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Factor IX (Human)

Pronunciation

(FAK ter nyne HYU man)

Index Terms

  • Factor IX Concentrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution Reconstituted, Intravenous [preservative free]:

AlphaNine SD: 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea) [contains polysorbate 80]

Mononine: 250 units (1 ea [DSC]); 500 units (1 ea); 1000 units (1 ea) [contains polysorbate 80]

Brand Names: U.S.

  • AlphaNine SD
  • Mononine

Pharmacologic Category

  • Antihemophilic Agent
  • Blood Product Derivative

Pharmacology

Replaces deficient clotting factor IX. Hemophilia B, or Christmas disease, is an X-linked 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 VII: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.

Half-Life Elimination

IX component: ~21 to 25 hours

Use: Labeled Indications

Prevention and control of bleeding in patients with hemophilia B (congenital factor IX deficiency or Christmas disease)

NOTE: Contains nondetectable levels of factors II, VII, and X. Therefore, NOT INDICATED for replacement therapy of any other clotting factor besides factor IX or for reversal of anticoagulation due to either vitamin K antagonists or other anticoagulants (eg, dabigatran), for hemophilia A patients with factor VIII inhibitors, or for patients in a hemorrhagic state caused by reduced production of liver-dependent coagulation factors (eg, hepatitis, cirrhosis).

Contraindications

AlphaNine SD: There are no contraindications listed in the manufacturer's labeling.

Mononine: Hypersensitivity to mouse protein

Dosing: Adult

NOTE: Contains nondetectable levels of factors II, VII, and X. Therefore, NOT INDICATED for replacement therapy of any other clotting factor besides factor IX or for reversal of anticoagulation due to either vitamin K antagonists or other anticoagulants (eg, dabigatran), for hemophilia A patients with factor VIII inhibitors, or for patients in a hemorrhagic state caused by reduced production of liver-dependent coagulation factors (eg, hepatitis, cirrhosis).

Control or prevention of bleeding in patients with factor IX deficiency (hemophilia B or Christmas disease): IV: AlphaNine SD, Mononine: Dosage is expressed in units of factor IX activity; dosing must be individualized based on severity of factor IX deficiency, extent and location of bleeding, and clinical status of patient. Refer to product information for specific manufacturer recommended dosing. Alternatively, the World Federation of Hemophilia (WFH) has recommended general dosing for factor IX products.

Formula to determine units required to obtain desired factor IX level: Note: If patient has severe hemophilia (ie, baseline factor IX level is or presumed to be <1%), then may just use “desired factor IX level” instead of “desired factor IX level increase”.

Number of factor IX units required = patient weight (in kg) x desired factor IX level increase (as % or units/dL) x 1 unit/kg

For example, to attain an 80% level in a 70 kg patient who has a baseline level of 20%: Number of factor IX units needed = 70 kg x 60% x 1 unit/kg = 4200 units

Alternative dosing (off-label): Note: The following recommendations may vary from those found within prescribing information or practitioner preference.

Prophylaxis: 15 to 30 units/kg/dose twice weekly (Utrecht protocol; WFH [Srivastava 2013]) or 25 to 40 units/kg/dose twice weekly (Malmö protocol; WFH [Srivastava 2013]) or 40 to 100 units/kg/dose 2 to 3 times weekly (National Hemophilia Foundation, MASAC recommendation, 2007); optimum regimen has yet to be defined.

Treatment:

2013 World Federation of Hemophilia Treatment Recommendations (When No Significant Resource Constraint Exists):

Site of Hemorrhage/Clinical Situation

Desired Factor IX Level to Maintain

Duration

Note: Factor IX level may either be expressed as units/dL or as %. Dosing frequency most commonly corresponds to the half-life of factor IX but should be determined based on an assessment of factor IX levels before the next dose.

Joint

40 to 60 units/dL

1 to 2 days, may be longer if response is inadequate

Superficial muscle/no neurovascular compromise

40 to 60 units/dL

2 to 3 days, sometimes longer if response is inadequate

Iliopsoas and deep muscle with neurovascular injury, or substantial blood loss

Initial: 60 to 80 units/dL

Maintenance: 30 to 60 units/dL

Initial: 1 to 2 days

Maintenance: 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy

CNS/head

Initial: 60 to 80 units/dL

Maintenance: 30 units/dL

Initial: 1 to 7 days

Maintenance: 8 to 21 days

Throat and neck

Initial: 60 to 80 units/dL

Maintenance: 30 units/dL

Initial: 1 to 7 days

Maintenance: 8 to 14 days

Gastrointestinal

Initial: 60 to 80 units/dL

Maintenance: 30 units/dL

Initial: 7 to 14 days

Maintenance: Not specified

Renal

40 units/dL

3 to 5 days

Deep laceration

40 units/dL

5 to 7 days

Surgery (major)

Preop: 60 to 80 units/dL

Postop:

40 to 60 units/dL

30 to 50 units/dL

20 to 40 units/dL

Postop:

1 to 3 days

4 to 6 days

7 to 14 days

Surgery (minor)

Preop: 50 to 80 units/dL

Postop: 30 to 80 units/dL

Postop: 1 to 5 days depending on procedure type

Table has been converted to the following text.

2013 World Federation of Hemophilia Treatment Recommendations (When No Significant Resource Constraint Exists):

Desired Factor IX Level to Maintain and Duration Based on Site of Hemorrhage/Clinical Situation:

Joint: 40 to 60 units/dL for 1 to 2 days, may be longer if response is inadequate

Superficial muscle (no neurovascular compromise): 40 to 60 units/dL for 2 to 3 days, sometimes longer if response is inadequate

Iliopsoas and deep muscle with neurovascular injury, or substantial blood loss: Initial: 60 to 80 units/dL for 1 to 2 days; Maintenance: 30 to 60 units/dL for 3 to 5 days, sometimes longer as secondary prophylaxis during physiotherapy

CNS/head: Initial: 60 to 80 units/dL for 1 to 7 days; Maintenance: 30 units/dL for 8 to 21 days

Throat and neck: Initial: 60 to 80 units/dL for 1 to 7 days; Maintenance: 30 units/dL for 8 to 14 days

Gastrointestinal: Initial: 60 to 80 units/dL for 7 to 14 days; Maintenance: 30 units/dL (duration not specified)

Renal: 40 units/dL for 3 to 5 days

Deep laceration: 40 units/dL for 5 to 7 days

Surgery (major): Preop: 60 to 80 units/dL; Postop: 40 to 60 units/dL for 1 to 3 days; then 30 to 50 units/dL for 4 to 6 days; then 20 to 40 units/dL for 7 to 14 days

Surgery (minor): Preop: 50 to 80 units/dL; Postop: 30 to 80 units/dL for 1 to 5 days depending on procedure type

Note: Factor IX level may either be expressed as units/dL or as %. Dosing frequency most commonly corresponds to the half-life of factor IX but should be determined based on an assessment of factor IX levels before the next dose.

Continuous infusion (for patients who require prolonged periods of treatment [eg, intracranial hemorrhage or surgery] to avoid peaks and troughs associated with intermittent infusions) (Batorova, 2002; Poon, 2012; Rickard, 1995; WFH [Srivastava 2013]): Following initial bolus to achieve the desired factor IX level: Initiate 4 to 6 units/kg/hour; adjust dose based on frequent factor assays and calculation of factor IX clearance at steady-state using the following equations:

Factor IX clearance (mL/kg/hour) = (current infusion rate in units/kg/hour) divided by (plasma level in units/mL)

New infusion rate (units/kg/hour) = (factor IX clearance in mL/kg/hour) x (desired plasma level in units/mL)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

NOTE: Contains nondetectable levels of factors II, VII, and X. Therefore, NOT INDICATED for replacement therapy of any other clotting factor besides factor IX or for reversal of anticoagulation due to either vitamin K antagonists or other anticoagulants (eg, dabigatran), for hemophilia A patients with factor VIII inhibitors, or for patients in a hemorrhagic state caused by reduced production of liver-dependent coagulation factors (eg, hepatitis, cirrhosis).

Control or prevention of bleeding in patients with factor IX deficiency (hemophilia B or Christmas disease): Infants, Children, and Adolescents: IV: AlphaNine SD, Mononine: Dosage is expressed in units of factor IX activity; dosing must be individualized based on severity of factor IX deficiency, extent and location of bleeding, and clinical status of patient. Refer to product information for specific manufacturer recommended dosing. Alternatively, the World Federation of Hemophilia (WFH) has recommended general dosing for factor IX products.

Formula to determine units required to obtain desired factor IX level: Note: If patient has severe hemophilia (ie, baseline factor IX level is or presumed to be <1%), then may just use “desired factor IX level” instead of “desired factor IX level increase”.

Number of factor IX units required = patient weight (in kg) x desired factor IX level increase (as % or units/dL) x 1 unit/kg

For example, to attain an 80% level in a 70 kg patient who has a baseline level of 20%: Number of factor IX units needed = 70 kg x 60% x 1 unit/kg = 4200 units

Alternative recommendations (off-label): Infants, Children, and Adolescents:

Prophylaxis, primary: Refer to adult dosing.

Treatment: Refer to adult dosing.

Reconstitution

Refer to instructions for individual products. Exact potency labeled on each vial. Diluent and factor IX should come to room temperature before combining.

Administration

Solution should be infused at room temperature.

IV administration only: Should be infused slowly over several minutes: Rate of administration should be determined by the response and comfort of the patient.

AlphaNine SD: Administer IV at a rate not exceeding 10 mL/minute

Mononine: Administer IV at a rate of ~2 mL/minute. Administration rates of up to 225 units/minute have been regularly tolerated without incident (when reconstituted as directed to ~100 units/mL).

World Federation of Hemophilia recommendations: Infuse by slow IV injection at a rate not to exceed 3 mL/minute (adults) or 100 units/minute (young children); may also administer as a continuous infusion in select patients. With patients who have anti-factor IX inhibitors who have had allergic reactions during factor IX infusion, administration of hydrocortisone prior to infusion may be necessary (WFH [Srivastava 2013]).

Storage

When stored at refrigerator temperature, 2°C to 8°C (36°F to 46°F), factor IX is stable for the period indicated by the expiration date on its label. Avoid freezing which may damage container for the diluent.

AlphaNine SD: May also be stored at room temperature not to exceed 30°C (86°F) for up to 1 month. Reconstituted solution should be used within 3 hours of preparation.

Mononine: May also be stored at room temperature not to exceed 25°C (77°F) for up to 1 month. Reconstituted solution should be at room temperature and used within 3 hours of preparation.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Frequency not defined.

Cardiovascular: Flushing, thrombosis

Central nervous system: Burning sensation (in jaw/skull), chills, headache, lethargy, paresthesia, rigors

Dermatologic: Skin photosensitivity, urticaria

Gastrointestinal: Diarrhea, nausea, vomiting

Hematologic & oncologic: Disseminated intravascular coagulation

Hepatic: Increased serum alkaline phosphatase, increased serum ALT, increased serum AST

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Local: Discomfort at injection site (stinging, burning), injection site reaction, pain at injection site

Neuromuscular & skeletal: Neck tightness

Ophthalmic: Visual disturbance

Respiratory: Allergic rhinitis, asthma, laryngeal edema, pulmonary disease

Miscellaneous: Fever (including transient fever following rapid administration)

<1% (Limited to important or life-threatening): Cerebral hemorrhage (intrathalamic [Douvas, 2004]), cyanosis, decreased therapeutic response, factor IX inhibitor development, hypotension, myocardial infarction (high doses), pulmonary embolism (high doses), superior vena cava syndrome (neonates [Douvas, 2004])

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: The development of factor IX antibodies (or inhibitors) has been reported with factor IX therapy (usually occurs within the first 10 to 20 exposure days); the risk of severe hypersensitivity reactions occurring may be greater in these patients. When clinical response is suboptimal, the patient has reached a specified number of exposure days, or patient is to undergo surgical procedure, screen for inhibitors. Patients with severe hemophilia compared to those with mild or moderate hemophilia are more likely to develop inhibitors (WFH [Srivastava 2013]).

• Hypersensitivity reactions: Hypersensitivity and anaphylactic reactions have been reported with use. Delayed reactions (up to 20 days after infusion) in previously untreated patients may also occur. Due to potential for allergic reactions, the initial ~10 to 20 administrations should be performed under appropriate medical supervision. Hypersensitivity reactions may be associated with factor IX inhibitor development; patients experiencing allergic reactions should be evaluated for factor IX inhibitors (WFH [Srivastava 2013]).

• Thrombotic events: Observe closely for signs or symptoms of intravascular coagulation or thrombosis; risk is generally associated with the use of factor IX complex concentrates (containing therapeutic amounts of additional factors); however, potential risk exists with use of factor IX products (containing only factor IX). Use with caution when administering to patients with liver disease, postoperatively, neonates, or patients at risk of thromboembolic phenomena, disseminated intravascular coagulation or patients with signs of fibrinolysis due to the potential risk of thromboembolic complications.

Disease-related concerns:

• Hepatic impairment: Use with extreme caution in patients with hepatic impairment due to the risk of thromboembolic complications.

Dosage form specific issues:

• Human plasma: Product of human plasma. Despite purification methods (AlphaNine SD - solvent detergent treated/virus filtered; Mononine - virus filtered); products may potentially contain infectious agents which could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Appropriate use: Contains nondetectable levels of factors II, VII, and X. Therefore, NOT INDICATED for replacement therapy of any other clotting factor besides factor IX. In addition, factor IX concentrate is NOT INDICATED for reversal of anticoagulation due to either vitamin K antagonists or other anticoagulants (eg, dabigatran), hemophilia A patients with factor VIII inhibitors, or patients in a hemorrhagic state caused by reduced production of liver-dependent coagulation factors (eg, hepatitis, cirrhosis).

• Clinical response: Response to factor IX administration may vary. If bleeding is not controlled with the recommended dose, determine plasma level of factor IX and follow with a sufficient dose to achieve satisfactory clinical response. If plasma levels of factor IX fail to increase as expected or bleeding continues, suspect the presence of an inhibitor; test as appropriate.

• Immune tolerance induction: Safety and efficacy have not been established in immune tolerance induction with factor IX products. Nephrotic syndrome has occurred following immune tolerance induction in patients with factor IX inhibitors and a history of allergic reactions to therapy.

Monitoring Parameters

Factor IX levels (measure 15 minutes after infusion to verify calculated doses) (WFH [Srivastava], 2013), aPTT, BP, HR, signs of hypersensitivity reactions; screen for factor IX inhibitors if the patient experiences hypersensitivity reaction or when patient is to undergo surgery, if suboptimal response to treatment occurs, if patient is being intensively treated for >5 days within 4 weeks of the last infusion, or at the following intervals (WFH [Srivastava], 2013):

Children: Screen for inhibitors every 5 exposure days until 20 exposure days, every 10 exposure days between 21 to 50 exposure days, and at a minimum of twice a year until 150 exposure days is reached.

Adults (with >150 exposure days apart from a 6 to 12 monthly review): Screen for inhibitors when suboptimal response occurs.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. Factor IX concentrations do not change significantly in pregnant women with coagulation disorders and women with factor IX deficiency may be at increased risk of postpartum hemorrhage. Pregnant women should have clotting factors monitored, particularly at 28 and 34 weeks gestation and prior to invasive procedures. Prophylaxis may be needed if factor IX concentrations are <50 units/mL at term and treatment should continue for 3 to 5 days postpartum depending on route of delivery. Because parvovirus infection may cause hydrops fetalis or fetal death, a recombinant product is preferred if prophylaxis or treatment is needed. The neonate may also be at an increased risk of bleeding following delivery and should be tested for the coagulation disorder (Chi, 2012; Kadir, 2009; Lee, 2006).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache; nausea; vomiting; flushing; loss of strength and energy; tingling; injection site burning, stinging, or redness; injection site irritation; or chills. Have patient report immediately to prescriber signs of parvovirus B19 or hepatitis A infection (chills, severe fatigue, rhinorrhea, rash, joint pain, lack of appetite, nausea, vomiting, abdominal pain, or jaundice), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), shortness of breath, severe dizziness, passing out, tachycardia, mouth discoloration, angina, or coughing up blood (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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