needleless Transfer Device, one Terumo Microbore Infusion set (2 mL only), 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. REFERENCES 1. Fischer K, Collins P, Björkman S, Blanchette V, Oh M, Fritsch S, Schroth P, Spotts G, Ewenstein B. Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials. Haemophilia 2011 17(3):433-8. 2. Collins PW, Blanchette VS, Fischer K, Björkman S, Oh M, Fritsch S, Schroth P, Astermark J, Spotts G, Ewenstein B, The rAHF-PFM Study Group. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe haemophilia A. J Thromb Haemost 2009 7(3):413-20. Baxter Healthcare Corporation, Westlake Village, CA 91362 USA. Issued July 2012 Last reviewed on RxList: 4/4/2014
This monograph has been modified to include the generic and brand name in many instances.

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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 pruritus. [See PATIENT INFORMATION] 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. Neutralizing Antibodies Carefully monitor patients treated with AHF products 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, perform an assay that measures Factor VIII inhibitor concentration. [See Monitoring Laboratory Tests] Monitoring Laboratory Tests The clinical response to ADVATE may vary. If bleeding is not controlled with the recommended dose, determine the plasma level of Factor VIII and administer a sufficient dose of ADVATE 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, suspect the presence of an inhibitor (neutralizing antibodies) and perform appropriate tests as follows:
  • 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]
  • 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 titer 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.
    • If the inhibitor titer is above 10 BU per mL, adequate hemostasis may not be achieved. 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.
Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use)
  • Advise patients to report any adverse reactions or problems following ADVATE administration to their physician or healthcare provider.
  • Allergic-type hypersensitivity reactions have been reported with ADVATE. Warn patients of the early signs of hypersensitivity reactions, including hives, pruritus, generalized urticaria, angioedema, hypotension, shock, anaphylaxis and acute respiratory distress. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen.
  • Inhibitor formation may occur with the treatment of a patient with Hemophilia A. Advise patients to contact their physician or treatment center for further treatment and/or assessment if they experience a lack of clinical response to Factor VIII replacement therapy, as this may be a manifestation of an inhibitor.
  • Advise patients to consult with their physicians or healthcare provider prior to travel.
  • While traveling advise patients to bring an adequate supply of ADVATE based on their current regimen of treatment.
To enroll in the confidential, industry-wide Patient Notification System, call 1-888-873-2838. 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 performed with the related product, RECOMBINATE, and with formulation buffers of ADVATE. 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 evaluate carcinogenic potential. Use In Specific Populations 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. Prescribe ADVATE only if clinically needed. Labor And Delivery There are no adequate and well-controlled human studies that have investigated the effects of ADVATE during labor and delivery. Prescribe ADVATE only if clinically needed. 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. Prescribe ADVATE only if clinically needed. Pediatric Use In comparison to adults, children present with higher Factor VIII clearance (based on per kg body weight) 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.5 Because clearance (based on per kg body weight) has been demonstrated to be higher in the pediatric population, larger or more frequent dosing based on per kg body weight may be needed in this population. [See CLINICAL PHARMACOLOGY] In the ADVATE Routine Prophylaxis Clinical Study, 3 children aged 7 to < 12 and 4 adolescents aged 12 to < 16 were included in the per-protocol analysis. The reductions in annualized bleeding rate per subject per year during any prophylaxis regimen as compared to during on-demand therapy were similar among children, adolescents, and adults. [See Clinical Studies] 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. Individualize dose selection for geriatric patients. REFERENCES 5. Björkman S, Blanchette VS, Fischer K, Oh M, Spotts G, Schroth P, Fritsch S, Patrone L, Ewenstein BM, Collins PW, ADVATE Clinical Program Group. Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thromb Haemost 2010 8(4):730-6. Last reviewed on RxList: 4/4/2014
This monograph has been modified to include the generic and brand name in many instances.

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