Alphanate by is a Other medication manufactured, distributed, or labeled by GRIFOLS USA, LLC, Grifols Biologicals LLC, LABORATORIOS GRIFOLS SA. Drug facts, warnings, and ingredients follow.
ALPHANATE, (antihemophilic factor/von Willebrand factor complex [human]), is indicated for: (1)
For intravenous injection after reconstitution only.
ALPHANATE contains the labeled amount of factor VIII expressed in International Units (IU) FVIII/vial and von Willebrand Factor:Ristocetin Cofactor activity in IU VWF:RCo/vial (2).
Dose (2.1)
Treatment and Prevention of Bleeding Episodes and Excess Bleeding During and After Surgery in Patients with Hemophilia A
Treatment and Prevention of Excess Bleeding During and After Surgery or Other Invasive Procedures in Patients with von Willebrand Disease
ALPHANATE is available as a lyophilized powder for intravenous injection after reconstitution in single dose vials containing 250, 500, 1000, 1500 IU and 2000 IU FVIII (3).
Do not use in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components (4).
The most frequent adverse drug reactions reported with ALPHANATE in >1% of infusions were pruritus, headache, back pain, paresthesia, respiratory distress, facial edema, pain, rash and chills (6).
To report SUSPECTED ADVERSE REACTIONS, contact Grifols Biologicals LLC at 1-888-GRIFOLS (1-888-474-3657) or FDA at 1-800-FDA-1088 www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 6/2018
ALPHANATE, (antihemophilic factor/von Willebrand factor complex [human]), is indicated for:
For intravenous injection after reconstitution only
Treatment and Prevention of Bleeding Episodes and Excess Bleeding During and After Surgery in Patients with Hemophilia A
Dosage (international units) = body weight (kg) x desired FVIII rise (IU/dL or % normal) x 0.5 (IU/kg per IU/dL)
or
IU/dL (or % of normal) = [Total Dose (IU)/body weight (kg)] x 2
Type of Bleeding | FVIII:C Level Required(% of normal) | Doses(IU/kg) | Frequency of Doses(hours) | Duration of Therapy (days) |
Minor Large bruises Significant cuts or scrapes Uncomplicated joint hemorrhage | 30 | 15 | 12 (twice daily) | Until hemorrhage stops and healing has been achieved (1–2 days). |
Moderate Nose, mouth and gum bleeds Dental extractions Hematuria | 50 | 25 | 12 (twice daily) | Until healing has been achieved (2–7 days, on average). |
Major
Joint hemorrhage Muscle hemorrhage Major trauma Hematuria Intracranial and intraperitoneal bleeding | 80–100 | Initial: 40–50 Maintenance: 25 | 12 (twice daily) | For at least 3–5 days Until healing has been achieved for up to 10 days. Intracranial hemorrhage may require prophylaxis therapy for up to 6 months. |
Surgery | Prior to surgery: 80–100 After surgery: 60–100 | 40–50 30–50 | Once 12 (twice daily) | Prior to surgery For the next 7–10 days, or until healing has been achieved. |
Treatment and Prevention of Excess Bleeding During and After Surgery or Other Invasive Procedures in Patients with von Willebrand Disease
a The therapeutic goal is referenced in the NHLBI Guidelines.7 |
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b The safety parameter is extracted from Mannucci 2009.8 |
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Minor Surgery/Bleeding | ||
Parameter | VWF:RCo | Target
FVIII:C Activity Levels |
Pre-operative/pre-procedure dose: | Adults: 60 IU VWF:RCo/kg body weight. Pediatrics: 75 IU VWF:RCo/kg body weight. |
40-50 IU/dL |
Maintenance dose: | Adults: 40 to 60 IU VWF:RCo/kg body weight at 8 to 12 hour intervals as clinically needed for 1-3 days. Pediatrics: 50 to 75 IU VWF:RCo/kg body weight at 8 to 12 hour intervals as clinically needed for 1-3 days. |
40-50 IU/dL |
Therapeutic Goal (Trough)a : | >50 IU/dL | >50 IU/dL |
Safety Monitoring: | Peak and trough at least once daily | Peak and trough at least once daily |
Safety Parameterb : | Should not exceed 150 IU/dL | Should not exceed 150 IU/dL |
Major Surgery/Bleeding | ||
Parameter | VWF:RCo | Target
FVIII:C Activity Levels |
Pre-operative/pre-procedure dose: | Adults: 60 IU VWF:RCo/kg body weight. Pediatrics: 75 IU VWF:RCo/kg body weight. | 100 IU/dL |
Maintenance dose: | Adults: 40 to 60 IU VWF:RCo/kg body weight at 8 to 12 hour intervals as clinically needed for at least 3-7 days. Pediatrics: 50 to 75 IU VWF:RCo/kg body weight at 8 to 12 hour intervals as clinically needed for at least 3-7 days. | 100 IU/dL |
Therapeutic Goal (Trough)a : | >50 IU/dL | >50 IU/dL |
Safety Monitoring: | Peak and trough at least daily | Peak and trough at least daily |
Safety Parameterb: | Should not exceed 150 IU/dL | Should not exceed 150 IU/dL |
For intravenous use after reconstitution only
ALPHANATE is available as a lyophilized powder for intravenous injection after reconstitution. It is available in the following potencies:
250 IU FVIII/5 mL single dose vial
500 IU FVIII/5 mL single dose vial
1000 IU FVIII/10 mL single dose vial
1500 IU FVIII/10 mL single dose vial
2000 IU FVIII/10 mL single dose vial
ALPHANATE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components [see Adverse Reactions (6)].
Anaphylaxis and severe hypersensitivity reactions are possible with ALPHANATE. Early signs of allergic reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, hypotension, rash, nausea, vomiting, paresthesia, restlessness, wheezing and dyspnea. Discontinue use of ALPHANATE if hypersensitivity symptoms occur, and initiate appropriate treatment.
Development of procoagulant activity-neutralizing antibodies (inhibitors) has been detected in patients receiving FVIII-containing products. Carefully monitor patients treated with AHF products for the development of FVIII inhibitors by appropriate clinical observations and laboratory tests. No specific studies have been conducted with ALPHANATE to evaluate inhibitor formation. If expected plasma FVIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an appropriate assay that measures FVIII inhibitor concentration.
Thromboembolic events have been reported in von Willebrand Disease patients receiving replacement therapy with Antihemophilic Factor/von Willebrand Factor Complexes, especially in those with known risk factors for thrombosis including but not limited to elderly age, previous thrombosis, metabolic syndrome, cancer, surgery, oral contraceptive and hormone therapy, diabetes, hypertension, hyperlipidemia, smoking, and pregnancy.9 Monitor plasma levels of VWF:RCo and FVIII activities to avoid sustained excessive VWF and FVIII activity levels (greater than 150 IU/dL), which may increase the risk of thrombotic events, during continued treatment of replacement therapy with Antihemophilic Factor/von Willebrand Factor Complexes. Consider antithrombotic measures in VWD patients at risk for thrombosis [see Adverse Reactions (6)].
ALPHANATE contains blood group specific isoagglutinins. Monitor the patient for signs of intravascular hemolysis and decreasing hematocrit when large and/or frequent doses of Antihemophilic Factor/von Willebrand Factor Complexes are required in patients of blood groups A, B, or AB, as cases of acute hemolytic anemia, increased bleeding tendency or hyperfibrinogenemia have been reported. These events typically subside after cessation of the factor concentrate infusion.10 Consider alternative therapy should this condition worsen despite discontinuation of ALPHANATE.
Rapid administration of a FVIII concentrate may result in vasomotor reactions. Do not administer ALPHANATE at a rate exceeding 10 mL/minute.
Because ALPHANATE is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob Disease (vCJD) agent and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain virus infections, and by inactivating and/or removing certain viruses during manufacturing. [see Description (11)].
Monitor for development of FVIII and VWF inhibitors. Perform appropriate assays to determine if FVIII and/or VWF inhibitor(s) are present if bleeding is not controlled with expected dose of ALPHANATE.
Monitor plasma levels of VWF:RCo and FVIII activities to avoid sustained excessive VWF and FVIII activity levels (greater than 150 IU/dL), which may increase the risk of thrombotic events, particularly in patients with known risk factors.
Serious adverse drug reactions (ADRs) observed in patients receiving ALPHANATE include anaphylaxis/hypersensitivity reactions. Thromboembolic events also have been observed in patients receiving ALPHANATE for VWD [see Warnings and Precautions (5.3)].
Because clinical trials are conducted under widely varying conditions, adverse drug reaction (ADR) 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.
Hemophilia A
In a prospective clinical study with ALPHANATE, 23 subjects were exposed to 1217 infusions (median=42, range 2-160). The total number of exposure days was 1133, and the total number of months on study across all subjects was 234 (19.5 subject years). No ADRs or inhibitors to FVIII were reported during the study.
von Willebrand Disease
In the prospective clinical study of ALPHANATE[using both ALPHANATE Solvent Detergent (A-SD, a previous generation product) and ALPHANATE Solvent Detergent/Heat Treated (A-SD/HT, the current generation product)] in subjects with von Willebrand Disease, ADRs occurred in 5 of 36 subjects (13.9%) treated with ALPHANATE.
Sixty-one total ADRs were reported in 204 infusions. The majority of ADRs were rated as mild (55 of 61 [90.2%]). Six ADRs (9.8%) were rated as moderate. No reactions rated as serious were reported. The adverse drug reaction grading scale is defined as follows:
Overall, the proportion of infusions associated with ADRs was 14 of 204 infusions (6.9%).
The most common ADRs reported (> 1% of infusions) were pruritus, headache, backpain, paresthesia, respiratory distress, facial edema, pain, rash, and chills.
One incident of pulmonary embolism was reported that was considered to have a possible relationship to the product. This subject received a dose of 60 IU VWF:RCo/kg body weight and the FVIII:C level achieved was 290%.
In the retrospective study conducted to determine the efficacy and safety of ALPHANATE (A-SD/HT) in a surgical or invasive procedure setting as perioperative prophylaxis against excessive bleeding, [see Clinical Studies (14)], 3 out of 39 subjects (7.7%) experienced 6 adverse drug reactions. Four were considered mild and 2 were considered moderate. No subject discontinued their treatment due to an adverse drug reaction. The adverse drug reactions were pruritus, paresthesia (2 events) and hemorrhage (all considered mild), and one event each of moderate hematocrit decrease and orthostatic hypotension.
One adverse drug reaction (pain) related to the treatment with heat-treated ALPHANATE (A-SD/HT) was reported in the four pediatric subjects with von Willebrand Disease during the course of the prospective study and in none of the five pediatric subjects in the retrospective clinical study.
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.
The most common post-marketing ADRs reported include allergic/hypersensitivity reactions, nausea, fever, joint pain, fatigue, and infusion site pain.
Pregnancy Category C. Animal reproduction studies have not been conducted with ALPHANATE. It is also not known whether ALPHANATE can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. ALPHANATE should be given to a pregnant woman only if clearly needed.
Hemophilia A
A total of 21 children (ages 7-16) were included in clinical trials with ALPHANATE. Subjects received ALPHANATE weekly for prophylaxis or suspected bleeds. They were successfully treated for 1499 bleeding episodes or as prophylaxis to prevent them (e.g. pain in the joint). The median number of units needed to treat the bleeds was 420 IU, with a range of 210 to 1620 IU. Adult and pediatric subjects did not differ in their response to treatment.
Von Willebrand Disease
The hemostatic efficacy of ALPHANATE has been studied in 20 pediatric subjects (ages 7-18) with VWD. Based on the data from a subset of these subjects, age had no effect on the pharmacokinetics of VWF:RCo. Adult and pediatric subjects did not differ in their response to treatment.
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:
a Supplied in a separate diluent vial |
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Name of Ingredients | Nominal Composition | Units/Container | ||||
Factor VIII | 250 | 500 | 1000 | 1500 | 2000 | IU |
von Willebrand Factor | > 400 | > 400 | > 400 | > 400 | > 400 | IU per 1000 IU 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 |
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.
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.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.
ALPHANATE contains antihemophilic factor (FVIII) and von Willebrand factor (VWF), constituents of normal plasma. FVIII is an essential cofactor in activation of factor X leading to formation of thrombin and fibrin. VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; it also serves as a stabilizing carrier protein for the procoagulant protein FVIII.12, 13
After administration, ALPHANATE temporarily replaces the missing coagulation factor VIII and von Willebrand factor needed for effective hemostasis.
Pharmacokinetics in Hemophilia A
Following the administration of ALPHANATE during clinical trials, the mean in vivo half-life of FVIII observed in 12 adult subjects with severe hemophilia A was 17.9 ± 9.6 hours. In this same study, the in vivo recovery was 96.7 ± 14.5% at 10 minutes postinfusion. Recovery at 10 minutes post-infusion was also determined as 2.4 ± 0.4 IU FVIII rise/dL plasma per IU FVIII infused/kg body weight.
Pharmacokinetics in von Willebrand Disease (VWD)
A pharmacokinetic crossover study was conducted in 14 non-bleeding subjects with VWD (1 type 1, 2 type 2A, and 11 type 3) comparing the pharmacokinetics of ALPHANATE (A-SD/HT) and an earlier formulation, ALPHANATE (A-SD). Subjects received, in random order at least seven days apart, a single intravenous dose of each product, 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg in subjects younger than 18 years of age). Pharmacokinetic parameters were similar for the two products and indicated that they were biochemically equivalent. Pharmacokinetic analysis of ALPHANATE (A-SD/HT) in the 14 subjects revealed the following results: the median plasma levels (% normal) of VWF:RCo rose from 10 IU/dL (range: 10 to 27 IU/dL) at baseline to 206 IU/dL (range: 87 to 440 IU/dL) 15 minutes post-infusion; median plasma levels of FVIII:C rose from 5 IU/dL (range: 2 to 114 IU/dL) to 206 IU/dL (range: 110 to 421 IU/dL). The median bleeding time (BT) prior to infusion was 30 minutes (mean, 28.8 ± 4.41 minutes; range: 13.5 to 30 minutes), which shortened to 10.38 minutes (mean, 10.4 ± 3.2 minutes; range: 6 to 16 minutes) 1 hour post-infusion.
Following infusion of ALPHANATE (A-SD/HT), the median half-lives for VWF:RCo, FVIII:C and VWF:Ag were 6.91 hours (range: 3.8 to 16.22 hours), 20.92 hours (range: 7.19 to 32.2 hours), and 12.8 hours (range: 10.34 to 17.45 hours), respectively. The median incremental in vivo recoveries of VWF:RCo and FVIII:C were 3.12 (IU/dL)/(IU/kg) [range: 1.28 to 5.73 (IU/dL)/(IU/kg)] for VWF:RCo and 1.95 (IU/dL)/(IU/kg) [range: 1.33 to 3.32 (IU/dL)/(IU/kg)] for FVIII:C.
The pharmacokinetic data in VWD are summarized in Table 4.
Parameter
| Plasma VWF:RCo
(Mean ± SD) | Plasma FVIII:C
(Mean ± SD) | Plasma VWF:Ag
(Mean ± SD) |
Number of subjects | 14 | 14 | 14 |
Mean plasma levels (IU/dL) | |||
Baseline | 11.86 ± 4.97 | 21.00 ± 33.83 | – |
15 minutes post infusion | 215.50 ± 101.70 | 215.29 ± 94.26 | – |
T½ (Half-life in hours) | 7.67 ± 3.32 | 21.58 ± 7.79 | 13.06 ± 2.20 |
Incremental in vivo recovery in (IU/dL)/(IU/kg) | 3.29 ± 1.46 | 2.13 ± 0.58 | – |
Following infusion of both ALPHANATE (A-SD) and ALPHANATE (A-SD/HT), an increase in the size of VWF multimers was seen and persisted for at least 24 hours. The shortening of the BT was transient, lasting less than 6 hours following treatment and did not correlate with the presence of large and intermediate size VWF multimers.14
In a prospective, multi-center clinical study, 37 subjects with VWD (6 Type 1, 19 Type 2, 12 Type 3) underwent 59 surgical procedures for which ALPHANATE (A-SD) or ALPHANATE (A-SD/HT) was administered [21 subjects received ALPHANATE (A-SD), 18 received ALPHANATE (A-SD/HT), and 2 received both products] for bleeding prophylaxis (see Table 5). An initial pre-operative infusion of 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg for subjects less than 18 years of age), was administered one hour before surgery. A blood sample was obtained 15 minutes after the initial infusion for the determination of the plasma FVIII:C level. The level had to equal or exceed 100% of normal for an operation to proceed. No cryoprecipitate or alternative FVIII product was administered during these surgical procedures. Platelets were required in two subjects. The protocol permitted intra-operative infusions of ALPHANATE (A-SD) and ALPHANATE (A-SD/HT) at 60 IU VWF:RCo/kg (75 IU VWF:RCo/kg for subjects less than 18 years of age) to be administered as required according to the judgment of the investigator.
^ Two subjects received both preparations; the total number of subjects is therefore less than the sum of the columns. |
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Parameter | Treatment with Alphanate | Total | |
Type of Surgical Procedure | A-SD | A-SD/HT | |
Number of Subjects | 21 | 18 | 37^ |
Dental | 14 | 6 | 20 |
Dermatologic | 1 | 1 | 2 |
Gastrointestinal | 4 | 4 | 8 |
Gastrointestinal (diagnostic) | 6 | 0 | 6 |
Genitourinary | 0 | 2 | 2 |
Gynecologic | 2 | 1 | 3 |
Head and neck | 1 | 1 | 2 |
Orthopedic | 4 | 3 | 7 |
Vascular | 3 | 6 | 9 |
Total number of procedures | 35 | 24 | 59 |
Post-operative infusions at doses of 40 to 60 IU VWF:RCo/kg (50 to 75 IU VWF:RCo/kg for pediatric subjects) were administered at 8 to 12-hour intervals until healing had occurred. For maintenance of secondary hemostasis (after primary hemostasis was achieved), the dose was reduced after the third post-operative day [see Dosage and Administration (2.2)].
Overall, in the surgical procedures using either product, the BT at 30 minutes post-infusion was fully corrected in 18 (32.7%) cases, partially corrected in 24 (43.6%) cases, not corrected in 12 (21.8%) cases, and was not done in one case (1.8%). Overall, the mean blood loss was lower than predicted prospectively.
Surgical infusion summary data are included in Table 6.
* Two subjects received both products |
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Parameter | A-SD | A-SD/HT | Total |
Number of subjects | 21 | 18 | 37* |
Number of surgical procedures | 35 | 24 | 59 |
Median number of infusions per surgical procedure (range) | 3 (1-13) | 4 (1 – 18) | 4 (1-18) |
Median dosage IU VWF:RCo/kg | |||
Infusion #1 (range) | 59.8 (19.8-75.1) | 59.9 (40.6 – 75.0) | 59.9 (19.8-75.1) |
Infusion ≥ #2 combined (range) | 40.0 (4.5-75.1) | 40.0 (10.0 – 63.1) | 40.0 (4.5-75.1) |
Additionally, surgical procedures using ALPHANATE SD/HT only were categorized as major, minor or invasive procedures according to definitions used in the study. The outcome of each surgery was evaluated according to a clinical rating scale (excellent, good, poor or none) and was considered successful if the outcome was excellent or good.
Study results also were evaluated independently by two referees with clinical experience in this field in the same way (surgery categorization and outcome of each surgery according to a clinical rating scale). There was a high level of agreement between the referee evaluations and the analyzed outcome data, with a decrease of only a single success in achieving hemostasis (21/24 [referees evaluation] vs. 22/24 [investigators evaluation]).
A retrospective, multi-center study was performed to assess the efficacy of ALPHANATE (A-SD/HT) as replacement therapy in preventing excessive bleeding in subjects with congenital VWD undergoing surgical or invasive procedures, for whom DDAVP was ineffective or inadequate. A total of 61 surgeries/procedures in 39 subjects were evaluated.15
Of the 39 subjects, 18 had Type 1 VWD (46.2%); 12 subjects (30.8%) had Type 2 VWD, and 9 subjects (23.1%) had Type 3 VWD. Median age was 40 years; approximately one-half of the subjects were male.
The primary efficacy variable was the overall treatment outcome for each surgical or invasive procedure, as rated by the investigator using a 4-point verbal rating scale (VRS): “excellent,” “good,” “poor,” or “none (no indication of efficacy).” The categorization of the replacement treatment outcome was based upon the investigator’s clinical experience and defined in Table 7.
* The efficacy assessment period included the entire perioperative period. |
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Rating | Clinical Efficacy* | |||
Hemostasis | Dosing | |||
Excellent | Hemostasis not different from that expected for subjects without known bleeding disorders. | No upward dosage adjustment for ALPHANATE replacement therapy. | ||
Good | Hemostasis slightly inferior from that expected for subjects without known bleeding disorders but judged as not clinically relevant. | Minor upward dosage adjustment for ALPHANATE replacement therapy. | ||
Poor | Less hemostasis than expected for subjects without known bleeding disorders attributed to vWD despite ALPHANATE replacement therapy. | Relevant upward dosage adjustment for ALPHANATE replacement therapy. No need for alternative therapy. No need for alternative therapy. |
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None | Severe bleeding attributed to vWD despite ALPHANATE replacement therapy. | Relevant upward dosage adjustment for ALPHANATE replacement therapy and/or need for alternative unexpected therapy. |
In addition, an independent referee committee was convened to evaluate the efficacy outcomes. More than 90% of the surgical outcomes received an investigator and referee’s overall and daily rating of “effective” (“excellent” or “good”) in achieving hemostasis/preventing bleeding.
The majority of ratings were considered “excellent” (≥ 81.3% in each VWD type). Nine Type 3 subjects underwent 1 major and 15 minor procedures. Two procedures (1 major and 1 minor) in 1 subject with Type 3 VWD received an overall efficacy rating of “none,” and one minor procedure in a subject with Type 2 VWD received an overall efficacy rating of “poor.”
How Supplied
ALPHANATE is supplied in sterile, lyophilized form in a single dose vial with a vial of diluent (Sterile Water for Injection, USP) and a Mix2Vial filter transfer set. IU activity of FVIII and VWF:RCo are stated on the carton and label of each vial.
ALPHANATE is available in the following potencies and color coded based upon assay on the carton and label as follows:
Potency | NDC | Assay Color Code |
250 IU FVIII/5 mL single dose vial | 68516-4601-1 or 68516-4611-1 | 250 IU FVIII Range - grey box |
500 IU FVIII/5 mL single dose vial | 68516-4602-1 or 68516-4612-1 | 500 IU FVIII Range - blue box |
1000 IU FVIII/10 mL single dose vial | 68516-4603-2 or 68516-4613-2 | 1000 IU FVIII Range - red box |
1500 IU FVIII/10 mL single dose vial | 68516-4604-2 or 68516-4614-2 | 1500 IU FVIII Range - black box |
2000 IU FVIII/10 mL single dose vial | 68516-4609-2 or 68516-4615-2 | 2000 IU FVIII Range - green box |
Advise the patient:
Manufactured by:
Grifols Biologicals LLC
5555 Valley Boulevard
Los Angeles, CA 90032, U.S.A.
U. S. License No. 1694
3051535
Principal Display Panel – 250 IU Vial Label
GRIFOLS
NDC: 68516-4605-1
Antihemophilic Factor/von Willebrand
Factor Complex (Human) Alphanate®
Solvent Detergent/Heat Treated 5 mL
250 IU FVIII Range
Storage: Store at temperatures not exceeding 25°C (77°F).
Rx only. Single dose container for intravenous
administration only.
Grifols Biologicals LLC
5555 Valley Boulevard Los Angeles, CA 90032, USA
U.S. License No. 1694
Instructions: Reconstitute with 5 mL of Sterile Water for Injection, USP. Administer promptly after reconstitution and do not refrigerate.
For information on dosage and directions for administration, see accompanying pamphlet.
Contains no preservatives.
The patient and physician should discuss the risks and benefits of this product.
3051536
Lot
EXP
IU FVIII/Vial
IU VWF:RCo/Vial
Lot
IU FVIII/Vial
IU VWF: RCo/Vial
Alphanate® 5 mL NDC: 68516-4605-1
Principal Display Panel – 250 IU Carton Label
GRIFOLS
NDC: 68516-4611-1
Antihemophilic Factor/von
Willebrand Factor Complex (Human)
Alphanate®
Solvent Detergent / Heat Treated
5 mL
250 IU FVIII Range
For Intravenous Administration
Contents: One vial Antihemophilic Factor/von Willebrand Factor Complex (Human), Alphanate®, one vial 5 mL Sterile Water for Injection, USP, one Mix2Vial® filter transfer set, and directions for use.
Composition:
Factor VIII, von Willebrand Factor, Arginine, Albumin and Histidine.
Contains no preservatives.
Administer within three hours of reconstitution.
Warning: This product is prepared from large pools of human plasma. Human blood and its components may transmit infectious agents. See package insert, WARNINGS AND PRECAUTIONS.
Instructions: The patient and physician should discuss the risks and benefits of this product. For information on dosage and directions for administration, see enclosed package insert.
Storage: Store at temperatures not exceeding 25 °C (77 °F). Do not freeze.
Rx only
Grifols Biologicals LLC
5555 Valley Boulevard
Los Angeles, CA 90032, USA
U.S. License No. 1694
3051538
GTIN 00368516461112
LOT XXXXXXXXXX
EXP DDMMMYYYY
SN XXXXXXXXXX XXXXXX
IU FVIII/Vial XXXX
IU VWF: RCo/Vial XXXX
Principal Display Panel – 500 IU Vial Label
GRIFOLS
NDC: 68516-4606-1
Antihemophilic Factor/von Willebrand
Factor Complex (Human) Alphanate®
Solvent Detergent/Heat Treated 5 mL
500 IU FVIII Range
Storage: Store at temperatures not exceeding 25°C (77°F).
Rx only. Single dose container for intravenous
administration only.
Grifols Biologicals LLC
5555 Valley Boulevard Los Angeles, CA 90032, USA
U.S. License No. 1694
Instructions: Reconstitute with 5 mL of Sterile Water for Injection, USP. Administer promptly after reconstitution and do not refrigerate.
For information on dosage and directions for administration, see accompanying pamphlet.
Contains no preservatives.
The patient and physician should discuss the risks and benefits of this product.
3051539
Lot
EXP
IU FVIII/Vial
IU VWF:RCo/Vial
Lot
IU FVIII/Vial
IU VWF: RCo/Vial
Alphanate® 5 mL NDC: 68516-4606-1
Principal Display Panel – 500 IU Carton Label
GRIFOLS
NDC: 68516-4612-1
Antihemophilic Factor/von
Willebrand Factor Complex (Human)
Alphanate®
Solvent Detergent / Heat Treated
5 mL
500 IU FVIII Range
For Intravenous Administration
Contents: One vial Antihemophilic Factor/von Willebrand Factor Complex (Human), Alphanate®, one vial 5 mL Sterile Water for Injection, USP, one Mix2Vial® filter transfer set, and directions for use.
Composition:
Factor VIII, von Willebrand Factor, Arginine, Albumin and Histidine.
Contains no preservatives.
Administer within three hours of reconstitution.
Warning: This product is prepared from large pools of human plasma. Human blood and its components may transmit infectious agents. See package insert, WARNINGS AND PRECAUTIONS.
Instructions: The patient and physician should discuss the risks and benefits of this product. For information on dosage and directions for administration, see enclosed package insert.
Storage: Store at temperatures not exceeding 25 °C (77 °F). Do not freeze.
Rx only
Grifols Biologicals LLC
5555 Valley Boulevard
Los Angeles, CA 90032, USA
U.S. License No. 1694
3051541
GTIN 00368516461211
LOT XXXXXXXXXX
EXP DDMMMYYYY
SN XXXXXXXXXX XXXXXX
IU FVIII/Vial XXXX
IU VWF: RCo/Vial XXXX
Principal Display Panel – 1000 IU Vial Label
GRIFOLS
NDC: 68516-4607-2
Antihemophilic Factor/von Willebrand
Factor Complex (Human) Alphanate®
Solvent Detergent/Heat Treated 10 mL
1000 IU FVIII Range
Storage: Store at temperatures not exceeding 25°C (77°F).
Rx only. Single dose container for intravenous
administration only.
Grifols Biologicals LLC
5555 Valley Boulevard Los Angeles, CA 90032, USA
U.S. License No. 1694
Instructions: Reconstitute with 10 mL of Sterile Water for Injection, USP. Administer promptly after reconstitution and do not refrigerate.
For information on dosage and directions for administration, see accompanying pamphlet.
Contains no preservatives.
The patient and physician should discuss the risks and benefits of this product.
3051542
Lot
EXP
IU FVIII/Vial
IU VWF:RCo/Vial
Lot
IU FVIII/Vial
IU VWF: RCo/Vial
Alphanate® 10 mL NDC: 68516-4607-2
Principal Display Panel – 1000 IU Carton Label
GRIFOLS
NDC: 68516-4613-2
Antihemophilic Factor/von
Willebrand Factor Complex (Human)
Alphanate®
Solvent Detergent / Heat Treated
10 mL
1000 IU FVIII Range
For Intravenous Administration
Contents: One vial Antihemophilic Factor/von Willebrand Factor Complex (Human), Alphanate®, one vial 10 mL Sterile Water for Injection, USP, one Mix2Vial® filter transfer set, and directions for use.
Composition:
Factor VIII, von Willebrand Factor, Arginine, Albumin and Histidine.
Contains no preservatives.
Administer within three hours of reconstitution.
Warning: This product is prepared from large pools of human plasma. Human blood and its components may transmit infectious agents. See package insert, WARNINGS AND PRECAUTIONS.
Instructions: The patient and physician should discuss the risks and benefits of this product. For information on dosage and directions for administration, see enclosed package insert.
Storage: Store at temperatures not exceeding 25 °C (77 °F). Do not freeze.
Rx only
Grifols Biologicals LLC
5555 Valley Boulevard
Los Angeles, CA 90032, USA
U.S. License No. 1694
3051544
GTIN 00368516461327
LOT XXXXXXXXXX
EXP DDMMMYYYY
SN XXXXXXXXXX XXXXXX
IU FVIII/Vial XXXX
IU VWF: RCo/Vial XXXX
Principal Display Panel – 1500 IU Vial Label
GRIFOLS
NDC: 68516-4608-2
Antihemophilic Factor/von Willebrand
Factor Complex (Human) Alphanate®
Solvent Detergent/Heat Treated 10 mL
1500 IU FVIII Range
Storage: Store at temperatures not exceeding 25°C (77°F).
Rx only. Single dose container for intravenous
administration only.
Grifols Biologicals LLC
5555 Valley Boulevard Los Angeles, CA 90032, USA
U.S. License No. 1694
Instructions: Reconstitute with 10 mL of Sterile Water for Injection, USP. Administer promptly after reconstitution and do not refrigerate.
For information on dosage and directions for administration, see accompanying pamphlet.
Contains no preservatives.
The patient and physician should discuss the risks and benefits of this product.
3051545
Lot
EXP
IU FVIII/Vial
IU VWF:RCo/Vial
Lot
IU FVIII/Vial
IU VWF: RCo/Vial
Alphanate®10 mL NDC: 68516-4608-2
Principal Display Panel – 1500 IU Carton Label
GRIFOLS
NDC: 68516-4614-2
Antihemophilic Factor/von
Willebrand Factor Complex (Human)
Alphanate®
Solvent Detergent / Heat Treated
10 mL
1500 IU FVIII Range
For Intravenous Administration
Contents: One vial Antihemophilic Factor/von Willebrand Factor Complex (Human), Alphanate®, one vial 10 mL Sterile Water for Injection, USP, one Mix2Vial® filter transfer set, and directions for use.
Composition:
Factor VIII, von Willebrand Factor, Arginine, Albumin and Histidine.
Contains no preservatives.
Administer within three hours of reconstitution.
Warning: This product is prepared from large pools of human plasma. Human blood and its components may transmit infectious agents. See package insert, WARNINGS AND PRECAUTIONS.
Instructions: The patient and physician should discuss the risks and benefits of this product. For information on dosage and directions for administration, see enclosed package insert.
Storage: Store at temperatures not exceeding 25 °C (77 °F). Do not freeze.
Rx only
Grifols Biologicals LLC
5555 Valley Boulevard
Los Angeles, CA 90032, USA
U.S. License No. 1694
3051547
GTIN 00368516461426
LOT XXXXXXXXXX
EXP DDMMMYYYY
SN XXXXXXXXXX XXXXXX
IU FVIII/Vial XXXX
IU VWF: RCo/Vial XXXX
Principal Display Panel – 2000 IU Vial Label
GRIFOLS
NDC: 68516-4610-2
Antihemophilic Factor/von Willebrand
Factor Complex (Human) Alphanate®
Solvent Detergent/Heat Treated 10 mL
2000 IU FVIII Range
Storage: Store at temperatures not exceeding 25°C (77°F).
Rx only. Single dose container for intravenous
administration only.
Grifols Biologicals LLC
5555 Valley Boulevard Los Angeles, CA 90032, USA
U.S. License No. 1694
Instructions: Reconstitute with 10 mL of Sterile Water for Injection, USP. Administer promptly after reconstitution and do not refrigerate.
For information on dosage and directions for administration, see accompanying pamphlet.
Contains no preservatives.
The patient and physician should discuss the risks and benefits of this product.
3051548
Lot
EXP
IU FVIII/Vial
IU VWF:RCo/Vial
Lot
IU FVIII/Vial
IU VWF: RCo/Vial
Alphanate®10 mL NDC: 68516-4610-2
Principal Display Panel – 2000 IU Carton Label
GRIFOLS
NDC: 68516-4615-2
Antihemophilic Factor/von
Willebrand Factor Complex (Human)
Alphanate®
Solvent Detergent / Heat Treated
10 mL
2000 IU FVIII Range
For Intravenous Administration
Contents: One vial Antihemophilic Factor/von Willebrand Factor Complex (Human), Alphanate®, one vial 10 mL Sterile Water for Injection, USP, one Mix2Vial® filter transfer set, and directions for use.
Composition:
Factor VIII, von Willebrand Factor, Arginine, Albumin and Histidine.
Contains no preservatives.
Administer within three hours of reconstitution.
Warning: This product is prepared from large pools of human plasma. Human blood and its components may transmit infectious agents. See package insert, WARNINGS AND PRECAUTIONS.
Instructions: The patient and physician should discuss the risks and benefits of this product. For information on dosage and directions for administration, see enclosed package insert.
Storage: Store at temperatures not exceeding 25 °C (77 °F). Do not freeze.
Rx only
Grifols Biologicals LLC
5555 Valley Boulevard
Los Angeles, CA 90032, USA
U.S. License No. 1694
3051550
GTIN 00368516461525
LOT XXXXXXXXXX
EXP DDMMMYYYY
SN XXXXXXXXXX XXXXXX
IU FVIII/Vial XXXX
IU VWF: RCo/Vial XXXX
Principal Display Panel – 5 mL Vial Label
NDC: 63323-185-05 18505
STERILE
WATER
FOR INJECTION, USP
FOR DRUG DILUENT USE ONLY
Rx only
5 mL Single Dose Vial
Sterile, Nonpyrogenic
Preservative Free
Discard unused portion.
WARNING: Do not administer intravenously unless rendered nearly isotonic.
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
APP Pharmaceuticals, LLC
Schaumburg, IL 60173
401745D
LOT/EXP
Principal Display Panel – 10 mL Vial Label
NDC: 63323-185-10 918510
STERILE WATER
FOR INJECTION, USP
FOR DRUG DILUENT USE ONLY
Rx only
10 mL Single Dose Vial
Sterile, Nonpyrogenic
Preservative Free
Discard unused portion.
Do not administer intravenously unless rendered nearly isotonic.
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
APP Pharmaceuticals, LLC
Schaumburg, IL 60173
401753E
LOT/EXP
Principal Display Panel – 5 mL Vial Label
NDC: 68516-1001-1
STERILE WATER for Injection, USP
5 mL
Rx only
3051532
For reconstitution of accompanying product
Single-Dose Container, Nonpyrogenic
Do not use unless clear. No antimicrobial agent or other substance has been added. Do not use for intravascular injection without making approximately isotonic by addition of suitable solute. Discard unused portion.
Mfd by: Laboratorios Grifols, S.A. Parets del Vallès, Barcelona 08150 Spain
Mfd for: Grifols Biologicals LLC Los Angeles, CA 90032, USA
Lot
EXP
Principal Display Panel – 10 mL Vial Label
NDC: 68516-1002-2
STERILE WATER for Injection, USP
10 mL
Rx only
3051533
For reconstitution of accompanying product
Single-Dose Container, Nonpyrogenic
Do not use unless clear. No antimicrobial agent or other substance has been added. Do not use for intravascular injection without making approximately isotonic by addition of suitable solute. Discard unused portion.
Mfd by: Laboratorios Grifols, S.A. Parets del Vallès, Barcelona 08150 Spain
Mfd for: Grifols Biologicals LLC Los Angeles, CA 90032, USA
Lot
EXP
ALPHANATE
antihemophilic factor/von willebrand factor complex (human) kit |
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ALPHANATE
antihemophilic factor/von willebrand factor complex (human) kit |
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ALPHANATE
antihemophilic factor/von willebrand factor complex (human) kit |
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ALPHANATE
antihemophilic factor/von willebrand factor complex (human) kit |
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ALPHANATE
antihemophilic factor/von willebrand factor complex (human) kit |
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ALPHANATE
antihemophilic factor/von willebrand factor complex (human) kit |
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ALPHANATE
antihemophilic factor/von willebrand factor complex (human) kit |
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ALPHANATE
antihemophilic factor/von willebrand factor complex (human) kit |
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ALPHANATE
antihemophilic factor/von willebrand factor complex (human) kit |
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ALPHANATE
antihemophilic factor/von willebrand factor complex (human) kit |
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Labeler - GRIFOLS USA, LLC (048987452) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
Grifols Biologicals LLC | 092694538 | manufacture(68516-4601, 68516-4602, 68516-4603, 68516-4604, 68516-4605, 68516-4606, 68516-4607, 68516-4608, 68516-4609, 68516-4610, 68516-4611, 68516-4612, 68516-4613, 68516-4614, 68516-4615) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
Grifols Biologicals LLC | 121076871 | manufacture(68516-4601, 68516-4602, 68516-4603, 68516-4604, 68516-4605, 68516-4606, 68516-4607, 68516-4608, 68516-4609, 68516-4610, 68516-4611, 68516-4612, 68516-4613, 68516-4614, 68516-4615) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
LABORATORIOS GRIFOLS SA | 463719725 | manufacture(68516-1001, 68516-1002) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
Fresenius Kabi USA LLC | 840771732 | manufacture(63323-185) |
Mark Image Registration | Serial | Company Trademark Application Date |
---|---|
ALPHANATE 74475193 1964502 Live/Registered |
GRIFOLS SHARED SERVICES NORTH AMERICA, INC. 1993-12-28 |