Factor IX (Systemic)


BAN:
Factor IX Fraction {44}

VA CLASSIFICATION
Primary: BL116

Commonly used brand name(s): AlphaNine SD; Bebulin VH; BeneFix; Immunine VH; Konyne 80; Mononine; Profilnine SD; Proplex T.

Other commonly used names are
Christmas factor, plasma thromboplastin component (PTC), and prothrombin complex concentrate (PCC) .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihemorrhagic. —

Indications

Note: Some of the indications for factor IX formulations vary among different brand name products because of differences in composition. Some brand name products contain clinically useful quantities of clotting factors other than factor IX; other brand name products contain only factor IX, or factor IX with clinically insignificant quantities of other clotting factors.


Accepted

Hemophilia B, hemorrhagic complications of (prophylaxis and treatment) —Factor IX is indicated for the control and prevention of bleeding in patients with hemophilia B (Christmas disease).{10} {11} {14} {15} {16} {17} {18} {23} {28} {33} {35} {37} {64}

Hemorrhagic complications of factor VII deficiency (prophylaxis and treatment)—Proplex T is indicated for the replacement of factor VII for the control and prevention of bleeding in patients lacking this clotting factor {06} {55} {56}.

Hemorrhage, anticoagulant-induced (treatment)— Factor IX complex concentrates may be indicated to reverse life-threatening hemorrhage induced by coumarin- and indandione-derivative anticoagulants {15} {51} {55}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Factor IX products are sterile, dried concentrates derived from pooled human plasma or produced by recombinant DNA technology {05} {07} {10} {13} {16} {17} {18} {23} {24} {25}. One type of factor IX product, which is also called prothrombin complex concentrate (PCC), may contain clinically useful quantities of vitamin K–dependent clotting factors II, VII, and X {06} {10} {15} {16} {25} {27} {35} in addition to factor IX. PCCs also may contain other proteins, including proteins C and S; high molecular weight kininogen; and small quantities of activated clotting factors II, VII, IX, or X {25} {27} {30}.
    A second type of factor IX product, which is called coagulation factor IX, is purified of extraneous plasma proteins, including clotting factors II, VII, and X, by affinity chromatography ( AlphaNine SD, BeneFix) or by immunoaffinity chromatography utilizing murine monoclonal antibodies to factor IX ( Mononine) {04} {07} {13} {14} {17} {18} {19} {23} {64}. Products of this type contain clinically useful quantities of factor IX only.
Molecular weight—
    Factor IX: 55,000 {04} {39} to 71,000 {12} {28}

Mechanism of action/Effect:

Hemorrhagic complications of Hemophilia B—Factor IX is a vitamin K–dependent clotting factor synthesized in the liver. It is part of the intrinsic pathway of blood coagulation. Factor IX is converted to its activated form, factor IXa, by factor XIa in the presence of calcium ions. Factor IXa, in combination with activated factor VIII, calcium ions, and phospholipids, converts factor X to its activated form, factor Xa, resulting ultimately in the conversion of prothrombin to thrombin, and the formation of a fibrin clot. {11} {23} Hemophilia B is an inherited, X chromosome–linked disorder in which there is a deficiency of factor IX. Hemophilia B is classified as mild, moderate, or severe when plasma factor IX concentrations are more than 5%, 1 to 5%, or less than 1% of normal, respectively. The average normal plasma activity of factor IX is designated as 60 to 100% {51}, and a plasma factor IX concentration of 25 to 40% of normal is required for hemostasis {04} {23} {39} {41}. The administration of factor IX products temporarily replaces the deficient clotting factor to correct or prevent bleeding episodes {06} {10} {13} {15} {16} {23}.

Hemorrhagic complications in hemophilic patients with factor VIII inhibitors—The exact mechanism of action is unclear. However, the clotting factors present in the prothrombin complex concentrates are believed to bypass the factor VIII inhibitors and directly activate factor X {05} {41}. In vitro experiments suggest the possibility of a factor Xa-like substance; or a complex of factor VIII coagulant antigen (FVIIIC:Ag), factor IXa, and phospholipid as the active principle, which is only minimally inhibited by an inhibitor {59} {60}.

Hemorrhagic complications of factor VII deficiency—Factor VII is part of the extrinsic pathway of blood coagulation. It is activated to factor VIIa by factor Xa. Factor VIIa, in combination with tissue factor, activates factors IX and X. {11} {36} The administration of the factor VII present in factor IX complex replaces the deficient clotting factor to correct or prevent bleeding episodes.

Anticoagulant-induced hemorrhage—Coumarin- and indandione-derivative anticoagulants act indirectly in the liver by inhibiting the vitamin K–mediated gamma-carboxylation of precursor proteins, thus preventing the activation of clotting factors II, VII, IX, and X. The administration of factor IX complex concentrates containing additional vitamin K–dependent clotting factors {57} increases the plasma concentration of these clotting factors to overcome the effect of the anticoagulant {49}.

Half-life:


Factor IX:

Distribution: 3 to 6 hours {07} {37}.

Elimination: 17 to 32 hours {04}.


Time to peak effect:

10 to 30 minutes after intravenous administration {07} {20}.


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans.

Studies have not been done in animals.

FDA Pregnancy Category C. {06} {10} {15} {16} {17} {18} {23}

Breast-feeding

It is not known whether the proteins present in factor IX products are distributed into breast milk. However, distribution into breast milk would be highly unlikely because of the large size of the protein molecules. {48}

Pediatrics

Premature infants and neonates may be at increased risk of developing thrombotic complications following the administration of factor IX products {01} {06} {23} {32}.


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of factor IX products in the elderly {02} {07} {12} {27} {28}.


Dental

Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, are used commonly in conjunction with clotting factor replacement to control excessive bleeding in hemophilic patients undergoing tooth extractions, or who have other oral bleeding {63}. Care should be taken, however, as systemic use of antifibrinolytic agents may potentiate the thrombogenic effects of the concentrate, particularly factor IX complex {61}. Using the antifibrinolytic agent as an oral rinse, or delaying its use for 8 to 12 hours after administration of the concentrate, may minimize this complication {61}.

Surgical

Factor IX concentrates should be used cautiously in patients undergoing surgical procedures, as the risk of thrombotic complications is increased in these patients who receive large, repeated doses of factor IX complex, or who have significant hepatic dysfunction {27} {40}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Aminocaproic acid or
Tranexamic acid    (although these antifibrinolytic agents are used commonly in conjunction with clotting factor replacement to control and prevent excessive bleeding in hemophilic patients undergoing tooth extractions or who have other oral bleeding, systemic use with factor IX products (particularly factor IX complex) may increase the risk of thrombotic complications {15} {32} {45} {46}; this may be less of a problem with the use of coagulation factor IX {62}; using the antifibrinolytic agent as an oral rinse, or delaying its use for 8 to 12 hours following injection of factor IX products, may minimize this complication {45} {61})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Disseminated intravascular coagulation (DIC) or
» Hyperfibrinolytic states or
» Thromboembolism, predisposition to or history of    (risk of thrombotic complications)

{06}{15}{17}{23}{40}{64}
Risk-benefit should be considered when the following medical problems exist
Crush injuries or
Hepatic function impairment, severe or
Surgery, recent    (increased risk of disseminated intravascular coagulation, fibrinolysis, or thrombosis)

{01}{06}{10}{15}{16}{18}{19}{23}{32}{35}{40}
Sensitivity to factor IX
Sensitivity to hamster protein    (risk of allergic reaction to protein, which is present in recombinant product, BeneFix)

{17}
Sensitivity to mouse protein    (risk of allergic reaction to protein, which is present in monoclonal antibody–derived product, Mononine)

{23}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Activated partial thromboplastin time (APTT) tests
Plasma fibrinogen determinations
Platelet count and
Prothrombin time (PT) tests    (recommended daily during therapy {56} {57} {58} to detect disseminated intravascular coagulation [DIC] {06} {15} {23}; prolonged APTT and PT test results in combination with a reduced fibrinogen concentration {39} {42} and thrombocytopenia {39} are highly suggestive of DIC; additional laboratory findings that further corroborate the diagnosis of DIC include prolonged thrombin time {39} {43}, an increase in plasma D-dimer {42} {43} and fibrinogen degradation products {39} {42} {51}, and a decrease in plasma clotting factors {42})


Factor IX plasma, determinations    (recommended daily during therapy to assure that adequate factor IX concentrations have been achieved and are maintained)

{10}{16}{23}{35}{56}{57}


Side/Adverse Effects

Note: To reduce the risk of transmission of viruses by blood and blood components, potential blood donors are screened, and donor blood is tested {04} {05} {16} {24} {66} and must be found negative for antibodies to human immunodeficiency virus (HIV), hepatitis B core antigen, hepatitis C (non-A, non-B) virus, and for hepatitis B surface antigen. The concentration of alanine aminotransferase (ALT) also must be within normal limits. {21} {66} However, these precautions are not totally effective in eliminating viral infectivity. To further reduce the risk, factor IX products are treated utilizing one or more methods of viral inactivation. Some of the methods employed include dry heating, vapor heating, heating in solvent suspension, use of solvent detergent, immunoaffinity chromatography, and ultrafiltration {03} {04} {66}. These processes substantially decrease the risk of transmission of lipid-enveloped viruses such as HIV, hepatitis B, and hepatitis C (non-A, non-B) {04} {24} {65} {66}. However, nonlipid-enveloped viruses, including human parvovirus B19 and hepatitis A, are potentially resistant to some of these measures and can still be transmitted {65} {66}. Also, unknown viruses and prions, such as the agent that causes Creutzfeldt-Jakob disease (CJD), may not be eliminated by current inactivation and purification methods and could be transmitted {67}. There is no evidence, however, of CJD transmission through any transfused blood component, and it remains only a theoretical concern {68}.
Approximately 1 to 4% of patients treated with factor IX products develop inhibitors, or antibodies, which neutralize the procoagulant activity of factor IX {69}. Patients with inhibitor antibodies to factor IX may be treated with increased quantities of factor IX, which complex with and thereby inactivate the antibodies, or with an anti-inhibitor coagulant complex {01} {36}, which directly activates factor X {47}. However, the success of either of these treatment options is variable. Recombinant activated factors VII {36} and X {41} are currently undergoing clinical trials to assess safety and efficacy in the treatment of patients with factor IX inhibitor antibodies.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Disseminated intravascular coagulation (cyanosis [bluish coloring], especially of the hands and feet; ecchymoses at injection sites [large, nonelevated blue or purplish patches in the skin]; excessive sweating; persistent bleeding or oozing from puncture sites or mucous membranes [bowel, mouth, nose, or urinary bladder]){01}{02}{04}{05}{26}{27}{28}{30}{33}{35}{41}{53}{55}{58}
    
myocardial infarction (anxiety; cold sweating; increased heart rate; nausea or vomiting; severe pain or pressure in the chest and/or the neck, back, or left arm; shortness of breath){01}{04}{05}{27}{28}{31}{32}{41}
    
pulmonary embolism (chest discomfort; convulsions; dizziness or lightheadedness when getting up from a lying or sitting position; shortness of breath or fast breathing){01}{06}{23}{30}
    
thrombosis or thromboembolism (pains in chest, groin, or legs [especially calves]; severe, sudden headache; sudden and unexplained shortness of breath, slurred speech, vision changes, and/or weakness or numbness in arm or legs; sudden loss of coordination)—depending on site of thrombus formation or embolization{05}{12}{27}{28}{32}

Note: The nonactivated clotting factors II, VII, and X; activated clotting factors II, VII, IX, and X; and coagulant-active phospholipids present in prothrombin complex concentrates (factor IX complex) are thought to be largely responsible for the thrombotic complications described {01} {13} {19} {25} {27} {35} {41}. Intravascular thrombosis has occurred most frequently in patients who received large, repeated doses of factor IX complex while undergoing surgery, and may be more common in patients with underlying liver disease {27} {68}. These complications are less likely to occur after the administration of purified coagulation factor IX products AlphaNine SD, BeneFix, Immunine VH, or Mononine {17} {19} {41} {64}.


Incidence less frequent
    
Anaphylaxis or other allergic reaction{02}{10}{16}{18}{23} (changes in facial skin color; fast or irregular breathing; puffiness or swelling of the eyelids or around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; skin rash, hives, and/or itching)—may include anaphylactic shock with sudden, severe decrease in blood pressure and collapse
    
injection reaction{02}{06}{15}{16}{18}{23} (burning or stinging at injection site; changes in blood pressure or pulse rate; chills; drowsiness; fever; flushing [redness of face]; headache; nausea or vomiting; shortness of breath)—occurs with too rapid an injection rate

Note: An allergic reaction to mouse protein (incidence rare) may occur after the administration of the monoclonal antibody–derived product, Mononine {12} {19} {23}.






Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Factor IX (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to factor IX or to hamster or mouse protein





Use in children—Thrombotic complications are more likely to occur in premature infants and neonates, who are usually more sensitive than adults to the effects of factor IX

Other medical problems, especially disseminated intravascular coagulation, hyperfibrinolytic states, or predisposition to or history of thromboembolism

Proper use of this medication
» Proper preparation of medication: bringing dry concentrate and diluent to room temperature before reconstitution; when reconstituting, directing stream of diluent against side of vial of concentrate to prevent foaming; gently swirling vial to dissolve contents; not shaking vigorously

» Administering within 3 hours of reconstitution

» Use of plastic disposable syringe and filter needle; safe handling and disposal of syringe and needle

Proper dosing
Missed dose: Contacting physician immediately for instructions

» Proper storage

Precautions while using this medication
Need for patients newly diagnosed with hemophilia to receive hepatitis A and hepatitis B vaccines

» Notifying physician if medication seems less effective than usual; this may indicate the development of antibodies to factor IX

» Need to carry identification stating condition


Side/adverse effects
Signs and symptoms of potential adverse effects, including disseminated intravascular coagulation, myocardial infarction, pulmonary embolism, thrombosis or thromboembolism, and allergic reaction to factor IX or mouse protein


General Dosing Information

Choice of product


• Because of the risk of thrombotic complications with the use of factor IX complex concentrates, use of a coagulation factor IX product should be strongly considered in the following situations: for surgery, for treatment of crush injuries, for treatment of large intramuscular hemorrhages for which several days of replacement therapy will be required, in persons with severe hepatocellular dysfunction, in neonates, and in persons who have a history of thrombotic complications associated with the use of factor IX complex {40}.

Some clinicians recommend the use of heparin with factor IX complex, either administered to the patient directly (5000 USP Units subcutaneously every eight hours) or added to the concentrate (5 to 10 USP Units per mL), as a way to prevent thrombotic complications {68}.

Factor IX products are recommended for intravenous use only {06} {10} {15} {16} {18} {23} {38}.

Factor IX products should be administered via plastic disposable syringes because the proteins present tend to adhere to the ground-glass surface of all-glass syringes {16} {23} {38}.

Factor IX products should be filtered before administration {23} {38}.

Factor IX may be administered as a continuous intravenous infusion via a minipump or syringe pump for severe, life-threatening bleeding, or following surgery {68}.

Long-term prophylactic therapy for severe hemophilia, in which factor replacement is given several times a week to maintain the factor level above 1%, has been used extensively in Europe {29}. The goal is to convert severe hemophilia to a mild or moderate form of the disease to prevent spontaneous bleeding and preserve joint function {61} {78}.

Antifibrinolytic therapy is useful adjunctive therapy in hemophilic patients with oral or mucous membrane bleeding, particularly that which occurs during dental and oral surgery {68}. It prevents or controls bleeding, thus reducing the need for replacement therapy. Aminocaproic acid may be given orally or intravenously at a dose of 75 mg per kg of body weight (up to 6 grams) immediately after surgery, then every six hours for seven to ten days {68}. Or, tranexamic acid may be given as a single dose of 25 mg per kg of body weight orally or 10 mg per kg of body weight intravenously two hours before surgery, followed, after surgery, by 25 mg per kg of body weight orally every six to eight hours for seven to ten days {68}. When antifibrinolytic agents are used in this manner, a single coagulation factor IX infusion of 60 International Units per kg of body weight prior to surgery is often enough for normal hemostasis {62}. These agents can also be given as an oral rinse (5 mL of aminocaproic acid syrup, or 10 mL of a 5% tranexamic acid solution four times a day for seven to ten days) {70}.


Parenteral Dosage Forms

FACTOR IX COMPLEX USP

Note: Each vial of factor IX concentrate is labeled with the factor IX activity expressed in International Units (IU) per vial. This potency assignment is referenced to the World Health Organization International Standard. One IU of factor IX activity per kg of body weight is approximately equal to the factor IX activity in 1 mL of fresh plasma {01} {10} {15} {16} {18} {23} and increases the plasma concentration of factor IX by 1% {06} {15} {16} {18} {23} {37}. The specific factor IX activity of the prothrombin complex concentrates ranges from 0.7 to 3 IU per mg of total protein {04} {25} {37}. Although the dose of factor IX should be individualized for each patient based on body weight, type of hemorrhage, and desired plasma factor IX concentration, the following formula may be used as a guide in determining dosage {06} {15} {16} {18} {23}:
Dose factor IX (IU) = Body weight (kg) × Desired factor IX increase (% of normal) × 1 IU/kg
Bebulin VH may be administered at a rate £ 2 mL per minute {10}, Konyne 80 at a rate of 100 IU per minute {15}, Profilnine SD at a rate £ 10 mL per minute {16}, and Proplex T at a rate between 2 and 3 mL per minute {06}. However, the rate at which factor IX complex is administered should be guided by the comfort of the patient.


Usual adult and adolescent dose
Hemophilia B


Prophylaxis of spontaneous hemorrhage:
Intravenous, 25 to 40 IU per kg of body weight, administered twice a week, maintaining the trough factor level above 1% between doses {29} {71}.



Treatment of hemorrhage:
Schedules for administration of clotting factor concentrates are based on the severity of the bleeding diathesis. Currently, there is no consensus among practitioners regarding the optimal dose of factor replacement therapy for the treatment of the various types of bleeding, and the optimal therapeutic level for control of such bleeding remains debatable {72}. The doses in Table 1 should be considered only as a guideline, since recommendations may vary from one hemophilia center to another {61} {68} {73} {78}. Doses and duration of treatment may be adjusted according to the patient"s condition.

Table 1. General Factor Replacement Guidelines for the Treatment of Bleeding in Hemophilia {61} {73} {74} {75}



Indication  Initial minimum desired factor level (%)  Factor IX dose * (IU/kg)  Duration (days) 
Severe epistaxis  20–30  20–30   1–2 
Oral mucosal bleeding   20–30  20–30  1–2  
Hemarthrosis   30–50  30–50  1–2 
Hematoma  30–50  30–50  1–2 
Persistent hematuria   30–50  30–50  1–2  
Gastrointestinal bleeding   30–50  30–50  at least 1–2 days after bleeding stops 
Retroperitoneal bleeding  30–50  30–50  at least 3 
Trauma without signs of bleeding  40–50  40–50  2–3  
Tongue/retropharyngeal bleeding   40–50  40–50  3–4  
Trauma with bleeding §  100  100  10–14 
Intracranial bleeding §  100  100  10–14 
* Dosing intervals are based on a half-life for Factor IX of 18 to 24 hours (1 to 2 doses/day). Maintenance doses of one half the initial dose may be given at these intervals. The frequency depends on the severity of bleeding, with more frequent dosing for serious bleeding.
 In addition to antifibrinolytics {74}.
 Painless spontaneous hematuria usually requires no treatment. Increased oral or intravenous fluids are necessary to maintain renal output.
{74}{76} § Continuous factor infusion may be administered. Following the initial loading dose, a continuous infusion at a dose of 3 IU/kg per hour is given {73} {77}. Subsequent doses are adjusted according to the plasma factor levels.




Control of perisurgical hemostasis:
Dental and oral surgery—Intravenous, 60 IU per kg of body weight prior to surgery. A single dose is often sufficient for normal hemostasis when an antifibrinolytic agent, such as aminocaproic acid or tranexamic acid, is used as adjunctive treatment. {62} Care should be taken, however, as systemic use of antifibrinolytic agents may potentiate the thrombogenic effects of the concentrate {61}. Using the antifibrinolytic agent as an oral rinse, or delaying its use for 8 to 12 hours after administration of the concentrate, may minimize this complication {61}. This may be less of a problem with the use of coagulation factor IX {62}.

Other surgery—Intravenous, 50 to 60 IU per kg of body weight {61} {74}, or a quantity sufficient to raise the plasma factor IX concentration to 50 to 60% of normal, administered one hour prior to surgery. Subsequent doses equal to half the initial dose are given every twelve to twenty-four hours to maintain that plasma level for the first few days after surgery {61} {73}. The dose can then be tapered to maintain a plasma factor level > 30% for the following one to two weeks {73} {78}. Major orthopedic surgery may require several weeks of replacement therapy {61}. However, because of the increased risk of thrombotic complications with the use of factor IX complex in surgical patients, the use of coagulation factor IX is preferred {40}.


Hemophilia A


Prevention and control of bleeding in patients with inhibitors to factor VIII:
Intravenous, 75 IU per kg of body weight. The dose may be repeated after six or twelve hours, if necessary. {68}


Factor VII deficiency


Control of perisurgical hemostasis:
Proplex T—Intravenous, a quantity sufficient to raise the plasma factor VII concentration to 25% of normal administered prior to the procedure, with repeat doses every four to six hours after the procedure, as needed, for at least seven days. To estimate the dose of factor IX complex required to treat factor VII deficiency, the following formula may be used {06}:

Dose factor IX complex (IU) = Body weight (kg) × Desired factor VII increase (% of normal) × 0.5 IU/kg


Anticoagulant-induced hemorrhage
Intravenous, 1500 IU, administered with vitamin K 1 if needed in severe cases {50}.


Usual pediatric dose
See Usual adult and adolescent dose .

Size(s) usually available:
U.S.—


400 to 1200 IU of factor IX, as specified on the label, with sterile water for injection provided as diluent (Rx) [Bebulin VH (heparin £ 0.15 IU per IU of factor IX) (diluent 20 mL)]


450 to 1000 IU of factor IX, as specified on the label, with sterile water for injection provided as diluent (Rx) [Proplex T (heparin £ 1.5 USP units per mL) (diluent 30 mL)]


500 IU of factor IX with sterile water for injection provided as diluent (Rx) [Konyne 80 (diluent 20 mL)] [Profilnine SD (diluent 5 mL)]


1000 IU of factor IX, with sterile water for injection provided as diluent (Rx) [Konyne 80 (diluent 40 mL)] [Profilnine SD (diluent 10 mL)]


1500 IU of factor IX, with sterile water for injection provided as diluent (Rx) [Profilnine SD (diluent 10 mL)]

Canada—


400 to 1200 IU of factor IX, as specified on the label, with sterile water for injection provided as diluent (Rx) [Bebulin VH (heparin £ 0.15 IU per IU of factor IX) (diluent 20 mL)]

Note: The products listed also contain factors II, VII, and X. The quantities may be specified on the individual product labels.


Packaging and storage:
The dry concentrates are stored preferably between 2 and 8 °C (36 and 46 °F) {01} {06} {10} {15} {16} {22}. However, Konyne 80 may be stored at room temperatures not exceeding 25 °C (77 °F) for up to 1 month, and Profilnine SD may be stored at room temperatures not exceeding 30 °C (86 °F) for up to 3 months. The solution should not be refrigerated after reconstitution. {10} {15} {16} The diluent should be protected from freezing {06} {10} {16}.

Preparation of dosage form:
The diluent and dry concentrate should be brought to room temperature prior to reconstitution. The solution should be gently swirled, not shaken, until all of the concentrate is dissolved. Reconstitution generally requires 5 to 10 minutes. {15} {16} The reconstituted solution should be approximately at room temperature at the time of administration {06} {16}.

Note: Heparin may be added to prothrombin complex concentrates at a concentration of 5 to 10 USP units per mL of reconstituted product. The addition of heparin has been shown, in some cases, to reduce the likelihood of development of thrombotic complications. {01} {35} {42} {43}


Stability:
Administration should begin within 3 hours after reconstitution {06} {10} {15} {16}. Partially used vials should be discarded {16}.

Incompatibilities:
It is recommended that factor IX complex, after reconstitution with the provided diluent, be administered through a separate line, by itself, and without mixing with other intravenous fluids or medications {51} {52} {53} {54} {55}.


COAGULATION FACTOR IX(HUMAN)

Note: Each vial of factor IX concentrate is labeled with the factor IX activity expressed in International Units (IU) per vial. This potency assignment is referenced to the World Health Organization International Standard. One IU of factor IX activity per kg of body weight is approximately equal to the factor IX activity in 1 mL of fresh plasma {01} {10} {15} {16} {18} {23}, and increases the plasma concentration of factor IX by 1% {06} {15} {16} {18} {23} {37}. The specific factor IX activities of coagulation factor IX products AlphaNine SD and Mononine are ³ 50 IU per mg of total protein and 180 to 200 IU per mg of total protein, respectively {07} {12} {19} {23} {25}. Although the dose of factor IX should be individualized for each patient based on body weight, type of hemorrhage, and desired plasma factor IX concentration, the following formula may be used as a guide in determining dosage {06} {15} {16} {18} {23}:
Dose factor IX (IU) = Body weight (kg) × Desired factor IX increase (% of normal) × 1 IU/kg
AlphaNine SD may be administered at a rate not exceeding 10 mL per minute {18}, and Mononine and Immunine VH at a rate of 2 mL per minute {23} {64}. However, the rate at which coagulation factor IX is administered should be guided by the comfort of the patient.


Usual adult and adolescent dose
Hemophilia B


Prophylaxis of spontaneous hemorrhage:
See Factor IX Complex USP .



Treatment of hemorrhage:
See Factor IX Complex USP .



Control of perisurgical hemostasis:
Dental and oral surgery— See Factor IX Complex USP .

Other surgery—Intravenous, 100 IU per kg of body weight {61} {68}, or a quantity sufficient to raise the plasma factor IX concentration to 100% of normal, administered one hour prior to surgery. Subsequent doses equal to half the initial dose are given every twelve to twenty-four hours to maintain that plasma level for the first few days after surgery {61} {73}. As an alternative to the intermittent dosing of replacement factor, continuous infusion of factor IX may be given following surgery at a dose of 3 IU per kg of body weight per hour via a minipump or syringe pump {61} {73} {77}. The dose can then be tapered to maintain a plasma factor level > 30% for the following one to two weeks {73} {78}. Major orthopedic surgery may require several weeks of replacement therapy {61}.



Usual pediatric dose
See Usual adult and adolescent dose .

Size(s) usually available:
U.S.—


250 IU, with sterile water for injection provided as diluent (Rx) [Mononine (factors II, VII, and X £ 0.0025 units per unit of factor IX) (sodium chloride 66 mmol) ( mouse protein £ 50 nanograms per 100 units of factor IX) (diluent 2.5 mL)]


500 IU, with sterile water for injection provided as diluent (Rx) [AlphaNine SD (factors II and VII < 5 units per 100 IU of factor IX) (factor X < 20 units per IU of factor IX) ( heparin £ 0.04 USP units per IU of factor IX) ( dextrose £ 1 mg per IU of factor IX) (diluent 10 mL)] [Mononine (factors II, VII, and X £ 0.0025 units per unit of factor IX) (sodium chloride 66 mmol) (mouse protein £ 50 nanograms per 100 units of factor IX) (diluent 5 mL)]


1000 IU, with sterile water for injection provided as diluent (Rx) [AlphaNine SD (factors II and VII < 5 units per 100 IU of factor IX) (factor X < 20 units per IU of factor IX) (heparin £ 0.04 USP units per IU of factor IX) (dextrose £ 1 mg per IU of factor IX) (diluent 10 mL)] [Mononine (factors II, VII, and X £ 0.0025 units per unit of factor IX) ( sodium chloride 66 mmol) (mouse protein £ 50 nanograms per 100 units of factor IX) (diluent 10 mL)]


1250 IU, with sterile water for injection provided as diluent (Rx) [AlphaNine SD (factors II and VII < 5 units per 100 IU of factor IX) (factor X < 20 units per IU of factor IX) (dextrose £ 1 mg per IU of factor IX) (diluent 10 mL)]


1500 IU, with sterile water for injection provided as diluent (Rx) [AlphaNine SD (factors II and VII < 5 units per 100 IU of factor IX) (factor X < 20 units per IU of factor IX) (dextrose £ 1 mg per IU of factor IX) (diluent 10 mL)]

Canada—


160 to 240 IU, with sterile water for injection provided as diluent (Rx) [Immunine VH (heparin < 0.1 IU per mL) ( factors II, VII, and X < 0.02 IU per IU of factor IX)]


500 IU, with sterile water for injection provided as diluent (Rx) [AlphaNine SD (factors II and VII < 5 units per 100 IU of factor IX) (factor X < 20 units per IU of factor IX) ( dextrose £ 1 mg per IU of factor IX) (diluent 10 mL)]


480 to 720 IU, with sterile water for injection provided as diluent (Rx) [Immunine VH (heparin < 0.1 IU per mL) ( factors II, VII, and X < 0.02 IU per IU of factor IX)]


1000 IU, with sterile water for injection provided as diluent (Rx) [AlphaNine SD (factors II and VII < 5 units per 100 IU of factor IX) (factor X < 20 units per IU of factor IX) (dextrose £ 1 mg per IU of factor IX) (diluent 10 mL)]


960 to 1440 IU, with sterile water for injection provided as diluent (Rx) [Immunine VH (heparin < 0.1 IU per mL) ( factors II, VII, and X < 0.02 IU per IU of factor IX)]


1250 IU, with sterile water for injection provided as diluent (Rx) [AlphaNine SD (factors II and VII < 5 units per 100 IU of factor IX) (factor X < 20 units per IU of factor IX) (dextrose £ 1 mg per IU of factor IX) (diluent 10 mL)]


1500 IU, with sterile water for injection provided as diluent (Rx) [AlphaNine SD (factors II and VII < 5 units per 100 IU of factor IX) (factor X < 20 units per IU of factor IX) (dextrose £ 1 mg per IU of factor IX) (diluent 10 mL)]

Packaging and storage:
The dry concentrates preferably are stored between 2 and 8 °C (36 and 46 °F) {18} {23}. However, Mononine may be stored at room temperatures not exceeding 30 °C (86 °F) for up to 1 month {23}. The diluent should be protected from freezing {18} {23}.

Preparation of dosage form:
The diluent and dry concentrate should be brought to room temperature prior to reconstitution. The reconstituted solution should be gently swirled, not shaken, until all of the concentrate is dissolved. {18} {23} Reconstitution generally requires 1 {23} to 5 {18} minutes. The reconstituted solution should be approximately at room temperature at the time of administration.

Stability:
Administration should begin within 3 hours after reconstitution. Partially used vials should be discarded. {18} {23}

Incompatibilities:
It is recommended that coagulation factor IX, after reconstitution with the provided diluent, be administered through a separate line, by itself, and without mixing with other intravenous fluids or medications {51} {52} {53} {55}.


COAGULATION FACTOR IX(RECOMBINANT)

Note: Each vial of factor IX concentrate is labeled with the factor IX activity expressed in International Units (IU) per vial. This potency assignment is referenced to the World Health Organization International Standard. One IU of factor IX activity per kg of body weight is approximately equal to the factor IX activity in 1 mL of fresh plasma {17}. The specific activity of BeneFix is ³ 200 IU per mg of total protein {17}. Although the dose of factor IX should be individualized for each patient based on body weight, type of hemorrhage, and desired plasma factor IX concentration, recombinant factor IX may require higher doses than those used for plasma-derived factor IX to attain the desired factor IX level {17}. Patients switching from plasma-derived factor IX to recombinant factor IX may be started at the same dose previously used for plasma-derived factor IX and titrated upward as needed, or the dose may be based on the following formula {17}:
Dose factor IX (IU) = Body weight (kg) × Desired factor IX increase (% of normal) × 1.2 IU/kg


Usual adult and adolescent dose
Hemophilia B


Prophylaxis of spontaneous hemorrhage:
See Factor IX Complex USP .



Treatment of hemorrhage:
See Factor IX Complex USP .



Control of perisurgical hemostasis:
See Coagulation Factor IX (Human) .



Usual pediatric dose
See Usual adult and adolescent dose .

Size(s) usually available:
U.S.—


250 IU, with sterile water for injection provided as diluent (Rx) [BeneFix]


500 IU, with sterile water for injection provided as diluent (Rx) [BeneFix]


1000 IU, with sterile water for injection provided as diluent (Rx) [BeneFix]

Canada—


250 IU, with sterile water for injection provided as diluent (Rx) [BeneFix]


500 IU, with sterile water for injection provided as diluent (Rx) [BeneFix]


1000 IU, with sterile water for injection provided as diluent (Rx) [BeneFix]

Packaging and storage:
The dry concentrate preferably is stored between 2 and 8 °C (36 and 46 °F) {17}. However, BeneFix may be stored at room temperatures not exceeding 25 °C (77 °F) for up to 6 months {17}. The diluent should be protected from freezing {17}.

Preparation of dosage form:
The diluent and dry concentrate should be brought to room temperature prior to reconstitution. The reconstituted solution should be gently swirled, not shaken, until all of the concentrate is dissolved. {17} The reconstituted solution should be approximately at room temperature at the time of administration.

Stability:
Administration should begin within 3 hours after reconstitution. Partially used vials should be discarded. {17}



Revised: 10/17/2001



References
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  1. Pierce GF, Lusher JM, Brownstein AP, et al. The use of purified clotting factor concentrates in hemophilia. Influence of viral safety, cost, and supply on therapy. JAMA 1989; 261: 3434-8.
  1. Thompson AR. Factor IX concentrates for clinical use. Semin Thromb Hemost 1993; 19: 25-36.
  1. Lusher JM. Perspectives on the use of factor IX complex concentrates in the treatment of bleeding in persons with acquired factor VIII inhibition. Am J Med 1991; 91(5A Suppl): 30S-34S.
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