Anti-inhibitor Coagulant Complex (Systemic)


VA CLASSIFICATION
Primary: BL116

Commonly used brand name(s): Autoplex T; FEIBA VH.

Another commonly used name is
activated prothrombin complex concentrate (APCC) .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihemorrhagic—

Indications

General considerations
The anti-inhibitor coagulant complex (AICC) concentrates and the factor IX complex concentrates (prothrombin complex concentrates [PCCs]) are used in the treatment of hemorrhagic disorders associated with inhibitors (alloantibodies or autoantibodies) to specific coagulation factors {01}. The use of AICC and PCCs is also referred to as bypass therapy, as the products are thought to bypass the need for factors VIII or IX for clot formation {02}. The AICC concentrates are essentially PCCs that have undergone an in vitro activation during manufacturing, resulting in an increased content of activated and precursor vitamin K-dependent clotting factors {02} {03} {04} {05}.

In general, AICC or PCC concentrates are used in patients with high factor VIII inhibitor titers (> 10 Bethesda units [BU]) and who are classified as high responders (individuals in whom administration of factor VIII results in a marked increase in the inhibitor level) {01} {02} {12}. Single doses of either agent are effective in treating bleeding episodes in these patients in about 50% of the cases {06} {07} {09}. Double-blind studies comparing activated PCCs to their nonactivated counterparts have shown activated PCCs to be not significantly different to only marginally more effective than nonactivated PCCs {06} {07}.

Accepted

Hemorrhagic complications in hemophilic patients with factor VIII or factor IX inhibitors (prophylaxis and treatment)—AICC is indicated for use in hemophilic patients with inhibitors who are bleeding or are to undergo surgery {03} {04} {05} {06} {09} {10} {11}.

Hemorrhagic complications in non-hemophilic patients with acquired inhibitors (prophylaxis and treatment)—AICC has been used in a few non-hemophilic patients with acquired inhibitors to factors VIII, XI, and XII {03} {04} {13} {14}.

Unaccepted
AICC is not to be used for the treatment of bleeding episodes in patients with coagulation factor deficiencies who do not have inhibitors {03} {04} {05}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Anti-inhibitor coagulant complex (AICC) is a sterile, dried concentrate prepared from pooled human Source Plasma and/or Plasma {03} {04} {05}. The product is heat-treated as a method of viral inactivation. Autoplex T is dry-heated for 144 hours at 60 °C (140 °F), while FEIBA VH undergoes vapor-heating for 10 hours at 60 °C (140 °F) with an excess pressure of 190 ± 20 millibars, followed by 1 hour at 80 °C (176 °F) with an excess pressure of 370 ± 30 millibars. {03} {04} {05}


Composition
    AICC contains variable amounts of activated and precursor vitamin K-dependent clotting factors (factors II, VII, IX, and X) {03} {04} {05}. Traces of factors of the kinin generating system are also present {03} {04} {05}. In addition, there are variable amounts of factor VIII coagulant antigen (FVIIIC:Ag), which may result in an anamnestic response to the product {03} {04} {05} {15}. AICC is standardized by its ability to correct the clotting time of factor VIII–deficient plasma or factor VIII inhibitor plasma {05}.

Mechanism of action/Effect:

The exact mechanism of action of AICC is unknown, although it may be related to one or more of the active clotting factors and their ability to bypass the factor VIII inhibitor {01} {08} {10} {11}. In vitro experiments suggest the possibility of a factor Xa–like substance; or a complex of FVIIIC:Ag, factor IXa, and phospholipid as the active principle, which is only minimally inhibited by an inhibitor {16} {17} {18}.


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans.

Studies have not been done in animals.

FDA Pregnancy Category C. {03} {04} {05}

Breast-feeding

It is not known whether the proteins present in coagulation factor concentrates are distributed into breast milk. However, distribution into breast milk would be highly unlikely because of the large size of the protein molecules. {19}

Pediatrics

Studies performed in which patients as young as 3 years of age were included have not demonstrated pediatrics-specific problems that would limit the usefulness of anti-inhibitor coagulant complex (AICC) in children {06} {09} {10} {11} {15}. However, premature infants and neonates may be at increased risk for developing thrombotic complications, and may experience higher morbidity and mortality associated with hepatitis acquired from contaminated concentrates {05} {20}.


Geriatrics


Appropriate studies on the relationship of age to the effects of AICC have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected.


Dental

AICC has been used successfully in patients with inhibitors who have had bleeding in the oral cavity (both surgical and nonsurgical in origin) {09} {10} {11}. 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 experiencing other oral bleeding {02}. However, care should be taken, as systemic use of antifibrinolytic agents may potentiate the thrombogenic effects of the concentrate {21}. Using the antifibrinolytic agent as an oral rinse, or delaying its use for 8 to 12 hours after administration of AICC, may minimize this complication {03} {04} {21}.

Surgical

AICC has been used successfully for the control of hemostasis in patients with inhibitors who are undergoing surgical procedures {09} {10}. However, it should be used cautiously, as the risk of thrombotic complications is increased in surgical patients who receive large, repeated doses of factor IX complex or who have significant hepatic dysfunction {01} {22}.

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 excessive bleeding in hemophilic patients undergoing tooth extractions or experiencing other oral bleeding, systemic use of antifibrinolytic agents may potentiate the thrombogenic effects of the concentrate; using the antifibrinolytic agent as an oral rinse, or delaying its use for 8 to 12 hours after administration of AICC, may minimize this complication)

{03}{04}{21}
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){03}{04}{05}{09} or
» Hyperfibrinolytic states{03}{04}{05}{09} or
» Thromboembolism, history of{09}{10}{23}    (risk of thrombotic complications)


Risk-benefit should be considered when the following medical problems exist
Crush injuries{23} or
Hepatic function impairment, severe{06}{07}{09}{10}{23} or
Surgery{23}    (risk of thrombotic complications)


Sensitivity to anti-inhibitor coagulant complex{09}{10}

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):


Note: Laboratory tests to monitor the effectiveness of factor replacement, such as the activated partial thromboplastin time (APTT), do not correlate with clinical improvement; therefore, response should be based on the patient's condition {02} {03} {04} {05}. Attempts to normalize laboratory values by increasing the dose of anti-inhibitor coagulant complex may result in DIC {03} {04}.

Coagulation tests, such as
Activated partial thromboplastin time (APTT)
D-dimer{29}
Fibrin/fibrinogen degradation products (FDPs)
Fibrinogen concentration
Prothrombin time (PT)
Thrombin time (TT) and
Platelet count    (used to confirm the presence of DIC following the occurrence of clinical signs of intravascular coagulation; severe DIC is indicated by absolute decreases in fibrinogen and platelet count, the presence of FDPs, an increased D-dimer, and significantly prolonged APTT, PT, and TT)

{03}{04}{05}{29}
» Observation for signs and symptoms of allergic reactions{03}{04}{05}
» Symptoms of thrombotic complications, such as chest pain, cough, and respiratory distress and
» Vital signs, such as blood pressure, pulse, and respiratory rate    (changes in blood pressure, pulse rate, and respiration, along with chest pain and cough, may be indicative of intravascular coagulation; also, hypotension may occur following infusion)

{03}{04}{05}


Side/Adverse Effects

Note: Anti-inhibitor coagulant complex (AICC) is prepared from pooled human plasma, which may contain the causative agents of hepatitis, human immunodeficiency virus (HIV) infection, and other viral diseases {03} {04} {05}. Improved donor screening and treatment of concentrates with viral inactivation procedures have greatly reduced the risk of transmission of HIV infection or hepatitis. However, the risk of virus transmission cannot be totally eliminated and, therefore, some patients may develop these viral infections {03} {04} {05}.
Anamnestic responses with a rise in factor VIII inhibitor titers have been observed in up to 20% of cases following treatment with AICC {03} {04} {05} {10} {15} {24}. These responses are more likely to occur in patients who have a low inhibitor titer at the time of treatment and have a marked increase in inhibitor level following factor VIII exposure, and in those patients treated with AICC over several days {15} {24}.

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 (DIC){03}{04}{05}{25} (cyanosis [bluish coloring], especially of the hands and feet; ecchymoses at injection sites [large, nonelevated blue or purplish patches in the skin]; persistent bleeding or oozing from puncture sites or mucous membranes [bowel, mouth, nose, or urinary bladder])
    
myocardial infarction{03}{04}{26}{27} (anxiety; cold sweating; dizziness, lightheadedness, or fainting; increased heart rate; nausea or vomiting; severe pain or pressure in the chest and/or the jaw, neck, back, or arms; shortness of breath)
    
thrombosis or thromboembolism{03}{04}{28} (pain in chest, groin, or legs [especially calves]; rapid breathing; 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

Note: The risk of thrombotic complications, DIC, and myocardial infarction is increased with the use of large, repetitive doses, especially following orthopedic surgical procedures, crush injuries, or for large, intramuscular hemorrhages. Significant hepatic function impairment also increases the risk. {22} {23}


Incidence less frequent
    
Allergic reaction{03}{04}{05} (changes in facial skin color; chills; fast or irregular breathing; fever; 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
    
hypotension{05} (feeling faint; lightheadedness)—occurs with too rapid an injection rate; also, with Autoplex T, may occur if the infusion is done later than 1 hour following reconstitution
    
injection reaction{05} (changes in blood pressure or pulse rate; flushing [redness of face]; headache)—occurs with too rapid an injection rate





General Dosing Information
Before initiating treatment with anti-inhibitor coagulant complex (AICC), it is essential to demonstrate the presence of circulating inhibitors to one or more coagulation factors {03} {04} {05}.

AICC is administered by intravenous injection through a syringe, or as an intravenous drip infusion {03} {04} {05}.

For treatment of adverse effects
Recommended treatment consists of the following:
   • Hypotension and injection reactions (particularly, headache)—Stop the infusion to allow the symptoms to disappear; the infusion may be resumed at a slower rate in all but the most reactive individuals {05}.
   • Allergic reactions—The administration of AICC should be discontinued and the patient should be treated as appropriate with antihistamines and corticosteroids {03} {04}.


Parenteral Dosage Forms

ANTI-INHIBITOR COAGULANT COMPLEX

Note: A unit of FEIBA VH is expressed as factor VIII inhibitor bypassing activity and is not equivalent to a unit of Autoplex T, which is expressed as factor VIII correctional units. However, the recommended dose is the same, regardless of the product used. {03} {04} {05} {12} {28}
Autoplex T should be infused initially at a rate of 2 mL per minute. If this infusion rate is well tolerated, the rate may be gradually increased to 10 mL per minute. {05} For FEIBA VH, the maximum infusion rate must not exceed 2 units per kilogram of body weight (units/kg) per minute. For a patient weighing 75 kg, this corresponds to an infusion rate of 2.5 to 7.5 mL per minute, depending on the number of units per vial. {03} {04}


Usual adult and adolescent dose
Prevention and control of bleeding in patients with inhibitors to one or more coagulation factors
Intravenous, 75 units per kg of body weight {12} {28}. A single dose may be sufficient, but additional doses, six or twelve hours apart, may be given depending on the patient's clinical response {03} {04} {05} {06} {09}.


Usual adult and adolescent prescribing limits
Single doses greater than 100 units per kg, and daily doses greater than 200 units per kg are not recommended. Higher doses and/or prolonged administration increase the risk of the development of thrombotic complications. {03} {04}

Usual pediatric dose
See Usual adult and adolescent dose .

Usual pediatric prescribing limits
See Usual adult and adolescent prescribing limits .

Strength(s) usually available
U.S.—


Each bottle is labeled with the number of units it contains, with sterile water for injection provided as diluent (Rx) [Autoplex T (heparin £ 2 USP units per mL) (sodium 177 ± 15 mEq per liter)] [FEIBA VH (sodium 183 mEq per liter)]

Canada—


Each bottle is labeled with the number of units it contains, with sterile water for injection provided as diluent (Rx) [FEIBA VH (sodium 183 mEq per liter)]

Packaging and storage:
Store the dried concentrates between 2 and 8 °C (36 and 46 °F). The solution should not be refrigerated after reconstitution. The diluent should be protected from freezing. {03} {04} {05}

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. The reconstituted solution should be approximately at room temperature at the time of administration. {03} {04} {05}

Note: Some clinicians recommend adding heparin to the reconstituted concentrate (5 to 10 USP units per mL) as a way to prevent thrombotic complications when anti-inhibitor coagulant complex is used in high, repeated doses {29} {30}.


Stability:
Administration should begin as soon as practical following reconstitution; however, it must be completed within 1 hour for Autoplex T, and within 3 hours for FEIBA VH {03} {04} {05}.



Developed: 03/24/1998



References
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  1. FEIBA VH IMMUNO package insert (IMMUNO-U.S.—US), Rev 12/93, Rec 8/96.
  1. FEIBA VH IMMUNO package insert (IMMUNO-Canada—Canada), Rev 12/93, Rec 8/96.
  1. Autoplex T package insert (Baxter—US), Rev 1/88, Rec 10/95.
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  1. Panel comment, 7/97.
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