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These highlights do not include all the information needed to use ALPHANATE safely and effectively. See full prescribing information for ALPHANATE. ALPHANATE (ANTIHEMEOPHILIC FACTOR/VON WILLEBRAND FACTOR COMPLEX [HUMAN])Lyophilized Powder for Solution for Intravenous InjectionInitial U.S. Approval: 1978
ALPHANATE- antihemophilic factor/von willebrand factor complex (human)
ALPHANATE (ANTIHEMEOPHILIC FACTOR/VON WILLEBRAND FACTOR COMPLEX [HUMAN])
ALPHANATE, (antihemophilic factor/von Willebrand factor complex [human]), is indicated for: (1)
Control and prevention of bleeding in adult and pediatric patients with hemophilia A.
Surgical and/or invasive procedures in adult and pediatric patients with von Willebrand Disease in whom desmopressin (DDAVP) is either ineffective or contraindicated. It is not indicated for patients with severe VWD (Type 3) undergoing major surgery.
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 (units) = body weight (kg) x desired FVIII rise (IU/dL or % of normal) x 0.5 (IU/kg per IU/dL).
Dosing frequency determined by the type of bleeding episode and the recommendation of the treating physician.
Adults: Pre-operative dose of 60 IU VWF:RCo/kg body weight; subsequent doses of 40-60 IU VWF:RCo/kg body weight.
Pediatric: Pre-operative dose of 75 IU VWF:RCo/kg body weight; subsequent doses of 50-75 IU VWF:RCo/kg body weight.
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).
Anaphylaxis and severe hypersensitivity reactions are possible. Discontinue treatment with ALPHANATE and administer appropriate emergency treatment should symptoms of anaphylaxis or severe hypersensitivity occur (5.1).
Development of activity-neutralizing antibodies may occur in patients receiving FVIII containing products (5.2).
Thromboembolic events (TE) may occur in VWD patients, especially with known risk factors. Monitor patients for signs and symptoms of TE (5.3).
Intravascular hemolysis may occur with infusion of large doses of Antihemophilic Factor/von Willebrand Factor Complex. Should this condition occur and lead to progressive hemolytic anemia, discontinue administration of ALPHANATE and consider alternative therapy (5.4).
Rapid administration may result in vasomotor reactions (5.5).
ALPHANATE is made from human plasma and 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 (5.6).
Perform assays to determine if FVIII inhibitors are present (5.7).
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 Inc. at 1-888-GRIFOLS (1-888-474-3657) or FDA at 1-800-FDA-1088 www.fda.gov/medwatch.
Pediatric: Age had no effect on the pharmacokinetics of ALPHANATE (8.4).
5.7 Monitoring Laboratory Tests
ALPHANATE, (antihemophilic factor/von Willebrand factor complex [human]), is indicated for:
Control and prevention of bleeding episodes and perioperative management in adult and pediatric patients with Factor VIII (FVIII) deficiency due to hemophilia A.
Each vial of ALPHANATE has the antihemophilic factor (AHF) potency (FVIII:C activity) expressed in International Units (IU) FVIII/vial on the label. Additionally, ALPHANATE contains von Willebrand Factor:Ristocetin Cofactor (VWF:RCo), which is expressed in IU VWF:RCo/vial for the treatment of VWD.
Dosing requirements and frequency of dosing is calculated on the basis of an expected initial response of 2% of normal FVIII:C increase per IU FVIII:C/kg body weight administered.1The expected in vivo peak increase in FVIII level expressed as IU/dL (or % of normal) can be estimated using the following formulas:
Titrate dose and frequency to the patient’s clinical response, including individualized needs, severity of the deficiency, severity of the hemorrhage, presence of inhibitors, and FVIII level desired. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to ALPHANATE.
Table 1 provides dosage guidelines for the control and prevention of bleeding episodes in hemophilia A patients. Dosing should aim at maintaining a plasma factor VIII activity level at or above the plasma levels (in IU/dL or in % of normal) outlined in the table.
Type of Bleeding FVIII:C Level Required(% of normal) Doses(IU/kg) Frequency of Doses(hours) Duration of Therapy (days)
Uncomplicated joint hemorrhage 30 15 12 (twice daily) Until hemorrhage stops and healing has been achieved (1–2 days).
Dental extractions Hematuria 50 25 12
Surgery Prior to surgery: 80–100
Monitor plasma FVIII levels periodically to evaluate individual patient response to the dosage regimen.
If dosing studies have determined that a particular patient exhibits a lower/higher than expected response and shorter/longer half-life, adjust the dose and the frequency of dosing accordingly.
Failure to achieve the expected plasma FVIII:C level or to control bleeding after an appropriately calculated dosage may be indicative of the development of an inhibitor (an antibody to FVIII:C). Quantitate the inhibitor level by appropriate laboratory procedures and document its presence. Treatment with AHF in such cases must be individualized.2
The ratio of VWF:RCo to FVIII in ALPHANATE varies by lot, so with each new lot, check IU VWF:RCo/vial to ensure accurate dosing.
Dosage and duration of treatment depend on the severity of the VWF deficiency, the location and extent of 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.
Table 2 provides dosing guidelines for pediatric and adult patients with von Willebrand Disease.3-6
Table 2: Dosage Guidelines for Patients with von Willebrand Disease (Except Type 3 Subjects Undergoing Major Surgery)
a The therapeutic goal is referenced in the NHLBI Guidelines.7
b The safety parameter is extracted from Mannucci 2009.8
Parameter VWF:RCo Target
Pre-operative/pre-procedure dose: Adults: 60 IU VWF:RCo/kg body weight.
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.
Therapeutic Goal (Trough)a : >50 IU/dL >50 IU/dL
Safety Parameterb : Should not exceed 150 IU/dL Should not exceed 150 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
Safety Parameterb: Should not exceed 150 IU/dL Should not exceed 150 IU/dL
Ensure that concentrate (ALPHANATE) and diluent (Sterile Water for Injection, USP) are at room temperature (but not above 37 ˚C) before reconstitution.
Open the Mix2Vial package by peeling away the lid (Figure 1). Leave the Mix2Vial in the clear outer packaging.
When reconstitution procedure is strictly followed, a few small particles may occasionally remain. The Mix2Vial set will remove particles and the labeled potency will not be reduced.
Discard all reconstitution equipment after use into the appropriate safety container. Do not reuse.
Do not refrigerate after reconstitution. Store reconstituted ALPHANATE at room temperature (not to exceed 30 °C) prior to administration, but administer intravenously within three hours.
Use plastic disposable syringes.
ALPHANATE is available as a lyophilized powder for intravenous injection after reconstitution. It is available in the following potencies:
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 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.
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.
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:
Mild: the event was noted but the administration of the compound was not interrupted; the event resolved spontaneously or no treatment was required beyond administration of nonprescription analgesics.
Moderate: the administration of the compound was not necessarily interrupted; the event required momentary treatment with prescription drugs and produced no sequelae.
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.
The most common post-marketing ADRs reported include allergic/hypersensitivity reactions, nausea, fever, joint pain, fatigue, and infusion site pain.
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.
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 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
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
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
(Model Virus for) 3.5% PEG
Precipitation Solvent-
Detergent Column
HIV–1 < 1.0 ≥ 11.1 ≥ 2.0 – – ≥ 13.1
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
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.
Table 4: Pharmacokinetic data in VWD
(Mean ± SD) Plasma FVIII:C
(Mean ± SD) Plasma VWF:Ag
Number of subjects 14 14 14
Baseline 11.86 ± 4.97 21.00 ± 33.83 –
15 minutes post infusion 215.50 ± 101.70 215.29 ± 94.26 –
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.
Table 5: Number of and Types of Surgical Procedures
^ Two subjects received both preparations; the total number of subjects is therefore less than the sum of the columns.
Parameter Treatment with Alphanate Total
Type of Surgical Procedure A-SD A-SD/HT
Number of Subjects 21 18 37^
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.
Table 6: Prophylaxis with ALPHANATE (A-SD) and/or ALPHANATE (A-SD/HT) in Surgery
* Two subjects received both products
Parameter A-SD A-SD/HT Total
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.
Table 7: Rating Scale and Clinical Efficacy of ALPHANATE Therapy
* The efficacy assessment period included the entire perioperative period.
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.
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.”
Srivastava, A., Brewer, A.K., et al. WFH Guidelines: Guidelines for the management of hemophilia. Haemophilia 2013; 19, e1-e47.
Kempton, C.L., White, G.C. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood 2009; 113:11-17.
Federici, A.B., Baudo, F., Caracciolo, C., Mancuso, G., Mazzucconi, M.G., Musso, R., Schinco, P.C., Targhetta. R., Mannucci, P.M. Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi) in the treatment of von Willebrand disease: a retrospective clinical study. Haemophilia 2002; 8:761-767.
Federici, A.B. Management of von Willebrand disease with factor VIII/von Willebrand factor concentrates: results from current studies and surveys. Blood Coagul Fibrinolysis 2005; 16(Suppl 1):S17-S21.
Mannucci, P.M. Treatment of von Willebrand’s Disease. N Engl J Med 2004; 351:47-58.
Nichols, W.L. et al.; NHLBI VWD Expert Panel. The Diagnosis, Evaluation, and Management of von Willebrand Disease. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute 2007; NIH No. 08-5832.
Mannucci, P.M., Franchini, M., Castaman, G., Federici, A.B.; Italian Association of Haemophilia Centres. Evidence-based recommendations on the treatment of von Willebrand disease in Italy. Blood Transfus 2009; 7:117-126.
Coppola, A., Franchini, M., Makris M. Santagostino, E. Minno, G.DI, Mannucci, P.M. Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies. Haemophilia 2012; 18, e173-e187.
Soni, N.S., Patel A.R., Vohra, R.M., Shah P.C. Hemophiliac with Hemolytic Anemia resulting from Factor VIII Concentrate. Acta Haemato 1977; 58:294-297.
Diez, J.M., Caballero, S., Belda, P., Otegui, M., Gajardo, R., Jorquera, J.I. 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.
Meyer, D., Girma, J-P. von Willebrand Factor: Structure and Function. Thrombosis and Haemostasis 1993; 70:99-104.
Rivard, G.E., Aledort, L., et al. Efficacy of factor VIII/von Willebrand factor concentrate Alphanate in preventing excessive bleeding during surgery in subjects with von Willebrand disease. Haemophilia 2008; 14, 271-275.
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:
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
ALPHANATE is stable for three years, up to the expiration date printed on its label, provided that the storage temperature does not exceed 25 °C (77 °F). Do not freeze.
To contact their healthcare provider or go to the emergency department right away if a hypersensitivity reaction occurs. Early signs of hypersensitivity reactions may include rash, hives, itching, facial swelling, tightness of the chest, and wheezing [see Warnings and Precautions (5.1)].
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 [see Warnings and Precautions (5.2)].
To contact their healthcare provider or go to the emergency department right away if a thromboembolic event should occur [see Warnings and Precautions (5.3)].
That despite stringent procedures designed to reduce risk, the risk of transmitting infectious agents cannot be totally eliminated. Advise patients, especially pregnant women and immunocompromised individuals, to report any signs and symptoms of fever, rash, joint pain, or sore throat, to their physician immediately [see Warnings and Precautions (5.6)].
Principal Display Panel – 250 IU Vial Label
NDC: 68516-4605-1
Antihemophilic Factor/von Willebrand
Factor Complex (Human) Alphanate®
Storage: Store at temperatures not exceeding 25°C (77°F).
5555 Valley Boulevard Los Angeles, CA 90032, USA
Principal Display Panel – 250 IU Carton Label
NDC: 68516-4601-1
Willebrand Factor Complex (Human)
NDC: 68516-4611-1
NDC: 68516-4606-1
Principal Display Panel – 500 IU Carton Label
NDC: 68516-4602-1
NDC: 68516-4612-1
NDC: 68516-4607-2
Solvent Detergent/Heat Treated 10 mL
Principal Display Panel – 1000 IU Carton Label
NDC: 68516-4603-2
NDC: 68516-4613-2
NDC: 68516-4608-2
1500 IU FVIII Range
Principal Display Panel – 1500 IU Carton Label
NDC: 68516-4604-2
NDC: 68516-4614-2
Principal Display Panel – 2000 IU Vial Label
NDC: 68516-4610-2
2000 IU FVIII Range
Principal Display Panel – 2000 IU Carton Label
NDC: 68516-4609-2
NDC: 68516-4615-2
NDC: 63323-185-05 18505
NDC: 68516-1001-1
Product Type PLASMA DERIVATIVE Item Code (Source) NDC: 68516-4601
NDC: 68516-4601-1 1 in 1 CARTON; Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product)
Item Code (Source) NDC: 68516-4605
HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX (UNII: 5T6B772R4Q) (HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX - UNII:5T6B772R4Q) HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX 250 [iU] in 5 mL
NDC: 68516-4605-1 5 mL in 1 VIAL; Type 0: Not a Combination Product
NDC: 63323-185-05 5 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
ANDA ANDA088400 01/31/2007
Product Type PLASMA DERIVATIVE Item Code (Source) NDC: 68516-4602
NDC: 68516-4602-1 1 in 1 CARTON; Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product)
Item Code (Source) NDC: 68516-4606
HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX (UNII: 5T6B772R4Q) (HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX - UNII:5T6B772R4Q) HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX 500 [iU] in 5 mL
NDC: 68516-4606-1 5 mL in 1 VIAL; Type 0: Not a Combination Product
Product Type PLASMA DERIVATIVE Item Code (Source) NDC: 68516-4603
NDC: 68516-4603-2 1 in 1 CARTON; Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product)
Item Code (Source) NDC: 68516-4607
HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX (UNII: 5T6B772R4Q) (HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX - UNII:5T6B772R4Q) HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX 1000 [iU] in 10 mL
NDC: 68516-4607-2 10 mL in 1 VIAL; Type 0: Not a Combination Product
NDC: 63323-185-10 10 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
Product Type PLASMA DERIVATIVE Item Code (Source) NDC: 68516-4604
NDC: 68516-4604-2 1 in 1 CARTON; Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product)
Item Code (Source) NDC: 68516-4608
HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX (UNII: 5T6B772R4Q) (HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX - UNII:5T6B772R4Q) HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX 1500 [iU] in 10 mL
NDC: 68516-4608-2 10 mL in 1 VIAL; Type 0: Not a Combination Product
Product Type PLASMA DERIVATIVE Item Code (Source) NDC: 68516-4609
NDC: 68516-4609-2 1 in 1 CARTON; Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product)
Item Code (Source) NDC: 68516-4610
HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX (UNII: 5T6B772R4Q) (HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX - UNII:5T6B772R4Q) HUMAN COAGULATION FACTOR VIII/VON WILLEBRAND FACTOR COMPLEX 2000 [iU] in 10 mL
NDC: 68516-4610-2 10 mL in 1 VIAL; Type 0: Not a Combination Product
Product Type PLASMA DERIVATIVE Item Code (Source) NDC: 68516-4611
NDC: 68516-4611-1 1 in 1 CARTON; Type 0: Not a Combination Product
BLA BLA102475 06/26/2014
Item Code (Source) NDC: 68516-1001
NDC: 68516-1001-1 5 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
Product Type PLASMA DERIVATIVE Item Code (Source) NDC: 68516-4612
NDC: 68516-4612-1 1 in 1 CARTON; Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product)
Product Type PLASMA DERIVATIVE Item Code (Source) NDC: 68516-4613
NDC: 68516-4613-2 1 in 1 CARTON; Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product)
NDC: 68516-1002-2 10 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
Product Type PLASMA DERIVATIVE Item Code (Source) NDC: 68516-4614
NDC: 68516-4614-2 1 in 1 CARTON; Type 9: Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product)
Product Type PLASMA DERIVATIVE Item Code (Source) NDC: 68516-4615
NDC: 68516-4615-2 1 in 1 CARTON; Type 0: Not a Combination Product
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)
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)
Document Id: a6268c9b-0c16-4079-adff-7da7b83595eb
Set id: 5a7aea94-654c-4113-9014-c3137de0a931