July 25, 2016
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Alphanate

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Alphanate

Alphanate®
(Antihemophilic Factor/von Willebrand Factor Complex [Human]) Lyophilized Powder for Solution for Intravenous Injection




DRUG DESCRIPTION

ALPHANATE, (antihemophilic factor/von Willebrand factor complex [human]), is a sterile, lyophilized concentrate of FVIII (AHF) and von Willebrand Factor (VWF).

ALPHANATE is prepared from pooled human plasma by cryoprecipitation of FVIII, fractional solubilization, and further purification employing heparin-coupled, cross-linked agarose which has an affinity to the heparin binding domain of VWF/FVIII:C complex. The product is treated with a mixture of tri-n-butyl phosphate (TNBP) and polysorbate 80 to inactivate enveloped viruses. The product is also subjected to an 80 °C heat treatment step for 72 hours to inactivate enveloped and non-enveloped viruses. However, no procedure has been shown to be totally effective in removing viral infectivity from coagulation factor products.

ALPHANATE is labeled with the antihemophilic factor potency (FVIII:C activity) in International Units (IU) FVIII/vial and with VWF:RCo activity expressed in IU VWF:RCo/vial. The activities are referenced to their respective international standards established by the World Health Organization. One IU of FVIII or one IU of VWF:RCo is approximately equal to the amount of FVIII or VWF:RCo activity in 1 mL of freshly-pooled human plasma.

ALPHANATE contains human albumin as a stabilizer, resulting in a final container concentrate with a specific activity of at least 5 FVIII:C IU/mg total protein. ALPHANATE contains no preservatives.

The composition of ALPHANATE after reconstitution is as follows:

Name of Ingredients Nominal Composition Units/ Container
Factor VIII
von Willebrand Factor
250
> 400
500
> 400
1000
> 400
1500
> 400
2000
> 400
I.U.
I.U. per 1000 I.U. Factor VIII
Albumin (Human) 25 25 50 50 50 mg
Arginine 90 90 175 175 175 mg
Histidine 20 20 40 40 40 mg
Water for Injectiona 5 5 10 10 10 mL
aSupplied in a separate diluent vial

Viral Reduction Capacity

The results of virus validation studies performed to determine virus reduction factors associated with several steps in the manufacturing process of ALPHANATE are summarized in Table 3.

In vitro inactivation studies to evaluate the solvent detergent treatment (0.3% Tri-n-butyl Phosphate and 1.0% Polysorbate 80) step in the manufacture of ALPHANATE were conducted to assess the capability of the step to inactivate enveloped viruses, such as Human Immunodeficiency viruses (HIV), as well as marker viruses such as Sindbis virus (SIN, a model for Hepatitis C virus), Vesicular Stomatitis virus (VSV, a model for large, enveloped RNA virus), Bovine Herpes virus (BHV, a model for Hepatitis B virus) and Bovine Viral Diarrhea virus (BVD, a model for Hepatitis C virus). In vitro inactivation studies to evaluate the dry heat treatment (80 °C, 72 hours) step in the manufacture of ALPHANATE were conducted to assess the capability of the step to inactivate both enveloped and non-enveloped viruses, such as Hepatitis A virus (HAV), human Poliovirus Sabin type 2 (POL, a model for HAV), Canine Parvovirus (CPV, a model for Parvovirus B19), BHV and BVD. Other steps in the manufacturing process of ALPHANATE (precipitation with 3.5% polyethylene glycol (PEG), heparin affinity chromatography and lyophilization) were also evaluated for virus elimination capability using several enveloped and non-enveloped viruses as shown in Table 3.

Table 3: Virus Log Reduction

Virus (Model Virus for) 3.5% PEG Precipitation Solvent- Detergent Column Chromatography Lyophilization Dry Heat Cycle (80°C, 72 h) Total Log Reduction
BHV (HBV) < 1.0 ≥ 8.0 7.6 1.3 2.1 ≥ 19.0
BVD (HCV) < 1.0 ≥ 4.5 < 1.0 < 1.0 ≥ 4.9 ≥ 9.4
POL (HAV) 3.3 - < 1.0 3.4 ≥ 2.5 ≥ 9.2
CPV (B19) 1.2 - < 1.0 < 1.0 4.1 5.3
VSV - ≥ 4.1 - - - ≥ 4.1
SIN (HCV) - ≥ 4.7 - - - ≥ 4.7
HIV-1 < 1.0 ≥ 11.1 > 2.0 - - ≥ 13.1
HIV-2 - ≥ 6.1 - - - ≥ 6.1
HAV - - - 2.1 > 5.8 ≥ 7.9

Additionally, the manufacturing process was investigated for its capacity to decrease infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.

Several of the individual production steps in ALPHANATE manufacturing process have been shown to decrease TSE infectivity of an experimental model agent.11 TSE reduction steps include: 3.5% polyethylene glycol precipitation (3.23 log10), affinity chromatography (3.50 log10) and saline precipitation (1.36 log10). These studies provide reasonable assurance that low levels of CJD/Vcjd agent infectivity, if present in the starting material, would be removed.

REFERENCES

11. Diez JM, Caballero S, Belda P, Otegui M, Gajardo R, Jorquera JI. Elimination capacity of a TSE-model agent in the manufacturing process of Alphanate/Fanhdi, a human factor VIII/VWF complex concentrate. Haemophilia. 2009. 15(6):1249-1257.

What are the precautions when taking antihemophilic factor (Alphanate)?

Before using this medication, tell your doctor or pharmacist if you are allergic to any antihemophilic factor (factor VIII) products; or to animal proteins (e.g., mouse); or to natural rubber/latex (found in the packaging of some brands); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history.

Manufacturers of some brands of this medication recommend that you monitor your heartbeat during treatment. If your heart starts to beat faster, it is recommended that you give this medication more slowly or temporarily stop the infusion until your heart rate returns to normal....

Read All Potential Precautions of Alphanate »

Last reviewed on RxList: 5/2/2016
This monograph has been modified to include the generic and brand name in many instances.

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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