"The U.S. Food and Drug Administration today notified Ranbaxy Laboratories, Ltd., that it is prohibited from manufacturing and distributing active pharmaceutical ingredients (APIs) from its facility in Toansa, India, for FDA-regulated drug product"...
Hemophilia B, or Christmas disease, is an X-linked recessively inherited disorder of blood coagulation characterized by insufficient or abnormal synthesis of the clotting protein Factor IX. Factor IX is a vitamin K-dependent coagulation factor which is synthesized in the liver. Factor IX is activated by Factor XIa in the intrinsic coagulation pathway. Activated Factor IX (IXa), in combination with Factor VIII: C, activates Factor X to Xa, resulting ultimately in the conversion of prothrombin to thrombin and the formation of a fibrin clot. The infusion of exogenous Factor IX to replace the deficiency present in Hemophilia B temporarily restores hemostasis. Depending upon the subject's level of biologically active Factor IX, clinical symptoms range from moderate skin bruising or excessive hemorrhage after trauma or surgery to spontaneous hemorrhage into joints, muscles or internal organs including the brain. Severe or recurring hemorrhages can produce death, organ dysfunction or orthopedic deformity.
Infusion of Factor IX Complex concentrates that contain varying but significant amounts of the other liver-dependent blood coagulation proteins (Factors II, VII and X) into subjects with Hemophilia B, results in Factor IX recoveries ranging from approximately 0. 57-1. 1 IU/dL rise per IU/kg body weight infused with plasma half-lives for Factor IX ranging from approximately 23 hours to 31 hours.1,2 Infusion of Mononine® (coagulation factor ix (human)) into ten subjects with severe or moderate Hemophilia B has shown a mean recovery of 0. 67 IU/dL rise per IU/kg body weight infused and a mean half-life of 22.6 hours.3 After six months of experience with repeated infusions performed on the nine subjects who remained in the study, it was shown that the half-life and recovery was maintained at a level comparable to that found with the initial infusion. The six-month data showed a mean recovery of 0. 68 IU/dL rise per IU/kg body weight infused and a mean half-life of 25.3 hours.3 The data show no statistically significant differences between the initial and six-month values.
Two studies were conducted to provide Mononine® (coagulation factor ix (human)) for treatment of hemophilia B subjects who required extensive Factor IX replacement for surgery, trauma, or spontaneous bleeding (73 unique subjects and eight subjects enrolled twice for a total of 81 subjects), as well as to evaluate the safety and efficacy of Mononine® (coagulation factor ix (human)) . The overall mean recovery during treatment was determined to be 1.23 ± 0.42 IU/dL rise/IU/kg (K) (range = 0.59 to 2.92 K) among the 55 subjects included in recovery analyses in the one study and to be 1. 12 ± 0.52 K (range = 0.61 to 2.08 K) among 10 subjects included in these analyses in the second study. Five (5/81,6%) subjects reported adverse events attributed to Mononine® (coagulation factor ix (human)) across the two studies. In these stud-ies, 100 doses of Mononine® (coagulation factor ix (human)) were administered at what are considered high doses for a Factor IX concen-trate, a range of 71 to 161 IU/kg to a total of 36 subjects. Sixty-seven (67) of these infusions were the subject of recovery analyses. Mean recovery tended to decrease as the dose of Mononine® (coagulation factor ix (human)) increased:1.09 ± 0.52 K at doses > 75-95 IU/kg (n=38), 0.98 ± 0.45 K at doses > 95-115 IU/kg (n=21), 0.70 ± 0.38 K at doses > 115-135 IU/kg (n=2), 0.67 K at doses > 135-155 IU/kg (n=1), and 0. 73 ± 0. 34 K at doses > 155 IU/kg (n=5). Among the 36 subjects who received these high doses, only one (2. 8%) reported an adverse experience with a possible relationship to Mononine® (coagulation factor ix (human)) (“difficulty in concentrating”; subject recovered). In no subjects were thrombogenic complications observed or reported.4
The manufacturing procedure for Mononine® (coagulation factor ix (human)) includes multiple processing steps that have been designed to reduce the risk of virus transmission. Validation studies of the monoclonal antibody (MAb) immunoaffinity chromatography/chemical treatment step and two sequential ultrafiltration steps used in the production of Mononine® (coagulation factor ix (human)) document the virus reduction capacity of the processes employed. These studies were conducted using the relevant viruses Human Immunodeficiency Virus (HIV) and Hepatitis AVirus (HAV), the specific model viruses Bovine Viral Diarrhea Virus (BVDV) for Hepatitis C Virus (HCV) and Canine Parvovirus (CPV) for Human Parvovirus B19, and the non-specific model virus Pseudorabies Virus (PRV). The results of these virus validation studies utilizing a wide range of viruses with different physicochemical properties are summarized in Table 1 below:
Table1 in vitroVirus Reduction Studies
|Virus||Cumulative Virus Reduction Capacity
The virus safety of Coagulation Factor IX (Human), Mononine® (coagulation factor ix (human)) , has been studied in clinical trials of two cohorts of hemophilia B subjects previously unexposed to blood or blood products.5 One cohort of subjects included those with moderate to severe factor IX deficiency requiring chronic replacement therapy (41 subjects were dosed); the second cohort included subjects with a mild deficiency requiring factor IX replacement for surgical procedures (10 subjects were dosed).
These subjects were followed for serum alanine aminotransferase (ALT) elevations, as well as for a range of viral serologies. Thirty-seven (37) subjects (30 with moderate to severe deficiency and seven with a mild deficiency) were evaluable for assessment of virus hepatitis safety by the International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee criteria. None of these subjects showed evidence of transmission of hepatitis A, B, C, or HIV.
Mononine® (coagulation factor ix (human)) contains trace amounts of the murine monoclonal antibody (MAb) used in its purification ( ≤ 50 ng mouse protein/100 IU). While the levels of mouse protein are extremely low, infusion of such proteins might theoretically induce human anti-mouse antibody (HAMA) responses. To test this possibility, human IgG, IgM, and IgE antibodies to mouse IgG were assessed by immunoradiometric assay (IRMA) in 11 hemophilia B subjects who received Mononine® (coagulation factor ix (human)) and were previously untreated with other blood products. HAMAs were evaluated prior to the first infusion and at 2 to 42 months after initial treatment. Human IgE antibodies to mouse IgG were below the level of detectability at all time points for all subjects, and there were no statistically significant increases in either human IgG antibodies or human IgM antibodies to mouse protein. 6
In clinical studies of Mononine® (coagulation factor ix (human)) , subjects were monitored for evidence of disseminated intravascular coagulation. In six subjects evaluated after infusion, fibrinogen levels and platelet counts were unchanged, and fibrin degradation products did not appear.3 In further clinical evaluations of Mononine® (coagulation factor ix (human)) , in a crossover study with a Factor IX Complex concentrate, Mononine® (coagulation factor ix (human)) was not associated with the formation of prothrombin activation fragment (F1+2) whereas the Factor IX Complex was associated with the formation of prothrombin activation fragment (F1+2).3,7 Prothrombin activation fragment (F1+2) is indicative of activation of prothrombin.
During the period from 1992 to 1996, five subjects showed transient ALTelevations that were greater than twice the upper normal limit. These subjects were investigated thoroughly and none of the ALTelevations was associated with seroconversion. In three of the five subjects, a single ALTelevation greater than 2 times the upper limit of normal was recorded during the course of the study. No concomitant symptoms occurred and the virus hepatitis serology tests did not reveal any abnormalities. In addition, in one of these three subjects with single ALTelevations, a relationship to Mononine® (coagulation factor ix (human)) could be excluded due to a span of 18 months between the infusion of Mononine® (coagulation factor ix (human)) and occurrence of the elevated ALTlevel. In one of the two remaining subjects, the ALTlevel had been elevated prior to the first infusion of Mononine® (coagulation factor ix (human)) and normalized thereafter. Subsequently, this subject's ALTlevels were elevated intermittently over a period of 24 months, which appeared to be temporally related to the administration of concomitant medications: acetaminophen, amoxicillin, cephalosporins, and halothane. These medications are known to cause liver enzyme elevations. Further, there were no clinical signs of viral hepatitis, nor any other viral disease in these four subjects. The remaining subject of the five was found to have recurring ALTelevations that persisted for a period of five months, gradually decreasing to normal levels. Approximately three days after his first Mononine® (coagulation factor ix (human)) infusion this subject received hepatitis Bimmune globulin and his first injection of hepatitis Bvaccine. At that time, the subject's ALTlevel was slightly above the upper limit of normal (55 IU/L, upper limit of normal:35). Five days later, the subject experienced flu-like symptoms, nausea and vomiting, which were treated with ampicillin and promethazine. The ALT value recorded eight days thereafter (approximately 13 days after the Mononine® (coagulation factor ix (human)) infusion) was found to be clearly elevated at 629 IU/L. ALTlevels subsequently decreased again and were in the range of 160 to 220 IU/Lfor the next four to five months, with mildly elevated aspartate aminotransferase and creatinine phosphokinase values. Serology for hepatits A, B, and C remained negative (except for the expected positive serology of anti-HBs due to the vaccination against hepatitis B). As a result, there was no serological evidence of hepatitis A, B, or C. This subject's idiosyncratic spikes in aminotrans-ferase values and gastrointestinal symptoms were not considered to be of viral origin. However, a causal relationship between prior administration of Mononine® (coagulation factor ix (human)) and these aminotransferase elevations and mild symptoms could not be ruled out.
1. Zauber NP, Levin J. Factor IX levels in patients with hemophilia B (Christmas disease) following transfusion with concentrates of Factor IX orfresh frozen plasma (FFP). Medicine (Baltimore) 56(3): 213-24, 1977.
2. Smith KJ, Thompson AR. Labeled Factor IX Kinetics in Patients withHemophilia-B. Blood 58(3): 625-629, 1981.
3. Kim HC, McMillan CW, White GC, Bergman GE, Horton MW, Saidi P. Purified Factor IX Using Monoclonal Immunoaffinity Technique: ClinicalTrials in Hemophilia B and Comparison to Prothrombin ComplexConcentrates. Blood 79(3): 568-575, 1992.
4. Warrier I, Kasper CK, White II GC, Shapiro AD, Bergman GE, theMononine® (coagulation factor ix (human)) Study Group. Safety of high doses of a monoclonal antibody-purified factor IX concentrate. Am J Hematol 49:92-94, 1995.
5. Shapiro AD, Ragni MV, Lusher JM, Culbert S, Koerper MA, Bergman GE, Hannan MM. Safety and Efficacy of Monoclonal Antibody Purified FactorIX Concentrate in Previously Untreated Patients with Hemophilia B. Thrombosis and Haemostasis 75:30-35, 1996.
6. Davis HM, Nash DW, Clymer MD, Frigo ML, Bergman GE. Lack of immune response to mouse IgG in previously untreated haemophilia A andhaemophilia B patients treated with monoclonal antibody purified factor VIIIand factor IX preparations. Haemophilia 3(2): 102-107, April 1997.
7. Kim HC, Matts L, Eisele J, Czachur M, Saidi P. Monoclonal AntibodyPurified Factor IX - Comparative Thrombogenicity to ProthrombinComplex Concentrate. Seminars in Hematology 28 (Suppl. 6tono. 3): 15-20, July 1991.
Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.
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