RECOTHROM

Thrombin is a hemostatic agent. It is a component of the clotting cascade and is known as factor IIa. Thrombin is derived from prothrombin, an alpha-2-globulin produced by the liver. Bovine and recombinant thrombin are commercially available. Potency of the thrombin products is measured in terms of the amount of thrombin required to form a clot. Solutions of different strengths may be prepared for use, depending on the severity of bleeding. Topical thrombin is used during surgery to control incisional or surgical bleeding. Thrombin is increasingly being used off-label to treat post-catheterization pseudoaneurysms; when used for this indication, thrombin is administered intravascularly, directly into the pseudoaneurysm via ultrasound-guided percutaneous injection. Most data regarding the use of thrombin intravascularly involve pseudoaneurysms of the femoral artery; however, successful thromboses have been demonstrated in many other anatomical locations including the abdominal aorta, brachial artery, epigastric artery, hepatic artery, radial artery, subclavian artery, and superior mesenteric artery. The use of thrombin for pseudoaneurysms is gaining popularity because it is less invasive than surgery and more successful than other less invasive modalities, such as ultrasound-guided compression; the success rate of thrombin for the treatment of pseudoaneurysms of the femoral artery is more than 90%, with some reports indicating an even higher rate of more than 97%. In addition, thrombin is effective in anticoagulated patients, unlike ultrasound-guided compression. Furthermore, the complication rates, including thromboembolism and hypersensitivity reactions, have been reported to be 4% or lower.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
Other Injectable Administration
Percutaneous Administration
-Thrombin is not FDA-approved for percutaneous administration.
-Thrombin has been administered intravascularly as a solution directly into pseudoaneurysms under ultrasound guidance via a percutaneous injection. NOTE: Thrombin is not FDA-approved for the treatment of pseudoaneurysms.
-In patients with a history of previous exposure to thrombin (topical or intravascular), a skin-prick test for hypersensitivity to thrombin using a 1,000 unit/mL concentration may be prudent. Wait 15 minutes after the skin-prick test to identify a test as negative if the wheal diameter is less than 4 mm with a flare diameter of less than 15 mm.

Reconstitution and Preparation for Percutaneous use:
-Reconstitute the thrombin to a concentration of 1,000 units/mL or 100 units/mL using sterile isotonic saline or the diluent provided prior to percutaneous puncture of the patient. For intravascular administration, aseptic techniques should be practiced. Some authors recommend the more dilute concentration in an effort to minimize the risk of thromboembolism in case of inadvertent systemic exposure.
-The thrombin can be drawn into sterile syringes as smaller aliquots (i.e., into 1 mL syringes) for ease of administration and to minimize the risk of administering more thrombin than desired. In children, using a smaller syringe such as a tuberculin syringe has been recommended.

Percutaneous injection:
-Monitor pulses and ankle-brachial index (if applicable) distal to the site of injection prior to the procedure.
-Prior to injection, visualize the pseudoaneurysm and assess for size, location, and the presence of arteriovenous fistulas or septations/loculations.
-Local anesthesia may be applied to the skin prior to percutaneous injection, although this is not necessary.
-Under direct visualization, percutaneously inject a 19 to 25 gauge, 2.5-inch needle into the sac of the pseudoaneurysm; confirmation of the tip of the needle within the pseudoaneurysm is essential prior to injection of thrombin. Position the needle away from the neck of the pseudoaneurysm to minimize the risk of systemic exposure.
-Under direct visualization with either a grey-scale or color-flow ultrasound, slowly and continuously inject the thrombin, usually over 10 seconds, into the pseudoaneurysm until flow ceases. Use the smallest dose necessary. If there is still flow within the pseudoaneurysm after the first dose, repeat the injection until all flow is absent. Do not inject thrombin into the neck of the pseudoaneurysm as this greatly increases the risk of thromboembolism.
-Monitor peripheral pulses distal to the site of injection as well as the ankle-brachial index after the procedure for detection of a thromboembolism.
-After the procedure, place the patient on bed rest for 4 to 6 hours.
-Perform an ultrasound confirming successful thrombosis at 24 hours and 7 to 10 days after the procedure.



Topical Administration
-For topical use on the surface of bleeding tissue only. Do NOT inject.
-Bovine thrombin is administered topically either as a solution or pad. The powder for solution can be used in a dry form on oozing surfaces.
-Recombinant thrombin (Recothrom) is administered topically as a solution.

Preparation of bovine topical solution:
-Reconstitute with sterile isotonic saline at a recommended concentration of 1,000 to 2,000 International Units/mL.
-Prepare the desired strength to suit the needs of the case by diluting the contents of the container with an appropriate volume of sterile isotonic saline. A concentration of 1,000 International Units/mL may be required where bleeding is profuse. A concentration of 100 International Units/mL is frequently used for plastic surgery, dental extractions, skin grafting, etc.
-Storage: Use solutions promptly upon removal from the container; however, the solution may be refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours or stored at room temperature for up to 8 hours after reconstitution.

Preparation of Recothrom 5,000 units topical solution:
-Insert the sharp end of the needle-free transfer device into the center of the vial stopper.
-Attach the prefilled diluent syringe to the needle-free transfer device.
-Inject the 5 mL of diluent from the syringe into the product vial; keep the syringe plunger depressed.
-Remove and discard the diluent syringe; do not use the diluent syringe for transfer of reconstituted product.
-Gently swirl and invert the vial until the powder is completely dissolved; avoid excessive agitation. The powder should dissolve in less than 1 minute at room temperature.
-Attach the empty syringe (provided) to the needle free transfer device and draw up the necessary amount of solution required for application.
-Label the syringe 'RECOTHROM - DO NOT INJECT'.

Preparation of Recothrom 20,000 units topical solution:
-Attach a needle-free transfer device to both the Recothrom and diluent vials.
-Open the sterile, empty 20 mL syringe package and apply the pre-printed "DO NOT INJECT" label to the syringe.
-Attach the labeled 20 mL syringe to the needle-free transfer device on the diluent vial (injection of air into the diluent vial may facilitate withdrawal of the diluent).
-Draw up 20 mL of diluent from the vial into the syringe. Remove the diluent-filled syringe from the diluent vial and attach it to the transfer device on the Recothrom vial.
-Transfer the 20 mL of diluent from the syringe into the Recothrom vial; the vacuum in the vial facilitates transfer.
-Leave the syringe attached and gently swirl and invert the Recothrom vial until the powder is completely dissolved. Avoid excessive agitation. The powder should dissolve in less than 1 minute at room temperature.
-With the same syringe, draw up the Recothrom solution.

Topical application:
-Sponge (not wipe) the surface to which thrombin is to be applied free of blood prior to thrombin application.
-Apply thrombin directly to the bleeding site surface or in conjunction with absorbable gelatin sponge. The amount required depends upon the area of tissue to be treated and the method of application.
-A spray may be used, or the surface may be flooded using a sterile syringe and small gauge needle. The most effective hemostasis occurs when the thrombin mixes freely with the blood as soon as it reaches the surface.
-Avoid sponging the treated surface to assure the clot remains securely in place.
-When using an absorbable gelatin sponge, immerse sponge strips of the desired size into the solution to completely saturate the sponge. Knead the sponge strips vigorously with moistened, gloves fingers to remove trapped air. Remove the sponge and gently squeeze to remove excess thrombin solution. Apply to sponge to the bleeding site in a single layer. Hold in place with a pledget of cotton or small gauze sponge until hemostasis occurs.

Topical thrombin can cause thrombosis if it enters the circulatory system. Thromboembolism has been reported in 5% to 6% of surgical patients receiving topical thrombin during clinical trials. Rarely thromboembolism causing extremity ischemia distal to the site of injection has been reported after intravascular injection of thrombin; take care to avoid entry of thrombin to areas outside of the pseudoaneurysm. Monitor peripheral pulses and ankle-brachial index before and after intravascular injection; changes in these parameters post-injection may indicate thromboembolism. If ischemic thromboembolism occurs, administer intra-arterial thrombolytics; some minor thromboembolisms may resolve without intervention. The data regarding the use of intravascular thrombin in children is limited; successful thrombosis of the brachial, femoral, and epigastric arteries has been reported. In contrast, thromboembolism of the brachial artery requiring an emergent thrombectomy occurred in a 10-month old infant; the authors postulate that the small size of the underlying artery may have played a role in thromboembolism for this patient.

Bleeding has been reported in 11% of patients receiving either recombinant or bovine topical thrombin during clinical trials. Anemia and thrombocytopenia were reported in 2% or more of patients receiving the bovine product. Prolonged prothrombin time (PT), prolonged activated partial thromboplastin time (aPTT), disseminated intravascular coagulation (DIC), factor V deficiency, and post-procedural hematoma have been reported with postmarketing use of the bovine product. Bleeding and alterations in laboratory values may be associated with the formation of antibodies against bovine thrombin and/or factor V. Additionally, unspecified cardiac adverse events occurred in 18% of patients receiving either recombinant or bovine topical thrombin during clinical trials; sinus tachycardia and hypotension were reported in 2% or more of patients receiving the bovine product.

The use of topical bovine thrombin preparations has occasionally been associated with abnormalities in hemostasis ranging from asymptomatic alterations in laboratory parameters to severe bleeding or thrombosis that have sometimes been fatal. These abnormalities appear to be related to antibody formation against bovine thrombin and/or factor V/Va, which in some cases may react to human factor V possibly resulting in factor V deficiency. Baseline elevated antibody concentrations to bovine coagulation proteins have been observed most frequently in persons with a prior history of a surgical procedure frequently associated with bovine thrombin use. In a clinical trial comparing recombinant human thrombin to bovine thrombin, 5% of subjects were positive for anti-bovine thrombin antibodies at baseline and 21.5% of subjects were positive for anti-bovine thrombin antibodies after treatment. The seroconversion rate in the bovine thrombin group was 18.4%. In an additional clinical trial comparing plasma-derived human thrombin to bovine thrombin, 12.7% of bovine thrombin-treated subjects demonstrated seroconversion for at least 1 of 4 antibodies assayed. Anti-bovine thrombin antibodies developed in 7.94% of subjects; anti-bovine factor V/Va antibodies developed in 9.52% of subjects, and anti-human thrombin antibodies developed in 2.38% of subjects. Low level titers of antibodies to bovine factor V were reported in 3.2% of subjects receiving bovine thrombin in another clinical trial comparing human thrombin to bovine thrombin. In studies with recombinant thrombin, antibody formation to the recombinant product was 1.5% or less; however, none of the antibodies were neutralizing. Monitor for abnormal coagulation parameters, bleeding, and thrombosis. Do not reexpose persons with antibodies to bovine thrombin to these products.

Hypersensitivity, including anaphylactoid reactions/anaphylaxis, have been reported after administration of topical thrombin. If an allergic reaction occurs, institute intensive supportive measures and treat individual symptoms. In clinical trials comparing recombinant and bovine topical thrombin, 17% of subjects in both treatment groups reported a hypersensitivity reaction. Pruritus was reported in more than 5% of subjects treated with human or bovine thrombin. Generalized urticaria and anaphylactoid reactions have been reported after intravascularly administered thrombin. An anaphylactoid reaction after intravascular thrombin was reported in a single subject who had end-stage renal disease and had been repeatedly exposed to topical thrombin. Because bovine thrombin is highly immunogenic, it may be prudent to test persons with a prior history of exposure to thrombin (topical or intravascular) for hypersensitivity via a skin prick test prior to intravascular thrombin administration.

An injection site reaction, including cellulitis or abscess formation, has also been reported after intravascular use of thrombin.

Postoperative wound infection (10%) and other infections (15%) were reported in both treatment groups in clinical trials comparing recombinant and bovine topical thrombin. Pyrexia or fever was reported in 2% or more of patients receiving the bovine product. Swelling and Staphylococcal wound infection have been reported with postmarketing use of the bovine topical product.

Insomnia was reported in more than 5% of subjects receiving human or bovine topical thrombin in a clinical trial.

Constipation, nausea, and vomiting were reported in more than 5% of subjects receiving human or bovine topical thrombin in a clinical trial.

Muscle cramps (spasms) and procedural pain were reported in more than 5% of subjects receiving human or bovine topical thrombin in a clinical trial.

Do not use thrombin to treat severe or brisk arterial bleeding. The use of topical thrombin preparations has resulted in fatal severe bleeding and thromboembolism. Monitor patients for abnormal coagulation parameters, bleeding, or thrombosis. Topical bovine thrombin preparations have occasionally been associated with abnormalities in hemostasis ranging from asymptomatic alterations in laboratory determinations, including the prothrombin time (PT) and activated partial thromboplastin time (aPTT), to severe bleeding or thromboembolism. These hemostatic effects appear to be related to the formation of antibodies against bovine thrombin and/or factor V, which in some cases may cross-react with human factor V, potentially resulting in factor V deficiency. Do not reexpose patients to bovine thrombin if there are known or suspected antibodies to bovine thrombin and/or factor V due to the potential for antibodies to interfere with hemostasis.

When used topically for hemostasis, thrombin is contraindicated for parenteral administration (including intravenous administration). Thrombosis, sometimes fatal, may occur if thrombin enters the circulatory system. Thrombin is increasingly being used off-label as an intravascular injection to thrombose pseudoaneurysms via ultrasound-guided percutaneous injection; thrombin is injected directly into the pseudoaneurysm. Take care to administer thrombin only into the pseudoaneurysm and to avoid systemic accidental exposure; thromboembolism with extremity ischemia has been reported after percutaneous injection of thrombin into pseudoaneurysms. Mechanisms to prevent systemic exposure and to therefore thromboembolism include minimizing the thrombin injection volume and injecting the thrombin away from the neck of the pseudoaneurysm. Some authors advocate using a more dilute concentration of 100 units/mL to minimize the amount of thrombin available systemically should accidental exposure occur.

Do not use thrombin in patients with a hypersensitivity to thrombin or any components of the specific product. Recombinant thrombin is contraindicated in patients with a known hamster protein hypersensitivity; this product is produced in a genetically modified Chinese Hamster Ovary cell line and may contain hamster or snake proteins. Bovine-derived thrombin is contraindicated in patients with a known bovine protein hypersensitivity. Hypersensitivity reactions, including anaphylactoid reactions, have been reported after topical application and percutaneous injection of thrombin in the treatment of pseudoaneurysms. The risk of such reactions may be higher in those patients previously exposed to thrombin (topically or via intravascular injection). In those patients with a history of previous exposure, a skin-prick test to rule out hypersensitivity prior to intravascular injection is recommended.

The use of intravascular thrombin off-label for the treatment of pseudoaneurysms has not been extensively studied in children or infants. In one report, thromboembolism and ischemia of the brachial artery requiring immediate thrombectomy occurred in a 10-month old infant. It is thought that the small size of the underlying artery may have played a role in the thrombotic event. However, successful treatment of femoral pseudoaneurysm have been reported in 3 children (ages 8 months, 13 years, and 17 years); additionally, successful thrombosis of a brachial artery pseudoaneurysm in a 3-week old infant and an epigastric artery pseudoaneurysm in a 15-year old child have been reported. When performing percutaneous injections into infants or small children the use of a small syringe, such as a tuberculin syringe, to slowly inject thrombin into the pseudoaneurysm is recommended.

Use thrombin during pregnancy only if clearly needed. It is not known whether thrombin can cause fetal harm when administered during pregnancy or if it can affect reproduction capacity. Animal reproduction studies with thrombin have not been conducted.

Use thrombin during breast-feeding only if clearly needed. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for thrombin and any potential adverse effects on the breast-fed infant from thrombin or the underlying maternal condition. It is not known whether thrombin is excreted in human milk.

For hemostasis of small vessels and capillaries associated with surgical bleeding:
Topical dosage (bovine thrombin):
Adults: Apply topically to the surface of bleeding tissues only; the amount of thrombin required depends upon the size and number of bleeding sites and the method of application. 100 International Units/mL concentration may be used for bleeding from skin or mucosal surfaces (e.g., plastic surgery, dental extractions, skin grafting). For profuse bleeding (e.g., abraded surfaces of liver or spleen), 1,000 International Units/mL concentration may be required. Application of dry powder may be used on oozing surfaces.
Topical dosage (recombinant thrombin, Recothrom):
Adults: Apply topically to the surface of bleeding tissues only; the amount of thrombin required depends upon the size and number of bleeding sites and the method of application.
Infants, Children, and Adolescents: Apply topically to the surface of bleeding tissues only; the amount of thrombin required depends upon the size and number of bleeding sites and the method of application.

For the treatment of pseudoaneurysms (false aneurysms)*:
NOTE: The majority of the reports for the percutaneous injection of thrombin involve pseudoaneurysm in association with the femoral artery; however, thrombosis of pseudoaneurysms at other anatomical locations has also been successful.
NOTE: In patients with a previous exposure to thrombin (topical or intravascular), a skin-prick test to rule out hypersensitivity to thrombin is recommended (see Administration).
Percutaneous dosage*:
Adults: Using ultrasound-guided direct visualization, thrombin is slowly injected percutaneously into the sac of the pseudoaneurysm until flow within the pseudoaneurysm has ceased; most authors recommend using 1-ml syringes of thrombin and administering this dose slowly over 10 seconds. If after the first dose, flow within the pseudoaneurysm is still present, the injection of thrombin should be repeated. The majority of studies have used a thrombin concentration of 1000 units/ml, although some have used a thrombin concentration of 100 units/ml without reporting a difference in efficacy; regardless of the concentration of thrombin, the majority of aneurysms require 0.3-3 ml of thrombin for thrombosis. The success rate of intravascular thrombin is reported to be as high as 97%.
Infants and Children: See adult dosage. Using a smaller syringe, such as a tuberculin syringe, has been suggested. There are reports of successful thrombosis of pseudoaneurysms with the use of thrombin in infants and children. However, administer with caution as upper extremity ischemia has been reported in a 10-month old infant.

Maximum Dosage Limits:
-Adults
No maximum dosage information is available.
-Geriatric
No maximum dosage information is available.
-Adolescents
No maximum dosage information is available.
-Children
No maximum dosage information is available.
-Infants
No maximum dosage information is available.
-Neonates
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

There are no drug interactions associated with Thrombin products.

Thrombin is a proteolytic enzyme which catalyzes the conversion of fibrinogen to fibrin. Thrombin removes 2 low-molecular-weight peptides from fibrinogen to form a fibrin monomer, which automatically polymerizes with other fibrin monomers, generating long fibrin threads. These fibrin threads serve as the framework for the creation of a clot. This polymerization process occurs within seconds. Topically administered thrombin provides a direct clotting effect on the exposed blood. The rate of the reaction is dependent on the concentration of thrombin, with higher concentrations providing faster clotting rates.

Pharmacokinetics:
Thrombin is administered topically. Typical pharmacokinetic parameters are not applicable. Thrombin is formed from prothrombin, an unstable protein that is continuously produced by the liver. Lack of vitamin K or hepatic failure causes plasma concentrations of prothrombin (and subsequently thrombin) to decline within 24 hours to levels too low to maintain normal hemostasis.