Advate

Name: Advate

Advate Interactions

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Other drugs may interact with recombinant antihemophilic factor, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Notes

Do not share this medication with others.Laboratory blood tests (e.g., factor VIII levels) should be performed frequently to determine your dosage and to check how well this medication is working. Consult your doctor for more details.

Storage

Store the medication according to the manufacturer's instructions. Ask your pharmacist if you have any questions. Do not freeze this product or store it in the bathroom. Protect the product from light. After mixing, use the product within the time frame stated in the manufacturer's instructions and throw away any unused portion. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details.MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-888-633-4298 (US) or 1-800-668-1507 (Canada).

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Reviewed on 4/16/2014 References

How supplied

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

Clinical pharmacology

Mechanism Of Action

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

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.

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.4 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)

Parameter RECOMBINATE
(n = 20)a
ADVATE
(n = 20)a
Mean ± SD Mean ± SD
AUCM8h (IUhrs/dL)b 1638± 357 1644± 338
In vivo recovery (IU/dL/IU/kg)c 2.74 ± 0.56 2.57 ± 0.53
Half-life (hrs) 11.16 ± 2.50 12.03 ± 4.15
Cmax (IU/dL) 136 ± 29 128 ± 28
MRT (hrs) 14.68 ± 3.82 15.81 ± 5.91
Vss (dL/kg) 0.43 ± 0.10 0.44 ± 0.10
CL (dL/hr/kg) 0.03 ± 0.01 0.03 ± 0.01
a 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.
b Area under the plasma Factor VIII concentration x time curve from 0 to 48 hours post-infusion.
c Calculated as (Cmax – baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-infusion Factor VIII measurement.

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. [See Clinical Studies]

In an analysis of data from 58 unique subjects with 65 surgical procedures in the perioperative management study, the target Factor VIII level was met or exceeded in all cases following a single loading dose ranging from 29 to 104 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). The extent to which these differences may be clinically significant is not known.

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

Parameters Infants (N = 3) (1 month to < 2 yrs) Children
(N = 8) (2 to < 5 yrs)
Older Children
(N = 13) (5 to < 12 yrs)
Adolescents
(N = 27) (12 to < 16 yrs)
AUC (IU hr/dL) 1385± 476 1545 ± 616 1282± 509 1447± 528
C™ (IU/dL) 98.0 ± 10.5 104.6 ± 34.5 111.8 ± 25.7 113.3 ± 21.7
MRT (hrs) 11.6 ± 3.0 12.8 ± 2.3 13.1 ± 3.5 15.0 ± 5.6
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
Vss (dL/kg)a 0.43 ± 0.08 0.46 ± 0.12 0.54 ± 0.07 0.53 ± 0.08
Recoveryb IU/dL/IU/kg 1.96 ± 0.21 2.05 ± 0.62 2.21 ± 0.44 2.26 ± 0.42
a Volume of distribution at steady state
b Incremental recovery at Cmax calculated as (Cmax – baseline Factor VIII) divided by the dose in IU/kg, where Cmax is the maximal post-infusion Factor VIII measurement

In a crossover pharmacokinetic study of rAHF-PFM reconstituted in 2 mL versus 5 mL Sterile Water for Injection, USP (sWFI) in previously treated severe Hemophilia A adult and adolescent patients, the AUCs of the two formulations were comparable and the 90% confidence interval ranged from 90.4 to 102.6, indicating that the two formulations are pharmacokinetically equivalent.

Clinical Studies

Original Safety And Efficacy Study

The original safety and efficacy study evaluated the pharmacokinetics (double-blinded, randomized, cross-over), safety, immunogenicity, and hemostatic efficacy (open-label) of ADVATE in 111 subjects. The study was conducted with 103 Caucasian; 7 Black and 1 Asian US and European previously treated subjects (PTPs with ≥ 150 exposure days) diagnosed with moderate to severe hemophilia A (FVIII level ≤ 2% of normal), who were ≥ 10 years of age (20 were 10 to < 13, 22 were 13 to < 16, and 69 were 16 years and older). Subjects with a history of or a detectable FVIII inhibitor, portal vein hypertension (INR > 1.4), presence of splenomegaly, spider angiomata, history of esophageal hemorrhage or documented esophageal varices, hypersensitivity to RECOMBINATE rAHF, or scheduled to receive immunomodulating drug were excluded. Subjects self-administered ADVATE for routine prophylaxis and for the treatment of bleeding episodes. 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 these 510 episodes, 439 (86%) were rated excellent or good in their response to treatment with ADVATE, 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%) 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%) bleeding episodes occurred spontaneously, 228 (45%) were the result of antecedent trauma, and for 120 (24%) bleeding episodes, the etiology was unknown.4

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 evaluable subjects (n = 274 new bleeding episodes).4 These rates are presented in Table 8.

Table 8: Rate of New Bleeding Episodes During Prophylaxis

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

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 a surgery study. The pharmacokinetics of ADVATE was investigated in an interim analysis of a study of pediatric previously treated subjects < 6 years of age. [See Pediatric Use and CLINICAL PHARMACOLOGY]

Continuation Study

Additional (open-label) safety and efficacy data were based on 82 subjects who continued with treatment following participation in the pivotal study. An interim analysis of efficacy from the continuation study was conducted for 27 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 pontaneously; 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.

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.

Perioperative Management Study

The study design, key inclusion and exclusion criteria, treatment, number of subjects and age range for the original perioperative management study can be found in Table 9.

Table 9: Study Design, Key Inclusion and Exclusion Criteria, Treatment, Number of Subjects and Age Range for ADVATE Perioperative Management Study6

Treatment(s) Number of Subjects Age Range, Race
Perioperative Management Interim: Interim:
1. Preoperative 10 Procedures: 14-64 years
  Dental loading dose: FVIII level 60-100% of normal; Major: 6
Minor: 4
Caucasian: 9
  Major/Minor loading dose: FVIII level 80-120% of normal Orthopedic: 5
Dental: 0
Black: 1
  Final:
2. Intra- and Post-Operative Final: 59 7-65 years
*BI: as clinically indicated; Procedures: 65
*CI: initial rate for subjects > 12y: Major: 22 Caucasian: 55
4 IU kg-1h-1; initial rate subjects Minor: 35 Black: 3
5-12y: 5 IUkg-1h-1 for; then investigator-determined Orthopedic: 40 Asian: 1
  Dental: 8  
3. Home Replacement Therapy 7 to

Manufacturer

  • Baxter Healthcare Bioscience Division

  • Baxter Healthcare Corporation

Advate and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Advate falls into category C. No studies have been done in animals, and no well-controlled studies have been done in pregnant women. Advate should be given to a pregnant woman only if clearly needed.

Advate Usage

Advate comes in an injectable form to be given directly into a vein (IV) by a healthcare professional. Advate is given as an infusion over a period of 5 minutes or less.

If you miss an appointment to receive a dose of Advate, contact your healthcare provider for instructions on when to receive your next dose.

Advate may also be administered at home. You should be trained on how to do infusions by your healthcare provider or hemophilia treatment center.

 

What are some things I need to know or do while I take Advate?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • Allergic side effects may rarely happen.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Call the doctor right away if the normal dose does not work as well.
  • Talk with the doctor before you travel. You will need to bring enough of Advate for use during travel.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Contraindications

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

Overdosage

No symptoms of overdose with Advate have been reported.

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)].

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 evaluable 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.

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.

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 evaluate 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.

  • Hemophilia
(web3)