Mononine Description

Coagulation Factor IX (Human), MONONINE is a sterile, stable, lyophilized concentrate of Factor IX prepared from pooled human plasma and is intended for use in therapy of Factor IX deficiency, known as Hemophilia B or Christmas disease. MONONINE is purified of extraneous plasma-derived proteins, including Factors II, VII and X, by use of immunoaffinity chromatography. A murine monoclonal antibody to Factor IX is used as an affinity ligand to isolate Factor IX from the source material. Factor IX is then dissociated from the monoclonal antibody, recovered, purified further, formulated and provided as a sterile, lyophilized powder. The immunoaffinity protocol utilized results in a highly pure Factor IX preparation. It shows predominantly a single component by SDS polyacrylamide electrophoretic evaluation and has a specific activity of not less than 190 Factor IX units per mg total protein.

All Source Plasma used in the manufacture of this product was tested by FDA-licensed Nucleic Acid Testing (NAT) for HBV, HCV, and HIV-1 and found to be nonreactive (negative).

This concentrate has been processed by monoclonal antibody immunoaffinity chromatography during its manufacture, which has been shown to be capable of reducing the risk of viral transmission. Additionally, a chemical treatment protocol and nanofiltration used in its manufacture have also been shown to be capable of significant virus reductions. However, no procedure has been shown to be totally effective in removing the risk of viral infectivity from coagulation factor concentrates (see CLINICAL PHARMACOLOGY and WARNINGS).

MONONINE is a purified preparation of Factor IX. When stored as directed, it will maintain its labeled potency for the period indicated on the container label.

Each vial contains the labeled amount of Factor IX activity expressed in International Units (IU). One IU represents the activity of Factor IX present in 1 mL of normal, pooled plasma. When reconstituted as recommended, the resulting solution is a clear, colorless, isotonic preparation of neutral pH, containing approximately 100 times the Factor IX potency found in an equal volume of plasma. Each mL of the reconstituted concentrate contains approximately 100 IU of Factor IX and non-detectable levels of Factors II, VII and X (<0.0025 IU per Factor IX unit using standard coagulation assays). Each vial also contains histidine (approx. 10mM), sodium chloride (approx. 0.066M), mannitol (approx. 3%) and polysorbate 80 (approx. 0.0075%). Hydrochloric acid and/or sodium hydroxide may have been used to adjust pH. MONONINE also contains trace amounts (≤50 ng mouse protein/100 Factor IX activity units) of the murine monoclonal antibody used in its purification (see CLINICAL PHARMACOLOGY).

MONONINE is to be administered only intravenously.

Mononine - Clinical Pharmacology

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 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 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. 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 reactions across the two studies. In these studies, 100 doses of MONONINE were administered at what are considered high doses for a Factor IX concentrate, 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 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 ("difficulty in concentrating"; subject recovered). In no subjects were thrombogenic complications observed or reported.4

The manufacturing procedure for MONONINE 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 nanofiltration step used in the production of MONONINE document the virus reduction capacity of the processes employed. These studies were conducted using the relevant enveloped and non-enveloped viruses. The results of these virus validation studies utilizing a wide range of viruses with different physicochemical properties are summarized in Table 1 below:

Clinical Studies

The virus safety of MONONINE 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 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 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 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 in a crossover study with a Factor IX Complex concentrate, MONONINE 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 ALT elevations that were greater than twice the upper normal limit. These subjects were investigated thoroughly and none of the ALT elevations was associated with seroconversion. In three of the five subjects, a single ALT elevation 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 ALT elevations, a relationship to MONONINE could be excluded due to a span of 18 months between the infusion of MONONINE and occurrence of the elevated ALT level. In one of the two remaining subjects, the ALT level had been elevated prior to the first infusion of MONONINE and normalized thereafter. Subsequently, this subject's ALT levels 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 ALT elevations that persisted for a period of five months, gradually decreasing to normal levels. Approximately three days after his first MONONINE infusion this subject received hepatitis B immune globulin and his first injection of hepatitis B vaccine. At that time, the subject's ALT level 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 infusion) was found to be clearly elevated at 629 IU/L. ALT levels subsequently decreased again and were in the range of 160 to 220 IU/L for the next four to five months, with mildly elevated aspartate aminotransferase and creatinine phosphokinase values. Serology for hepatitis 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 aminotransferase values and gastrointestinal symptoms were not considered to be of viral origin. However, a causal relationship between prior administration of MONONINE and these aminotransferase elevations and mild symptoms could not be ruled out.

Indications and Usage for Mononine

MONONINE is indicated for the prevention and control of bleeding in Factor IX deficiency, also known as Hemophilia B or Christmas disease.

Contraindications

Known hypersensitivity to mouse protein is a contraindication to MONONINE.

Warnings

Precautions

Adverse Reactions/Side Effects

The patient should be monitored closely during the infusion of MONONINE to observe for the development of any reaction. If any reaction takes place that is thought to be related to the administration of MONONINE, the rate of infusion should be decreased or the infusion stopped, as dictated by the response of the patient.

Should evidence of an acute hypersensitivity reaction be observed, the infusion should be stopped promptly and appropriate countermeasures and supportive therapy should be administered.

Mononine Dosage and Administration

MONONINE is intended for intravenous administration only. It should be reconstituted with the volume of Sterile Water for Injection, USP supplied with the lot, and administered within three hours of reconstitution. Do not refrigerate after reconstitution. After administration, any unused solution and the administration equipment should be discarded.

As a general rule, 1 IU of Factor IX activity per kg can be expected to increase the circulating level of Factor IX by 1% [IU/dL] of normal. The following formula provides a guide to dosage calculations:

The amount of MONONINE to be infused, as well as the frequency of infusions, will vary with each patient and with the clinical situation.11,12

As a general rule, the level of Factor IX required for treatment of different conditions is as follows:

Recovery of the loading dose varies from patient to patient. Doses administered should be titrated to the patient's response. MONONINE administered in doses of ≥75 IU/kg were well tolerated (see CLINICAL PHARMACOLOGY).

In the presence of an inhibitor to Factor IX, higher doses of MONONINE might be necessary to overcome the inhibitor (see PRECAUTIONS). No data on the treatment of patients with inhibitors to Factor IX with MONONINE are available.

For information on rate of administration, see Rate of Administration, below.

Storage and Handling

When stored at refrigerator temperature, 2-8°C (36-46°F), MONONINE is stable for the period indicated by the expiration date on its carton and vial label. Within this period, MONONINE may be stored at room temperature not to exceed 25°C (77°F), for up to one month.

Avoid freezing, which may damage container for the diluent.

How is Mononine supplied

MONONINE is supplied in a single dose vial with Sterile Water for Injection, USP, and a Mix2Vial filter transfer set for reconstitution and withdrawal. Factor IX activity in IU is stated on the carton and vial label.

Each product package consists of the following:

References

1. Zauber NP, Levin J. Factor IX levels in patients with hemophilia B (Christmas disease) following transfusion with concentrates of Factor IX or fresh frozen plasma (FFP). Medicine (Baltimore) 56(3):213-24, 1977.
2. Smith KJ, Thompson AR. Labeled Factor IX Kinetics in Patients with Hemophilia-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: Clinical Trials in Hemophilia B and Comparison to Prothrombin Complex Concentrates. Blood 79(3):568-575, 1992.
4. Warrier I, Kasper CK, White II GC, Shapiro AD, Bergman GE, the Mononine® 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 Factor IX 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 and haemophilia B patients treated with monoclonal antibody purified factor VIII and factor IX preparations. Haemophilia 3(2):102-107, April 1997.
7. Kim HC, Matts L, Eisele J, Czachur M, Saidi P. Monoclonal Antibody Purified Factor IX - Comparative Thrombogenicity to Prothrombin Complex Concentrate. Seminars in Hematology 28 (Suppl. 6 to no. 3):15-20, July 1991.
8. Aledort LM: Factor IX and Thrombosis. Scand J Haematology Suppl. 30:40, 1977.
9. Cederbaum AI, Blatt PM, Roberts HR. Intravascular coagulation with use of human prothrombin complex concentrates. Ann Intern Med 84:683-687, 1976.
10. Kurczynski E, Lusher JM, Pitel P, Shapiro AD, Bergman GE, the Mononine® Study Group. Safety and efficacy of monoclonal antibody-purified factor IX concentrate for management of bleeding and surgical prophylaxis in previously treated children with hemophilia B. Int J Ped Hemat/Oncol 2:211-216, 1995.
11. Kasper CK, Dietrich SL. Comprehensive Management of Hemophilia. Clin Haematol 14(2):489-512, 1985.
12. Johnson AJ, Aronson DL, Williams WJ. Preparation and clinical use of plasma and plasma fractions. Chap 167 in Hematology 3rd Edition, Williams WJ, Beutler E, Erslev AJ, Lichtman MA (Eds.), McGraw Hill Book Co. New York: pp 1563-1583, 1983.
13. Tuinenburg A, Mauser-Bunschoten EP, Verhaar MC, Biesma DH, Schutgens REG. Cardiovascular disease in patients with hemophilia. J Thromb Haemost 7:247-254, 2009.

Manufactured by:
CSL Behring LLC
Kankakee, IL 60901 USA

US License No. 1767

Revised 12/2018

Mix2Vial® is a registered trademark of West Pharma. Services IL, Ltd., a subsidiary of West Pharmaceuticals Services, Inc.

PRINCIPAL DISPLAY PANEL - 500 IU Carton

NDC 0053-6232-02
One vial with diluent

MID

Coagulation Factor IX
(Human)
Mononine®
Monoclonal Antibody Purified

For Intravenous Administration Only.
Rx only

Storage: Mononine® stored in a refrigerator at 2-8°C (36-46°F) is
stable for the period indicated by the expiration date on the label.
Within this period Mononine® may be stored at room temperature not
to exceed 25°C (77°F), for up to 1 month. Avoid freezing.

Manufactured by:
CSL Behring LLC
Kankakee, IL 60901 USA
US License No. 1767

CSL Behring

PRINCIPAL DISPLAY PANEL - Kit Carton

HIGH

NDC 0053-6233-02
One vial with diluent

Coagulation Factor IX (Human)
Mononine®
Monoclonal Antibody Purified

CSL Behring

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