Alphanate
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FDA Labeling Changes
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Uses
Alphanate®, Antihemophilic Factor/von Willebrand Factor Complex (Human), is indicated for the control and prevention of bleeding in patients with Factor VIII (FVIII) deficiency due to hemophilia A.1
Alphanate is indicated for surgical and/or invasive procedures in adult and pediatric patients with von Willebrand Disease (VWD) in whom desmopressin (DDAVP®) is either ineffective or contraindicated. It is not indicated for patients with severe VWD (Type 3) undergoing major surgery.
History
There is currently no drug history available for this drug.
Other Information
Alphanate 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.20 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 Albumin (Human) as a stabilizer, resulting in a final container concentrate with a specific activity of at least 5 FVIII:C IU/mg total protein. Prior to the addition of the Albumin (Human) stabilizer, the specific activity is significantly higher.
| Active Ingredients: Factor VIII von Willebrand Factor |
250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU > 400 IU/1000 IU Factor VIII |
| Excipients: | Albumin Human, Arginine and Histidine |
Alphanate contains no preservatives.
Viral Reduction Capacity
The solvent detergent treatment process has been shown by Horowitz et al., to possess effective viral inactivation capabilities without compromising protein structure and function.21 The susceptibility of human pathogenic viruses such as Human Immunodeficiency viruses (HIV), hepatitis viruses, as well as marker viruses such as Sindbis virus (SIN, a model for Hepatitis C virus) and Vesicular Stomatitis virus (VSV, a model for large, enveloped RNA virus), to inactivation by organic solvent detergent treatment has been discussed in the literature.22
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 demonstrated a log inactivation of ≥ 11.1 for HIV-1, ≥ 6.1 for HIV-2, ≥ 4.1 for VSV and ≥ 4.7 for SIN. No residual virus was detected after solvent detergent treatment in any of these studies.
Additional steps in the manufacturing process of Alphanate were evaluated for virus elimination capability. The dry heat cycle of 80 °C for 72 hours was shown to inactivate greater than 5.8 logs of Hepatitis A virus (HAV). Precipitation with 3.5% polyethylene glycol (PEG) and heparin-actigel-ALD chromatography are additional steps studied using Bovine Herpes virus (BHV, a model for Hepatitis B virus), Bovine Viral Diarrhea virus (BVD, a second model for Hepatitis C virus), human Poliovirus Sabin type 2 (POL, a model for Hepatitis A virus), Canine Parvovirus (CPV, a model for Parvovirus B19) and HIV-1.
Table 5 summarizes the reduction factors for each virus validation study performed for the manufacturing process of Alphanate.
| Virus (Model Virus for) |
3.5% PEG Precipitation |
Solvent–Detergent | Column Chromatography |
Lyophilization | Dry Heat Cycle (80 °C, 72 h) |
Total Log Removal |
| 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. 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.
Sources
Alphanate Manufacturers
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Grifols Usa, Llc
![Alphanate (Antihemophilic Factor/von Willebrand Factor Complex (Human)) Kit [Grifols Usa, Llc]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Alphanate | Pd-rx Pharmaceuticals, Inc.
Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who require doses greater than 4 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects.
Anxiety Disorders and Transient Symptoms of AnxietyTreatment for patients with anxiety should be initiated with a dose of 0.25 to 0.5 mg given three times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment.
In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction.
Panic DisorderThe successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 to 10 mg daily were used. The mean dosage employed was approximately 5 to 6 mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received alprazolam in dosages of greater than 7 mg/day, including approximately 100 patients who received maximum dosages of greater than 9 mg/day. Occasional patients required as much as 10 mg a day to achieve a successful response.
Dose TitrationTreatment may be initiated with a dose of 0.5 mg three times daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg/day may be advisable to allow full expression of the pharmacodynamic effect of alprazolam. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, that is, on a three or four times per day schedule.
Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response (ie, a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.
Dose MaintenanceFor patients receiving doses greater than 4 mg/day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than 4 mg/day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided. (See WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE.)
The necessary duration of treatment for panic disorder patients responding to alprazolam is unknown. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena.
Dose ReductionBecause of the danger of withdrawal, abrupt discontinuation of treatment should be avoided (see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).
In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction.
In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be attempted. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every 3 days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.
Dosing in Special PopulationsIn elderly patients, in patients with advanced liver disease or in patients with debilitating disease, the usual starting dose is 0.25 mg, given two or three times daily. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose may be lowered.
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