ALPHANINE SD Coagulation Factor IX (Human) 500IU Lyophilized Powder for IV Injection 1's
RXDRUG-BR-593
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
Prevention and control of bleeding, in patients with Factor IX deficiency due to hemophilia B. AlphaNine SD contains low, nontherapeutic levels of Factor II, VII and X and therefore, is not recommended for the treatment of Factor II, VII or X deficiencies. AlphaNine SD is also not indicated for the reversal of coumarin anticoagulant-induced hemorrhage, nor in the treatment of hemophilia A patients with inhibitors to Factor VIII.
Dosage/Direction for Use
Adults: AlphaNine SD should be administered IV promptly following reconstitution. Administration of AlphaNine SD within 3 hrs after reconstitution is recommended to avoid the potential ill effect of any inadvertent bacterial contamination occurring during reconstitution. Discard any unused contents into the appropriate safety container.
Each vial of AlphaNine SD is labeled with the total units expressed as international units (iu) of Factor IX, which is referenced to the WHO international standard. One unit approximates the activity in 1 mL of pooled normal human plasma.
The amount of AlphaNine SD requires to establish hemostasis will vary with each patient and depend upon the circumstances. The following formula may be used as a guide in determining the number of units to be administered.
In clinical practice there is variability between patients and their clinical response. Therefore, the Factor IX level of each patient should be monitored frequently during replacement therapy.
For pediatric usage: See Precautions.
Administration: Use aseptic technique.
Reconstitution: Warm diluent (sterile water for injection, USP) and concentrate (AlphaNine SD) to at least room temperature (but not above 37°C).
Remove plastic caps from the diluent and concentrate vials.
Swab the exposed stopper surfaces with a cleansing agent eg, alcohol.
Do not leave excess cleansing agent on the stoppers.
Remove cover from one end of the double-ended transfer needle. Insert the exposed end of the needle through the center of the stopper in the diluent vial.
Remove the plastic cap from the other end of the double-ended transfer needle now seated in the stopper of the diluent vial. To reduce any foaming, invert the vial of diluent and insert the exposed end of the needle through the center of the stopper in the concentrate vial at an angle, making certain that the diluent vial is always above the concentrate vial. The angle of insertion directs the flow of diluent against the side of the concentrate vial. There should be enough vacuums in the vial to transfer all the diluent.
Disconnect the 2 vials by removing the transfer needle from the diluent vial stopper. Remove the double-ended transfer needle from the concentrate vial and discard the needle into the appropriate safety container.
Let the vial stand until contents are in solution, then gently swirl until all concentrate is dissolved. Reconstitution requires <5 min.
Do not shake the contents of the vial. Do not invert the concentrate vial until ready to withdraw contents.
Use as soon as possible after reconstitution.
After reconstitution, parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstitution procedure is strictly followed, a few small particles may occasionally remain. The microaggregate filter will remove particles and the labeled potency will not be reduced.
Administration by Syringe: Peel cover from microaggregate filter spike package and securely install the syringe into the exposed Luer inlet of the filter spike, using a slight clockwise twisting motion.
Remove filter spike from packaging. Remove protective cover from the spike end of the filter spike.
Pull back plunger drawing sufficient air into the syringe to allow reconstituted product top be withdrawn as described in the next step.
Insert the spike end of the filter spike into the reconstituted concentrate vial. Inject air and withdraw the reconstituted product from the vial into the syringe.
Remove the filter spike from the syringe; discard the filter spike and the empty concentrate vial into the appropriate safety container. Attach syringe to an infusion set expel air from the syringe and infusion set. Perform venipuncture and administer slowly at a rate not exceeding 10 mL/min.
If the patient is to receive >1 vial concentrate, the infusion set will allow administration of multiple vials to be performed with a single venipuncture.
Discard all administration equipment after use into the appropriate safety container. Do not re-use.
Each vial of AlphaNine SD is labeled with the total units expressed as international units (iu) of Factor IX, which is referenced to the WHO international standard. One unit approximates the activity in 1 mL of pooled normal human plasma.
The amount of AlphaNine SD requires to establish hemostasis will vary with each patient and depend upon the circumstances. The following formula may be used as a guide in determining the number of units to be administered.
In clinical practice there is variability between patients and their clinical response. Therefore, the Factor IX level of each patient should be monitored frequently during replacement therapy.
For pediatric usage: See Precautions.
Administration: Use aseptic technique.
Reconstitution: Warm diluent (sterile water for injection, USP) and concentrate (AlphaNine SD) to at least room temperature (but not above 37°C).
Remove plastic caps from the diluent and concentrate vials.
Swab the exposed stopper surfaces with a cleansing agent eg, alcohol.
Do not leave excess cleansing agent on the stoppers.
Remove cover from one end of the double-ended transfer needle. Insert the exposed end of the needle through the center of the stopper in the diluent vial.
Remove the plastic cap from the other end of the double-ended transfer needle now seated in the stopper of the diluent vial. To reduce any foaming, invert the vial of diluent and insert the exposed end of the needle through the center of the stopper in the concentrate vial at an angle, making certain that the diluent vial is always above the concentrate vial. The angle of insertion directs the flow of diluent against the side of the concentrate vial. There should be enough vacuums in the vial to transfer all the diluent.
Disconnect the 2 vials by removing the transfer needle from the diluent vial stopper. Remove the double-ended transfer needle from the concentrate vial and discard the needle into the appropriate safety container.
Let the vial stand until contents are in solution, then gently swirl until all concentrate is dissolved. Reconstitution requires <5 min.
Do not shake the contents of the vial. Do not invert the concentrate vial until ready to withdraw contents.
Use as soon as possible after reconstitution.
After reconstitution, parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstitution procedure is strictly followed, a few small particles may occasionally remain. The microaggregate filter will remove particles and the labeled potency will not be reduced.
Administration by Syringe: Peel cover from microaggregate filter spike package and securely install the syringe into the exposed Luer inlet of the filter spike, using a slight clockwise twisting motion.
Remove filter spike from packaging. Remove protective cover from the spike end of the filter spike.
Pull back plunger drawing sufficient air into the syringe to allow reconstituted product top be withdrawn as described in the next step.
Insert the spike end of the filter spike into the reconstituted concentrate vial. Inject air and withdraw the reconstituted product from the vial into the syringe.
Remove the filter spike from the syringe; discard the filter spike and the empty concentrate vial into the appropriate safety container. Attach syringe to an infusion set expel air from the syringe and infusion set. Perform venipuncture and administer slowly at a rate not exceeding 10 mL/min.
If the patient is to receive >1 vial concentrate, the infusion set will allow administration of multiple vials to be performed with a single venipuncture.
Discard all administration equipment after use into the appropriate safety container. Do not re-use.
Warnings
Because coagulation Factor IX (human), AlphaNine SD is made from pooled human plasma, it may carry a risk of transmitting infectious agents eg, viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. Stringent procedures designed to reduce the risk of adventitious agent transmission have been employed in the manufacture of AlphaNine SD, from the screening of plasma donors and the collection and testing of plasma to the application of viral elimination/reduction steps eg, column chromatography, solvent detergent treatment and nanofiltration in the manufacturing process. Despite these measures, such product can potentially transmit disease, therefore the risk of infectious agents cannot be totally eliminated. The physician should weigh the risks and benefits of the use of this product and should discuss this with the patient.
Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections. Scientific opinion encourages hepatitis B and hepatitis A vaccinations at birth or diagnosis for patients with hemophilia.
Incidences of thrombosis or disseminated intravascular coagulation (DIC), have been reported following administration of Factor IX complex concentrates which contain high amounts of Factor II, VII and X.
Following administration of coagulation Factor IX (human), AlphaNine SD in surgery patients and individuals with known liver disease, the physician should closely observe the patient for signs or symptoms of potential disseminated intravascular coagulation (DIC). Continued administration of the product should be felt to the discretion of the physician.
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported for all Factor IX products. Frequently these events have occurred in close temporal association with the development of Factor IX inhibitors. Patients should be informed of the early symptoms and signs of hypersensitivity reactions, including hives, generalized urticaria, angioedema, chest tightness, dyspnea, wheezing, faintness, hypotension, tachycardia and anaphylaxis. Patients should be advised to discontinue use of the product and contact a physician and/or seek immediate emergency care, depending on the severity of the reactions, if any of these symptoms occur.
Nephrotic syndrome has been reported following attempted immune tolerance induction with Factor IX products in hemophilia B patients with Factor IX inhibitors and a history of severe allergic reactions to Factor IX. The safety and efficacy of using AlphaNine SD in attempted immune tolerance induction has not been established.
In previously untreated patients (PUPs), it is possible that anaphylaxis may occur after a median exposure of 11 days. It is recommended that these patients be monitored closely between the 10th and 20th exposure day.
Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections. Scientific opinion encourages hepatitis B and hepatitis A vaccinations at birth or diagnosis for patients with hemophilia.
Incidences of thrombosis or disseminated intravascular coagulation (DIC), have been reported following administration of Factor IX complex concentrates which contain high amounts of Factor II, VII and X.
Following administration of coagulation Factor IX (human), AlphaNine SD in surgery patients and individuals with known liver disease, the physician should closely observe the patient for signs or symptoms of potential disseminated intravascular coagulation (DIC). Continued administration of the product should be felt to the discretion of the physician.
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported for all Factor IX products. Frequently these events have occurred in close temporal association with the development of Factor IX inhibitors. Patients should be informed of the early symptoms and signs of hypersensitivity reactions, including hives, generalized urticaria, angioedema, chest tightness, dyspnea, wheezing, faintness, hypotension, tachycardia and anaphylaxis. Patients should be advised to discontinue use of the product and contact a physician and/or seek immediate emergency care, depending on the severity of the reactions, if any of these symptoms occur.
Nephrotic syndrome has been reported following attempted immune tolerance induction with Factor IX products in hemophilia B patients with Factor IX inhibitors and a history of severe allergic reactions to Factor IX. The safety and efficacy of using AlphaNine SD in attempted immune tolerance induction has not been established.
In previously untreated patients (PUPs), it is possible that anaphylaxis may occur after a median exposure of 11 days. It is recommended that these patients be monitored closely between the 10th and 20th exposure day.
Use In Pregnancy & Lactation
Use in pregnancy: Animal reproduction has not been conducted with AlphaNine SD. It is also not known whether AlphaNine SD can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. AlphaNine SD should be given to a pregnant woman only if clearly indicated.
Adverse Reactions
The administration of plasma preparations may cause allergic reactions, mild chills, nausea or stinging at the infusion site. For most reactive individuals, slowing the infusion rate relieves the symptoms. For those highly reactive individuals, a different lot may be satisfactory.
Adverse reactions, characterized by either thrombosis or disseminated intravascular coagulation (DIC), have been reported following administration of Factor IX complex concentrates. Patients who receive coagulation Factor IX (human), AlphaNine SD, following operation, or those with known liver disease, should be kept under close observation for potential signs and symptoms of intravascular coagulation. Continued administration should be left to the discretion of the physician.
In the clinical study that compared the in vivo half-life and recovery of AlphaNine SD and HT products, no adverse events were associated with 18 infusions of AlphaNine SD administered to 18 individuals with severe to moderate hemophilia B. Short-term study safety of the earlier version of this product, AlphaNine was demonstrated by an absence of adverse events after 225 infusions of this product were received by 31 patients participating in 3 clinical trials. In the clinical trial to evaluate efficacy of AlphaNine in providing hemostatic protection during and after surgery, 13 patients received a total of 370,655 iu of AlphaNine. In 208 total infusions, each patient received approximately 15,000 iu (range 3295-52,200 iu Factor IX) in an average of 16 infusions (range 2-26 infusions). Results from this study showed no bleeding episodes during the course of postsurgery therapy. There was no hematological evidence (measured by hematocrit, partial thromboplastin time, prothrombin time, fibrinogen/fibrin degradation products, fibrin monomers, D-dimers and platelet counts) of thrombogenicity.
Adverse reactions, characterized by either thrombosis or disseminated intravascular coagulation (DIC), have been reported following administration of Factor IX complex concentrates. Patients who receive coagulation Factor IX (human), AlphaNine SD, following operation, or those with known liver disease, should be kept under close observation for potential signs and symptoms of intravascular coagulation. Continued administration should be left to the discretion of the physician.
In the clinical study that compared the in vivo half-life and recovery of AlphaNine SD and HT products, no adverse events were associated with 18 infusions of AlphaNine SD administered to 18 individuals with severe to moderate hemophilia B. Short-term study safety of the earlier version of this product, AlphaNine was demonstrated by an absence of adverse events after 225 infusions of this product were received by 31 patients participating in 3 clinical trials. In the clinical trial to evaluate efficacy of AlphaNine in providing hemostatic protection during and after surgery, 13 patients received a total of 370,655 iu of AlphaNine. In 208 total infusions, each patient received approximately 15,000 iu (range 3295-52,200 iu Factor IX) in an average of 16 infusions (range 2-26 infusions). Results from this study showed no bleeding episodes during the course of postsurgery therapy. There was no hematological evidence (measured by hematocrit, partial thromboplastin time, prothrombin time, fibrinogen/fibrin degradation products, fibrin monomers, D-dimers and platelet counts) of thrombogenicity.
Storage
Store at temperatures between 2°C and 8°C. Do not freeze to prevent damage to diluent vial. May be stored at room temperature not to exceed 30°C for 1 month.
Action
AlphaNine SD is a purified formulation of Factor IX containing not less than 150 iu Factor IX activity/mg of total protein. AlphaNine SD contains nontherapeutic levels of Factors II, VII and X. Thrombogenicity of AlphaNine SD in animals is markedly lower than that of Factor IX complex, Profilnine heat-treated. Five lots of AlphaNine SD (3 lots of non-virus filtered product and 2 lots of virus filtered product) failed to show any evidence of thrombogenicity when tested directly in the Wessler rabbit stasis model for thrombogenicity at a dose of 200 iu Factor IX/kg body weight. When various lots of AlphaNine SD were further tested at doses between 300 and 650 iu Factor IX/kg, only 5 out of 40 animals (12.5%) showed evidence of thrombus formation (Wessler scores of +1, +2, +1, +1, +1 out of +4 maximum). In comparison, Factor IX complex concentrate, Profilinine was thrombogenic 100% of the animals tested at a dose of 100 iu Factor IX/kg.
At a dose of 200 iu Factor IX/kg body weight in a porcine model, the heptanes heat-treated formulation of AlphaNine showed little evidence of disseminated intravascular coagulation (DIC) following infusion. This model exhibited no depletion of coagulation factors, a minimal increase in fibrin monomer (+1 in protamine test), a slight temporary decrease in platelet counts and no evidence of intravascular coagulation upon gross autopsy. In contrast, Harrison, et al, report that all Factor IX complex concentrates studied in the same porcine model were thrombogenic at doses between 50 and 100 iu of Factor IX/kg animal weight.
A clinical evaluation of AlphaNine SD half-life and recovery characteristics was performed. A total of 18 patients with severe to moderate hemophilia B each received a single infusion of 40-50 iu Factor IX/kg body weight of AlphaNine SD. Following the administration of AlphaNine SD, the mean half-life of Factor IX observed was approximately 21 hrs. This half-life value was computed using the biphasic linear regression model recommended by the International Society of Thrombosis and Haemostasis. The half-life obtained for the solvent detergent treated product is comparable to that of AlphaNine (approximately 19 hrs) as well as the range of 18-36 hrs reported for Factor IX complex preparations. The mean recovery observed in clinical trials was approximately 48% and was comparable to that of AlphaNine (approximately 51%).
A clinical trial was conducted using the heptanes heat-treated product, AlphaNine to evaluate the efficacy of the product in providing hemostatic protection during and after surgery in 13 patients with hemophilia B. The types of surgical procedures performed included bilateral knee replacement (1), total knee replacement with synovectomy (2), hip replacement (1), below the knee amputation (1), herniorrhaphy (2), hemorrhoidectomy (1), rhinoplasty (2), oral surgery (2) and Hickman catheter insertion with temporalis muscle transfer (1). Presurgery doses ranged from 30.1-65 iu Factor IX/kg; postsurgery replacement therapy doses ranged from approximately 9.4-52 iu Factor IX/kg. The number of postsurgery days of treatment ranged from 1-23; the number of postsurgery infusions ranged from 2-26. No bleeding episodes were reported and hemostatsis was maintained during the course of postsurgery therapy. None of the hematologic parameters examined (hematocrit, partial thromboplastin time, prothrombin time, fibrinogen/fibrin degradation products, fibrin monomers, d-dimers and platelet counts) provided any evidence that AlphaNine possessed thrombogenic potential.
A randomized crossover study with 11 hemophilia patients was conducted with the heptanes heat-treated version of the product, AlphaNine, to determine whether an infusion of AlphaNine SD caused less activation of the hemostatic system than the Factor IX complex concentrate preparation, Profilinine heat-treated. Each subject received a single infusion of either AlphaNine or Profilnine heat-treated for the treatment of a bleeding episode, at a dose of 50 iu Factor IX/kg body weight. Each subject received the other Factor IX concentrate for the treatment of a subsequent bleeding episode, separated by an interval of not less than 10 days. The level of prothrombin fragment 1+4 (F1+4) is a sensitive index of the cleavage of prothrombin by activated factor X. The level of fibrinopeptide A (FPA) released into the plasma measures the activity of thrombin on fibrinogen in the formation of fibrin, following infusion of Factor IX complex, statistically significant increases in F1+2 and in FPA were detected at all monitored time points (15, 60, 90, 120 and 240 min post-infusion). The statistically significant elevation these 2 hemostatic parameters, indicates increased activation of the coagulation cascade.
Administration of AlphaNine resulted in no increase in F1+2 at any monitored time points, and a statistically non-significant increase in FPA at 15, 60 and 90 min following infusion. Only at 120 and 240 min after infusion of AlphaNine were statistically significant increases in FPA levels detected. These resulted suggest that the infusion of a high purity Factor IX eg, AlphaNine may result in a lower level of activation of the coagulation cascade than does Factor IX complex.
The ability of the manufacturing process to inactivate and eliminate virus from the coagulation Factor IX (human) products was evaluated at key stages in the process (see Table 1). Known amounts of different viruses were added to samples obtained prior to those steps most likely to reduce virus load (DEAE chromatography, solvent detergent dual affinity chromatography and nanofiltration) in the AlphaNine and AlphaNine SD process to determine the level of viral inactivation/elimination of these specific steps in the process.
The retrovirus known as human immunodeficiency virus (HIV) has been identified as a causative agent of acquired immunodeficiency syndrome (AIDS) and has been shown to be transmissible via blood or blood products. The solvent detergent process used in the manufacture of AlphaNine SD was shown to inactivate >12.2 logs of HIV-1 when the retrovirus was intentionally added to product samples under laboratory evaluation (as measured by virus antigen capture and reverse transcriptase assays). In addition, this process was shown to inactivate 6 logs of HIV-2 (as measured by reverse transcriptase assays) when the retrovirus was intentionally added to product samples. In an ongoing efficacy and safety study of 26 patients, no subjects tested positive for HIV or viral hepatitis in relation to the investigation of drug.
In order to assess the ability of the solvent detergent treatment process to inactivate other viruses eg, hepatitis B and C virus, the inactivation of the model viruses, Sindbis virus, a model virus for hepatitis C virus and vesicular stomatitis virus (VSV), a model RNA virus for lipid enveloped viruses, by solvent detergent treatment was studied. Prior to solvent detergent treatment, samples were inoculated with a titer of either sindbis or VSV. The results demonstrated that a minimum of 5.3 logs of Sindbis and a minimum of 4.9 logs of VSV were inactivated after 180 min of incubation with solvent detergent (when compared to an untreated control). It should be noted that the incubation time in the actual AlphaNine SD process is twice (360 min total) that used in the model virus studies.
The ability of the AlphaNine SD process to eliminate virus, by physically partitioning virus from product was evaluated at key stages of the manufacturing process. Studies were performed using a lipid-enveloped model virus (Sindbis) and nonlipid model viruses (porcine parvovirus, encephalomyocarditis virus and reovirus). Known amounts of these viruses were added to samples obtained from the AlphaNine SD process. The amount of virus removed at each subsequent purification step was then determined by plaque assay.
Addition of sindbis or porcine parvovirus prior to Factor IX complex adsorption by DEAE chromatography showed this step to eliminate 1.4 logs of sindbis and 1.5 logs (95% confidence interval: 1.51-2.33) of added porcine parvovirus. When sindbis of parvovirus was introduced into the process after the barium citrate precipitation step of the AlphaNine SD process, the subsequent dual affinity chromatography step was found to eliminate 4.7 logs of sindbis and 2.2 logs (95% confidence interval: 2.25-2.75) of added parvovirus. When parvovirus, encephalomyocarditis virus (EMC) or reovirus was introduced into the process after the dual affinity chromatography step, the subsequent nanofiltration step of the AlphaNine SD process was found to eliminate 3.6 logs of parvovirus, 3.4 logs of EMC and 4.1 logs of added reovirus. The studies mentioned previously, indicate that the manufacturing process of AlphaNine SD is capable of reducing viruses by approximately 6 logs, in addition to virus reduction achieved by the solvent detergent process. In another study, the nanofiltration step removed ≥4.4 logs of hepatitis A virus (HAV), a nonlipid enveloped virus. Table 1 summarizes the reduction factors obtained for each virus when individual steps in the manufacturing process for AlphaNine SD were validated for virus removal/inactivation.
At a dose of 200 iu Factor IX/kg body weight in a porcine model, the heptanes heat-treated formulation of AlphaNine showed little evidence of disseminated intravascular coagulation (DIC) following infusion. This model exhibited no depletion of coagulation factors, a minimal increase in fibrin monomer (+1 in protamine test), a slight temporary decrease in platelet counts and no evidence of intravascular coagulation upon gross autopsy. In contrast, Harrison, et al, report that all Factor IX complex concentrates studied in the same porcine model were thrombogenic at doses between 50 and 100 iu of Factor IX/kg animal weight.
A clinical evaluation of AlphaNine SD half-life and recovery characteristics was performed. A total of 18 patients with severe to moderate hemophilia B each received a single infusion of 40-50 iu Factor IX/kg body weight of AlphaNine SD. Following the administration of AlphaNine SD, the mean half-life of Factor IX observed was approximately 21 hrs. This half-life value was computed using the biphasic linear regression model recommended by the International Society of Thrombosis and Haemostasis. The half-life obtained for the solvent detergent treated product is comparable to that of AlphaNine (approximately 19 hrs) as well as the range of 18-36 hrs reported for Factor IX complex preparations. The mean recovery observed in clinical trials was approximately 48% and was comparable to that of AlphaNine (approximately 51%).
A clinical trial was conducted using the heptanes heat-treated product, AlphaNine to evaluate the efficacy of the product in providing hemostatic protection during and after surgery in 13 patients with hemophilia B. The types of surgical procedures performed included bilateral knee replacement (1), total knee replacement with synovectomy (2), hip replacement (1), below the knee amputation (1), herniorrhaphy (2), hemorrhoidectomy (1), rhinoplasty (2), oral surgery (2) and Hickman catheter insertion with temporalis muscle transfer (1). Presurgery doses ranged from 30.1-65 iu Factor IX/kg; postsurgery replacement therapy doses ranged from approximately 9.4-52 iu Factor IX/kg. The number of postsurgery days of treatment ranged from 1-23; the number of postsurgery infusions ranged from 2-26. No bleeding episodes were reported and hemostatsis was maintained during the course of postsurgery therapy. None of the hematologic parameters examined (hematocrit, partial thromboplastin time, prothrombin time, fibrinogen/fibrin degradation products, fibrin monomers, d-dimers and platelet counts) provided any evidence that AlphaNine possessed thrombogenic potential.
A randomized crossover study with 11 hemophilia patients was conducted with the heptanes heat-treated version of the product, AlphaNine, to determine whether an infusion of AlphaNine SD caused less activation of the hemostatic system than the Factor IX complex concentrate preparation, Profilinine heat-treated. Each subject received a single infusion of either AlphaNine or Profilnine heat-treated for the treatment of a bleeding episode, at a dose of 50 iu Factor IX/kg body weight. Each subject received the other Factor IX concentrate for the treatment of a subsequent bleeding episode, separated by an interval of not less than 10 days. The level of prothrombin fragment 1+4 (F1+4) is a sensitive index of the cleavage of prothrombin by activated factor X. The level of fibrinopeptide A (FPA) released into the plasma measures the activity of thrombin on fibrinogen in the formation of fibrin, following infusion of Factor IX complex, statistically significant increases in F1+2 and in FPA were detected at all monitored time points (15, 60, 90, 120 and 240 min post-infusion). The statistically significant elevation these 2 hemostatic parameters, indicates increased activation of the coagulation cascade.
Administration of AlphaNine resulted in no increase in F1+2 at any monitored time points, and a statistically non-significant increase in FPA at 15, 60 and 90 min following infusion. Only at 120 and 240 min after infusion of AlphaNine were statistically significant increases in FPA levels detected. These resulted suggest that the infusion of a high purity Factor IX eg, AlphaNine may result in a lower level of activation of the coagulation cascade than does Factor IX complex.
The ability of the manufacturing process to inactivate and eliminate virus from the coagulation Factor IX (human) products was evaluated at key stages in the process (see Table 1). Known amounts of different viruses were added to samples obtained prior to those steps most likely to reduce virus load (DEAE chromatography, solvent detergent dual affinity chromatography and nanofiltration) in the AlphaNine and AlphaNine SD process to determine the level of viral inactivation/elimination of these specific steps in the process.
The retrovirus known as human immunodeficiency virus (HIV) has been identified as a causative agent of acquired immunodeficiency syndrome (AIDS) and has been shown to be transmissible via blood or blood products. The solvent detergent process used in the manufacture of AlphaNine SD was shown to inactivate >12.2 logs of HIV-1 when the retrovirus was intentionally added to product samples under laboratory evaluation (as measured by virus antigen capture and reverse transcriptase assays). In addition, this process was shown to inactivate 6 logs of HIV-2 (as measured by reverse transcriptase assays) when the retrovirus was intentionally added to product samples. In an ongoing efficacy and safety study of 26 patients, no subjects tested positive for HIV or viral hepatitis in relation to the investigation of drug.
In order to assess the ability of the solvent detergent treatment process to inactivate other viruses eg, hepatitis B and C virus, the inactivation of the model viruses, Sindbis virus, a model virus for hepatitis C virus and vesicular stomatitis virus (VSV), a model RNA virus for lipid enveloped viruses, by solvent detergent treatment was studied. Prior to solvent detergent treatment, samples were inoculated with a titer of either sindbis or VSV. The results demonstrated that a minimum of 5.3 logs of Sindbis and a minimum of 4.9 logs of VSV were inactivated after 180 min of incubation with solvent detergent (when compared to an untreated control). It should be noted that the incubation time in the actual AlphaNine SD process is twice (360 min total) that used in the model virus studies.
The ability of the AlphaNine SD process to eliminate virus, by physically partitioning virus from product was evaluated at key stages of the manufacturing process. Studies were performed using a lipid-enveloped model virus (Sindbis) and nonlipid model viruses (porcine parvovirus, encephalomyocarditis virus and reovirus). Known amounts of these viruses were added to samples obtained from the AlphaNine SD process. The amount of virus removed at each subsequent purification step was then determined by plaque assay.
Addition of sindbis or porcine parvovirus prior to Factor IX complex adsorption by DEAE chromatography showed this step to eliminate 1.4 logs of sindbis and 1.5 logs (95% confidence interval: 1.51-2.33) of added porcine parvovirus. When sindbis of parvovirus was introduced into the process after the barium citrate precipitation step of the AlphaNine SD process, the subsequent dual affinity chromatography step was found to eliminate 4.7 logs of sindbis and 2.2 logs (95% confidence interval: 2.25-2.75) of added parvovirus. When parvovirus, encephalomyocarditis virus (EMC) or reovirus was introduced into the process after the dual affinity chromatography step, the subsequent nanofiltration step of the AlphaNine SD process was found to eliminate 3.6 logs of parvovirus, 3.4 logs of EMC and 4.1 logs of added reovirus. The studies mentioned previously, indicate that the manufacturing process of AlphaNine SD is capable of reducing viruses by approximately 6 logs, in addition to virus reduction achieved by the solvent detergent process. In another study, the nanofiltration step removed ≥4.4 logs of hepatitis A virus (HAV), a nonlipid enveloped virus. Table 1 summarizes the reduction factors obtained for each virus when individual steps in the manufacturing process for AlphaNine SD were validated for virus removal/inactivation.
MedsGo Class
Haemostatics
Features
Brand
Alphanine SD
Full Details
Dosage Strength
500 IU
Drug Ingredients
- Alphanine
Drug Packaging
Lyophilized Powder for IV Injection 1's
Generic Name
Coagulation Factor IX (Human
Dosage Form
Lyophilized Powder for IV Injection
Registration Number
BR-593
Drug Classification
Prescription Drug (RX)
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