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Prothrombin Complex Concentrate (Human) [(Factors II, VII, IX, X), Protein C, and Protein S]

Pronunciation

(PRO throm bin KOM pleks KON cen trate HYU man FAK ters too SEV en nyne ten PROE teen cee & PROE teen ess)

Index Terms

  • 4 Factor PCC
  • 4-Factor PCC
  • Beriplex P/N
  • Confidex
  • Four-Factor PCC
  • PCC (Caution: Confusion-prone synonym)
  • Prothrombin Complex Concentrate (Caution: Confusion-prone synonym)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Kit, Intravenous [preservative free]:

Kcentra: ~500 units, ~1000 units [pyrogen free; contains albumin human, antithrombin iii (human), heparin]

Brand Names: U.S.

  • Kcentra

Pharmacologic Category

  • Blood Product Derivative
  • Hemostatic Agent
  • Prothrombin Complex Concentrate (PCC)

Pharmacology

Prothrombin complex concentrate provides an increase in the levels of the vitamin K-dependent coagulation factors (II, VII, IX, and X) with the addition of protein C and protein S. Coagulation factors II, IX, and X are part of the intrinsic coagulation pathway, while factor VII is part of the extrinsic coagulation pathway. In the extrinsic pathway, damaged blood vessels release endothelial tissue factor (TF) which complexes with factor VII to form TF-factor VIIa. Within the intrinsic pathway, factor IX is converted to IXa. Factor IXa (as well as TF-factor VIIa) converts factor X to factor Xa in the final common pathway of coagulation. Factor Xa activates prothrombin (factor II) into thrombin (IIa) which converts fibrinogen into fibrin resulting in clot formation. Proteins C and S are vitamin K-dependent inhibiting enzymes involved in regulating the coagulation process. Protein S serves as a cofactor for protein C which is converted to activated protein C (APC). APC is a serine protease which inactivates factors Va and VIIIa, limiting thrombotic formation.

Distribution

Vdss: Factor II: 71.4 mL/kg; Factor VII: 45 mL/kg; Factor IX: 114.3 mL/kg; Factor X: 55.5 mL/kg; Protein C: 62.2 mL/kg; Protein S: 78.8 mL/kg

Onset of Action

Rapid; significant INR decline within 10 minutes

Duration of Action

~6 to 8 hours

Half-Life Elimination

Factor II: 48 to 60 hours; Factor VII: 1.5 to 6 hours; Factor IX: 20 to 24 hours; Factor X: 24 to 48 hours; Protein C: 1.5 to 6 hours; Protein S: 24 to 48 hours

Note: Half-lives may be significantly reduced in severe hepatocellular damage, DIC, or extended catabolic metabolism.

Use: Labeled Indications

Bleeding, treatment and prophylaxis: Urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (VKA) (eg, warfarin) therapy in patients with acute major bleeding or a need for an urgent surgery/invasive procedure

Contraindications

Kcentra, Beriplex P/N [Canadian product]: Hypersensitivity (ie, anaphylaxis or severe systemic reaction) to prothrombin complex concentrate (PCC) or any component of the formulation including factors II, VII, IX, X, protein C and S, antithrombin III and human albumin; disseminated intravascular coagulation (DIC); known heparin-induced thrombocytopenia (product contains heparin).

Octaplex [Canadian product]: Hypersensitivity to prothrombin complex concentrate (PCC) or any component of the formulation; heparin-induced thrombocytopenia type II or known allergy to heparin (product contains heparin); non-life-threatening bleeding episodes in individuals with recent myocardial infarction, high risk of thrombosis, or angina pectoris; non-life-threatening bleeding episodes in individuals with untreated disseminated intravascular coagulation (DIC) who can be given fresh frozen plasma (FFP); coagulation disorders due to chronic liver disease or liver transplantation; bleeding associated with hepatic parenchyme disorders, esophageal varices, or major hepatic surgery; immunoglobulin A (IgA) deficiency, with known antibodies against IgA

Dosing: Adult

Note: Prothrombin complex concentrate (Human) [(Factors II, VII, IX, X), Protein C, Protein S] (Kcentra, Beriplex P/N [Canadian product], and Octaplex [Canadian product]) contains therapeutic levels of factor VII component and should not be confused with Factor IX complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) which contains low or nontherapeutic levels of factor VII.

Kcentra, Beriplex P/N [Canadian product]: Vitamin K antagonist (VKA) reversal in patients with acute major bleeding or need for an urgent surgery/invasive procedure: IV: Individualize dosing based on current pre-dose INR. Dosage is expressed in units of factor IX activity. Administer with vitamin K concurrently. Repeat dosing is not recommended (has not been studied).

Pretreatment INR: 2 to <4: Administer 25 units/kg; maximum dose: 2,500 units

Pretreatment INR: 4 to 6: Administer 35 units/kg; maximum dose: 3,500 units

Pretreatment INR: >6: Administer 50 units/kg; maximum dose: 5,000 units

Octaplex [Canadian product]: Bleeding/perioperative prophylaxis of bleeding during vitamin K antagonist therapy: Individualize dosing based on severity of disorder, extent and location of bleeding, and clinical status of patient. IV: Approximate doses required for normalization of INR (≤1.2 within 1 hour); dosage is expressed in units of factor IX activity:

Pretreatment INR: 2 to 2.5: Administer 22.5 to 32.5 units/kg; maximum dose: 3,000 units (or 120 mL)

Pretreatment INR: 2.5 to 3: Administer 32.5 to 40 units/kg; maximum dose: 3,000 units (or 120 mL)

Pretreatment INR: 3 to 3.5: Administer 40 to 47.5 units/kg; maximum dose: 3,000 units (or 120 mL)

Pretreatment INR: >3.5: Administer >47.5 units/kg; maximum dose: 3,000 units (or 120 mL)

With the correction of vitamin K antagonist-induced impairment of hemostasis in patients who have been treated concomitantly with an appropriate vitamin K dose, repeat dosing with PCC is usually not necessary.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Octaplex [Canadian product]: Adolescents ≥17 years: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Obesity

Kcentra, Beriplex [Canadian product]: In patients weighing >100 kg; do not exceed maximum dose recommended according to pretreatment INR.

Reconstitution

Kcentra, Beriplex P/N [Canadian product], or Octaplex [Canadian product]: Prior to reconstitution, allow diluent (SWFI) and prothrombin complex concentrate (PCC) vials to warm to room temperature. Aseptically push the plastic spike at the blue end of the Mix2Vial transfer set through the center of the stopper of the diluent vial. After carefully removing only the clear package from the Mix2Vial transfer set, invert the diluent vial with the transfer set still attached and push the plastic spike through the center of the stopper of PCC vial; diluent will automatically transfer. While still attached, gently swirl PCC vial to ensure product is dissolved; do not shake. Disconnect the 2 vials; contents of PCC vial are now available for removal by screwing a syringe onto the transfer set. Inject appropriate amount of air into vial, invert vial, and withdraw amount needed. Remove syringe from transfer set and attach an administration set to the syringe.

Note: Kcentra vials may contain differing amounts of factor IX units per vial. The exact amount of factor IX units in each vial should be used when calculating and preparing the total dose to be administered. Overdosage errors have occurred when the dose has been improperly calculated. (ISMP 2014)

Administration

Kcentra, Beriplex P/N [Canadian product]: IV: Administer at room temperature at a rate of 0.12 mL/kg/minute (~3 units/kg/minute); do not exceed 8.4 mL/minute (~210 units/minute). Do not allow blood to enter into syringe; since fibrin clot formation may occur.

Octaplex [Canadian product]: IV: Administer at a rate of 1 mL/minute initially, followed by 2 to 3 mL/minute. Reduce infusion rate or interrupt infusion if patient’s pulse rate increases significantly.

Compatibility

Do not introduce other medications into the same IV line.

Storage

Kcentra, Beriplex P/N [Canadian product]: Store at 2°C to 25°C (36°F to 77°F); do not freeze. Protect from light. Reconstituted product may be stored at 2°C to 25°C (36°F to 77°F) and used within 4 hours (Kcentra) or 3 hours (Beriplex P/N) following reconstitution. If cooled, warm to 20°C to 25°C (68°F to 77°F) prior to administration.

Octaplex [Canadian product]: Store at 2°C to 25°C (36°F to 77°F); do not freeze. Protect from light. Reconstituted solution should be administered immediately, but may be stored for up to 8 hours at 2°C to 25°C (36°F to 77°F) if sterility is maintained.

Test Interactions

aPTT (formulation contains heparin)

Adverse Reactions

1% to 10%:

Cardiovascular: Hypotension (5% to 7%), tachycardia (3% to 5%), atrial fibrillation (4%), hypertension (1% to 3%), pulmonary embolism (≤2%), pulmonary edema (2%), cerebrovascular accident (1% to 2%), arteriovenous fistula site complication (clot, ≤1%), chest pain (1%), deep vein thrombosis (1%), venous thrombosis (calf, 1%; radial vein: ≤1%), thrombosis (microthrombosis of toes, ≤1%)

Central nervous system: Headache (1% to 8%), insomnia (1% to 5%), intracranial hemorrhage (3%), mental status changes (3%)

Endocrine & metabolic: Hypervolemia (1% to 6%), hypokalemia (2% to 5%)

Gastrointestinal: Nausea and vomiting (4% to 6%), constipation (2%), diarrhea (2%)

Hematologic and oncologic: Anemia (3% to 6%), prolonged bleeding time (skin laceration, contusion, subcutaneous hematoma, 4%)

Hepatic: Increased serum transaminases (1%)

Immunologic: Antibody development (parvovirus B19 seropositive, 3%)

Local: Burning sensation at injection site (1%)

Neuromuscular & skeletal: Arthralgia (4%)

Respiratory: Pleural effusion (4%), respiratory distress (2% to 4%), rales (1%)

Postmarketing and/or case reports (Limited to important or life-threatening): Angioedema, arterial thrombosis, bronchospasm, disseminated intravascular coagulation, hypersensitivity reaction, myocardial infarction, peripheral ischemia, thromboembolic complications, thrombosis, transient ischemic attacks, venous insufficiency

ALERT: U.S. Boxed Warning

Arterial and venous thromboembolic complications:

Patients being treated with vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Weigh potential benefits of reversing vitamin K antagonist against the potential risks of thromboembolic events, especially in patients with history of a thromboembolic event. Carefully consider resumption of anticoagulation as soon as the risk of thromboembolic events outweighs the risk of acute bleeding.

Both fatal and nonfatal arterial and venous thromboembolic complications have been reported with prothrombin complex concentrate in clinical trials and postmarketing surveillance. Monitor patients receiving prothrombin complex concentrate for signs and symptoms of thromboembolic events.

Prothrombin complex concentrate was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Prothrombin complex concentrate may not be suitable in patients with thromboembolic events in the prior 3 months.

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: Octaplex [Canadian product]: Development of antibodies to one or more of the human prothrombin factors may occur rarely resulting in an inadequate clinical response; monitor for signs of antibody formation.

• Hypersensitivity reactions: Hypersensitivity reaction (eg, angioedema, bronchospasm, dyspnea, flushing, hypotension, nausea/vomiting, pulmonary edema, urticaria, tachycardia, tachypnea) may occur; if serious reaction occurs, discontinue administration and begin appropriate treatment. Since severe hypersensitivity and anaphylactic reactions may rarely occur with use; immediate medical treatment (including epinephrine 1 mg/mL) should be readily available in the event of a severe reaction. May consider prophylactic treatment (eg, antihistamines, glucocorticoids) in patients predisposed to allergies.

• Thromboembolic events: [US Boxed Warning]: Because patients being treated with vitamin K antagonist (VKA) therapy have an underlying risk of or a diagnosed thromboembolic disease state, administration of prothrombin complex concentrate (PCC) may predispose the patient to a thromboembolic complication. Benefits of reversing VKA therapy should be weighed against the potential risk of a thromboembolic event. Resumption of anticoagulation should occur once the risk of thromboembolism outweighs the risk of acute bleeding. Fatal and nonfatal arterial and venous thromboembolic complications and DIC have been reported; closely monitor for thromboembolic events during and after administration. Use has not been evaluated in patients who have experienced a thromboembolic event, MI, DIC, CVA, TIA, unstable angina, or severe peripheral vascular disease within the prior 3 months.

Disease-related concerns:

• Chronic liver disease or transplantation: Octaplex [Canadian product] labeling recommends monitoring antithrombin (AT) levels in patients being treated for bleeding as a result of chronic liver disease or liver transplantation. If AT levels are deficient, AT should be administered concomitantly with PCC. No clinical data are available for use of PCC to treat bleeding due to liver parenchyme disorders, major liver surgery, or esophageal varices; use of PCC for these indications is contraindicated and the preferred method of treatment is fresh frozen plasma (FFP).

• Hypercoagulopathy: Administration of PCC may exacerbate underlying hypercoagulable states in recipients of vitamin K antagonists.

Dosage form specific issues:

• Heparin: Formulations contain heparin.

• Human plasma: Product of human plasma; 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. Hepatitis B vaccination is recommended for all patients. Beriplex P/N and Octaplex [Canadian products] labeling recommends consideration of hepatitis A and hepatitis B vaccination for all patients receiving regular/repeated administration of human plasma-derived prothrombin complex products.

Other warnings/precautions:

• Appropriate use: Prothrombin complex concentrate (Human) [(Factors II, VII, IX, X), Protein C, Protein S] (Kcentra, Beriplex P/N [Canadian product], and Octaplex [Canadian product]) contains therapeutic levels of factor VII component and should not be confused with Factor IX complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) which contains low or nontherapeutic levels of factor VII.

• Coagulation factor deficiency: Hepatic synthesis of the prothrombin complex (Factors II, VII, IX and X) coagulation factors is vitamin K dependent. Severe hepatic dysfunction, inadequate absorption of vitamin K (eg, pancreatic disorders, diarrhea) or vitamin K antagonist therapy or overdose may lead to coagulation factor deficiencies. In patients with an acquired deficiency of the vitamin K dependent coagulation factors, administer PCC only if a rapid correction (eg, emergency surgery, major bleeding) is necessary. If not indicated and caused by Vitamin K antagonist therapy, coagulation factor deficiencies may be managed by reducing or discontinuing therapy of the vitamin K antagonist and/or administration of vitamin K.

Monitoring Parameters

Kcentra: INR (baseline and at 30 minutes post dose); clinical response during and after treatment; signs of thromboembolism

Octaplex [Canadian product]: Coagulation factor assays, protein C, protein S, aPTT, PT, INR, CBC, AT, D-dimer, fibrinogen; development of circulating coagulation factor antibodies (inhibitors); heart rate (before and during administration)

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. Parvovirus B19 or hepatitis A, which may be present in plasma-derived products, may affect a pregnant woman more seriously than a nonpregnant woman.

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?)

• Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), flushing, tachycardia, anxiety, severe nausea, vomiting, severe dizziness, passing out, fast breathing, severe headache, angina, shortness of breath, coughing up blood, illogical thinking, burning or numbness feeling, or abdominal edema (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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