Factor IX Complex

Factor IX Complex, Konyne® 80, heat-treated at 80°C for 72 hours, is a sterile, dried, plasma fraction comprising coagulation factors II, IX, X and low levels of factor VII.

Konyne 80 is standardized in terms of factor IX content and each vial of Konyne 80 is labeled for factor IX. One international unit (IU) of factor IX as defined by the World Health Organization standard for blood coagulation factor IX is approximately equal to the level of factor IX found in 1.0 mL of fresh, normal plasma.

The factor IX content is approximately 50 times purified over whole plasma, and when reconstituted as directed, Konyne 80 contains 25 times as much factor IX as an equal volume of fresh plasma. Konyne 80, containing approximately 1000 IU of factor IX administered in 40 mL, contains the factor IX content of 1 liter of fresh plasma. Konyne 80 must be administered intravenously.

CLINICAL PHARMACOLOGY

Factor IX Complex raises the plasma level of factor IX and restores hemostasis in patients with factor IX deficiency. In general, a level of factor IX less than 5% of normal will give rise to spontaneous hemorrhage, while levels greater than 20% of normal will lead to satisfactory hemostasis even in the face of trauma or surgery. Approximately 30% to 50% of the factor IX activity can be detected in a hemophilia B (factor IX deficiency) recipient's plasma immediately after infusion. ^1,2 The biological activity of the infused factor IX disappears from the plasma with a half-life of approximately 24 hours. ² A pharmacokinetic study in six patients found similar recoveries and half-lives for Konyne® 80 as for Konyne®-HT. It must be noted that administration of Factor IX Complex causes an increase in blood levels of factors II, VII, IX and X.

Factors II, VII, IX and X are the vitamin K dependent coagulation factors and are synthesized in the liver. Congenital deficiencies of each of the four factors do occur and may result in a bleeding tendency. Naturally low levels of the vitamin K dependent factors may also be found in vitamin K deficiency and in severe liver disease.

This product has been heated at 80°C for 72 hours and there is no evidence of adverse effects upon the product. In a study ³ designed to assess the effectiveness of heat treatment at 68°C for 72 hours, hepatitis naive chimpanzees were inoculated with heated Antihemophilic Factor (Human) and Factor IX Complex preparations to which had been previously added non-A, non-B hepatitis Hutchinson Strain ⁴ to a total level of 2500 chimpanzee infectious doses (CID). The chimpanzees receiving heated preparations failed to exhibit any symptoms of non-A, non-B hepatitis. In contrast, one chimpanzee receiving Antihemophilic Factor (Human) concentrate which was not heated after the non-A, non-B inoculum was added, developed abnormally elevated alanine aminotransferase (ALT) levels beginning 10 weeks postinoculation and liver histopathology at 6 weeks. From these results, it was concluded that the heat treatment employed inactivated a known quantity of non-A, non-B hepatitis: at least 2500 CID.

Additional in vitro studies ⁵ on the effect of heating Factor IX Complex, Konyne® 80, in a dried state at 80°C for 72 hours, on virus inactivation were carried out with a number of viruses, including human immunodeficiency virus (HIV), added to Factor IX Complex prior to heating. The following table shows the amount of each model virus inactivated by the process:

Factor IX Complex, Konyne® 80 is indicated for the prevention and control of bleeding caused by Factor IX deficiency due to hemophilia B.

Konyne 80 is not indicated for use in the treatment of factor VII deficiency.

Konyne 80 is appropriate for use in:

1. Hemophilia B (Christmas disease); demonstrated factor IX deficiency in children or adults with real or impending bleeding episodes. Spontaneous bleeding can occur even in the absence of any trauma.
2. Reversal of coumarin anticoagulant induced hemorrhage; in situations where prompt reversal is required (e.g., preceding emergency surgery, trauma, etc.), administration of fresh-frozen plasma should be initially considered as treatment; however, Konyne 80 may be considered as a secondary approach if the risk of transmitting hepatitis is considered justifiable in the face of a life-threatening situation. ^{6 - 8}
3. Treatment of bleeding episodes in patients with hemophilia A (factor VIII deficiency) who have inhibitors to factor VIII. ⁹
   In addition to coumarin anticoagulant induced deficiencies, low levels of factors II, VII, IX and X may be found in vitamin K deficiency, in patients with gut sterilization due to oral antibiotics, in patients with liver disease, and in those with nephrotic syndrome. However, Factor IX Complex, Konyne 80® is not indicated in these situations and treatment should be aimed at correcting the primary condition.

Note: For publications on the clinical use of Konyne®, please refer to references 1,2, 6-17.

DOSAGE AND ADMINISTRATION

Each bottle of Konyne 80 has the factor IX activity, in IU, stated on the bottle label. One IU is defined as the activity present in 1 mL of fresh, normal plasma. The potency is standardized in terms of factor IX content.

The amount of Konyne 80 required for normalizing hemostasis will depend upon the patient and upon the circumstances. Sufficient Konyne 80 should be administered to achieve and maintain a plasma level of at least 20% until hemostasis is achieved.

Levels of factor IX of 30 to 40 percent are considered effective in stopping hemorrhages. ¹ Bleeds in life- or limb-threatening areas require factor IX levels of 50 to 80 percent which should be maintained at 30 to 40 percent for a few days. ¹ The desired hemostatic plasma level in surgical patients for minor procedures or invasive dental surgery is between 30 and 40 percent of normal. ¹ This can be achieved by a dosage not exceeding 30 to 40 units per kg body weight. In major hemorrhage, as during surgery or severe accidental trauma, plasma levels of 60 to 80 percent just prior to surgery, maintained above 30 percent for a further 5 to 7 days and then above 15 to 20 percent for 7 to 10 additional days, until healing occurs, are required. ¹

While the range of values in normal clinical practice is likely to vary depending upon differences between patients, their clinical condition and the type of assay employed, it is again stressed that high dosages, especially if frequently repeated (e.g., more than once per day) are hazardous. Such regimens can induce major thrombotic complications and hence must be avoided.

The following formulas may be used as guidelines to calculate an appropriate dose or to estimate the expected percentage increase obtained from a given dose:

Prophylaxis

The ideal treatment for proven congenital deficiency of procoagulants is prophylactic administration. For prophylaxis against hemorrhage during times of extensive physical activity, the plasma factor IX levels should be raised to 15 to 30 percent. Maintenance dosage should be adapted to the individual patient's needs. Additional Factor IX Complex, Konyne® 80 should be administered when a patient on prophylaxis is exposed to trauma or surgery.

Maintenance Dose

Maintenance dosage should be administered according to the clinical response and the factor IX level achieved. Such dosage is usually about 10-20 IU per kg body weight per day.

Inhibitor Patients

For treatment of bleeding episodes in patients with hemophilia A (factor VIII deficiency) who have inhibitors to factor VIII, the recommended dose should be 75 IU/kg. A second dose may be administered after 12 hours if necessary. ⁹

Reconstitution

Vacuum Transfer

Rate of Administration

The rate of administration should be adapted to the response of the individual patient, but is generally well-tolerated at a rate of approximately 100 IU per minute.

  HOW SUPPLIED

Factor IX Complex, Konyne® 80 is supplied in single dose bottles with the total IU of factor IX activity stated on the label of each bottle. A suitable volume of Sterile Water for Injection, USP, a sterile double-ended transfer needle, and a sterile filter needle are provided.

STORAGE

Konyne 80 should be stored under refrigeration (2-8°C; 36-46°F). Freezing should be avoided as breakage of the diluent bottle might occur.

Konyne 80 concentrate may be stored for a period of up to 1 month at temperatures not to exceed 25°C (77°F) during travel.

CAUTION

U.S. federal law prohibits dispensing without prescription.

LIMITED WARRANTY

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors it is important that this product be stored properly, that the directions be followed carefully during use, and that the risk of transmitting viruses be carefully weighed before the product is prescribed.

No warranty, express or implied, including any warranty of merchantability or fitness is made. Representatives of the Company are not authorized to vary the terms or the contents of the printed labeling, including the package insert, for this product except by printed notice from the Company's headquarters. The prescriber and user of this product must accept the terms hereof.

REFERENCES

1. Johnson AJ, Aronson DL, Williams WJ: Preparation and clinical use of plasma and plasma fractions. In: Williams WJ (ed): Hematology, 4th ed, New York, McGraw-Hill, 1990, ch 170, pp 1659-1673.
2. 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.
3. Mozen MM, Louie RE, Mitra G: Heat inactivation of viruses in antihemophilic factor concentrates. Abstracts, XVIth International Congress of the World Federation of Hemophilia, Rio de Janeiro, Aug. 24-28, 1984. Number 240.
4. Feinstone SM, Alter HJ, Dienes HP, et al: Non-A, non-B hepatitis in chimpanzees and marmosets. J Infect Dis 144(6):588-98, 1981.
5. Unpublished data in files of Bayer Corporation.
6. Taberner DA, Thompson JM, Poller L: Comparison of prothrombin complex concentrate and vitamin K ₁ in oral anticoagulant reversal. Br Med J  2(6027):83-5, 1976.
7. Menache D, Roberts HR: Summary report and recommendations of the task force members and consultants. Thromb Diath Haemorrh 33:645-7, 1975.
8. Aronson DL: Factor IX Complex. Semin Thromb Hemostas 6(1):28-43, 1979.
9. Lusher JM, Shapiro SS, Palascak JE, et al: Efficacy of prothrombin-complex concentrates in hemophiliacs with antibodies to factor VIII: a multicenter therapeutic trial. N Engl J Med 303(8):421-5, 1980.
10. Hoag MS, Johnson FF, Robinson AJ, et al: Treatment of hemophilia B with a new clotting-factor concentrate. N Engl J Med 280(11):581-6, 1969.
11. Hoag MS, Johnson FF, Robinson AJ, et al: Use of plasma concentrate in congenital factor VII and IX deficiencies. Clin Res 17:152, 1969.
12. Breen FA Jr, Tullis JL: Prothrombin concentrates in treatment of Christmas disease and allied disorders. JAMA 208(10):1848-52, 1969.
13. Kasper CK: Postoperative thrombosis in hemophilia. N Engl J Med 289(3):160, 1973.
14. Kasper CK: Surgical operation in hemophilia B. Use of factor IX concentrate. Calif Med 113(1):4-8, 1970.
15. George JN, Breckenridge RT: The use of factor VIII and factor IX concentrates during surgery. JAMA 214(9):1673-6, 1970.
16. Gunay U, Choi HS, Maurer HS, et al: Commercial preparations of prothrombin complex. A clinical comparison. Am J Dis Child 126(6):775-7, 1973.
17. White GC 2d, Lundblad RL, Kingdon HS: Prothrombin complex concentrates: preparation, properties, and clinical uses. Curr Top Hematol 2:203-44, 1979.
18. Colombo M, Mannucci PM, Carnelli V, et al: Transmission of non-A, non-B hepatitis by heat-treated factor VIII concentrate. Lancet 2(8445):1-4, 1985.
19. National Hemophilia Foundation Medical and Scientific Advisory Council. Hemophilia Information Exchange AIDS Update: Recommendations concerning AIDS and the treatment of hemophilia. HIV infection, Section I.G. (Rev. Jan., 1988).

In some patients the rapid administration of Konyne 80 can cause transient fever, chills, headache, flushing or tingling.

DRUG INTERACTIONS

No Information Provided.

WARNINGS

PRECAUTIONS

General

1. Reconstitute only with Sterile Water for Injection, USP.
2. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution.
3. Administer only by the intravenous route.
4. The administration equipment and any reconstituted Factor IX Complex, Konyne® 80 not immediately used should be discarded.
5. E-aminocaproic acid should not be administered with Factor IX Complex as this may increase the risk of thrombosis.
6. Patients who receive Konyne 80 either postoperatively or with known liver disease should be kept under close observation for signs and symptoms of intravascular coagulation or thrombosis. Any suspicious findings of this nature indicate the dosage should be markedly decreased if the patient's conditions are such that the treatment cannot be discontinued entirely. In the event of thrombohemorrhagic disorders occurring, reduction in dosage should be considered, and treatment with heparin may be warranted. Although this preparation does not contain heparin, it has been suggested that reconstitution with heparin in a concentration of 2-5 IU per mL may reduce the risk of development of thrombosis. ¹⁷ However, thrombosis can occur even in the presence of heparin.
7. Patients receiving Konyne 80 for prolonged periods should be continually monitored at least for levels of factors II, IX and X. The same comments as in No. 6 above are indicated. Half-lives of factors II and X are considerably longer than the half-life of factor IX. Hence frequent repeated high-dose administration may result in build-up of factors II and X, with increasing risk of thrombotic side effects.
8. Product administration and handling of the needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs.
   Place needles in sharps container after single use. Discard all equipment including any reconstituted Konyne 80 product in accordance with biohazard procedures.

Pregnancy Category C

Animal reproduction studies have not been conducted with Konyne 80. It is also not known whether Konyne 80 can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Konyne 80 should be given to a pregnant woman only if clearly needed.

Information for Patient

Some viruses, such as parvovirus B19 or hepatitis A, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women, or immune-compromised individuals.

Symptoms of parvovirus B19 infection include fever, drowsiness, chills and runny nose followed about 2 weeks later by a rash and joint pain. Evidence of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting, and pain in the belly. Dark urine and a yellowed complexion are also common symptoms. Patients should be encouraged to consult their physician if such symptoms appear.