Bivalirudin

Angiomax contains bivalirudin which is a specific and reversible direct thrombin inhibitor. Bivalirudin is a synthetic, 20 amino acid peptide, with the chemical name of D-phenylalanyl-Lprolyl- L-arginyl-L-prolyl-glycyl-glycyl-glycyl-glycyl-L-asparagyl-glycyl-L-aspartyl-Lphenylalanyl- L-glutamyl-L-glutamyl-L-isoleucyl-L-prolyl-L-glutamyl-L-glutamyl-L-tyrosyl-Lleucine. The active pharmaceutical ingredient is in the form of bivalirudin trifluoroacetate as a white to off-white powder. The chemical name for bivalirudin trifluoroacetate is D-phenylalanyl- L-prolyl-L-arginyl-L-prolyl-glycyl-glycyl-glycyl-glycyl-L-asparagyl-glycyl-L-aspartyl-Lphenylalanyl- L-glutamyl-L-glutamyl-L-isoleucyl-L-prolyl-L-glutamyl-L-glutamyl-L-tyrosyl-Lleucine trifluoroacetate (Figure 1). The molecular weight of bivalirudin is 2180 daltons (anhydrous free base peptide).

Figure 1: Structure formula for bivalirudin trifluoroacetate

Angiomax is supplied as a sterile white lyophilized cake, in single-dose vials. Each vial contains 250 mg bivalirudin, equivalent to an average of 275 mg of bivalirudin trifluoroactetate*, 125 mg mannitol, and sodium hydroxide to adjust the pH to 5-6 (equivalent of approximately 12.5 mg sodium). When reconstituted with Sterile Water for Injection, the product yields a clear to opalescent, colorless to slightly yellow solution, pH 5-6.

*The range of bivalirudin trifluoroacetate is 270 mg to 280 mg based on a range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents.

You should not receive bivalirudin if you are allergic to bivalirudin, or if you have any major bleeding from a surgery, injury, or other medical trauma.

To make sure bivalirudin is safe for you, tell your doctor if you have:

• heart disease;

• kidney disease;

• a bleeding or blood clotting disorder, such as hemophilia; or

• if you use a blood thinner (warfarin, Coumadin, Jantoven) and you have routine "INR" or prothrombin time tests.

Tell your doctor if you are pregnant or plan to become pregnant.

Bivalirudin is not expected to be harmful to an unborn baby. However, aspirin is sometimes given with bivalirudin, and taking aspirin during late pregnancy may cause bleeding in the mother or the baby during delivery.

Tell your doctor if you are pregnant before you are treated with bivalirudin and aspirin.

It is not known whether bivalirudin passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Avoid drinking alcohol. It may increase your risk of bleeding in your stomach or intestines.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers right away if you have:

• a light-headed feeling, like you might pass out;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• any bleeding that will not stop;

• slow heartbeats;

• little or no urinating;

• signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

• signs of a blood clot in the lung--chest pain, sudden cough, wheezing, rapid breathing;

• signs of a blood clot in your leg--pain, swelling, warmth, or redness in one or both legs; or

• increased blood pressure--severe headache, blurred vision, pounding in your neck or ears.

Common side effects may include:

• headache, anxiety;

• nausea, vomiting;

• pelvic pain, back pain;

• sleep problems (insomnia); or

• pain or irritation where the injection was given.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Usual Adult Dose for Angina Pectoris:

For patients who do not have heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS): 0.75 mg/kg as an IV bolus dose, followed immediately by 1.75 mg/kg/hr IV for the duration of the percutaneous coronary intervention (PCI)/percutaneous transluminal coronary angioplasty (PTCA) procedure; 5 minutes after the bolus dose, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg IV should be given if needed
-Administration of a glycoprotein IIb/IIIa inhibitor (GPI) should be considered in the event that any of the following conditions are present: decreased TIMI flow (0 to 2) or slow reflow; dissection with decreased flow; new or suspected thrombus; persistent residual stenosis; distal embolization; unplanned stent; suboptimal stenting; side branch closure; abrupt closure; clinical instability; and prolonged ischemia

For patients who have HIT/HITTS undergoing PCI:
0.75 mg/kg IV as a bolus dose, followed immediately by 1.75 mg/kg/hr IV for the duration of the procedure

For ongoing treatment post procedure:
-The infusion may be continued following PCI/PTCA for up to 4 hours post procedure at the discretion of the physician.
-In patients with ST segment elevation myocardial infarction (STEMI), continuation of the infusion at a rate of 1.75 mg/kg/hr IV following PCI/PTCA for up to 4 hours post procedure should be considered to mitigate risk of stent thrombosis.
-After 4 hours, an additional IV infusion may be initiated at a rate of 0.2 mg/kg/hr IV (low-rate infusion) for up to 20 hours, if needed.

Comments:
-This drug is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin.

Uses:
-For use as an anticoagulant in patients with unstable angina undergoing PTCA
-For use an anticoagulant in patients undergoing PCI with provisional use of GPI
-For use as an anticoagulant in patients with, or at risk of, HIT or HITTS, undergoing PCI

Usual Adult Dose for Percutaneous Coronary Intervention:

For patients who do not have heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS): 0.75 mg/kg as an IV bolus dose, followed immediately by 1.75 mg/kg/hr IV for the duration of the percutaneous coronary intervention (PCI)/percutaneous transluminal coronary angioplasty (PTCA) procedure; 5 minutes after the bolus dose, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg IV should be given if needed
-Administration of a glycoprotein IIb/IIIa inhibitor (GPI) should be considered in the event that any of the following conditions are present: decreased TIMI flow (0 to 2) or slow reflow; dissection with decreased flow; new or suspected thrombus; persistent residual stenosis; distal embolization; unplanned stent; suboptimal stenting; side branch closure; abrupt closure; clinical instability; and prolonged ischemia

For patients who have HIT/HITTS undergoing PCI:
0.75 mg/kg IV as a bolus dose, followed immediately by 1.75 mg/kg/hr IV for the duration of the procedure

For ongoing treatment post procedure:
-The infusion may be continued following PCI/PTCA for up to 4 hours post procedure at the discretion of the physician.
-In patients with ST segment elevation myocardial infarction (STEMI), continuation of the infusion at a rate of 1.75 mg/kg/hr IV following PCI/PTCA for up to 4 hours post procedure should be considered to mitigate risk of stent thrombosis.
-After 4 hours, an additional IV infusion may be initiated at a rate of 0.2 mg/kg/hr IV (low-rate infusion) for up to 20 hours, if needed.

Comments:
-This drug is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin.

Uses:
-For use as an anticoagulant in patients with unstable angina undergoing PTCA
-For use an anticoagulant in patients undergoing PCI with provisional use of GPI
-For use as an anticoagulant in patients with, or at risk of, HIT or HITTS, undergoing PCI

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take bivalirudin.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Very bad and sometimes deadly bleeding problems have happened with this medicine. Talk with the doctor.
• If you have had spinal anesthesia, surgery, or any spinal care, talk with your doctor.
• If you fall or hurt yourself, or if you hit your head, call your doctor right away. Talk with your doctor even if you feel fine.
• If you are 65 or older, use bivalirudin with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Bivalirudin is supplied as a sterile, lyophilized powder in single-dose, ADD-VantageTM vials. After reconstitution, each vial delivers 250 mg of Bivalirudin.

Bivalirudin is contraindicated in patients with:

Bleeding Events

Although most bleeding associated with the use of Bivalirudin in PCI/PTCA occurs at the site of arterial puncture, hemorrhage can occur at any site. An unexplained fall in blood pressure or hematocrit should lead to serious consideration of a hemorrhagic event and cessation of Bivalirudin administration [see Adverse Reactions (6.1)]. Bivalirudin should be used with caution in patients with disease states associated with an increased risk of bleeding.

5.2 Acute Stent Thrombosis in Patients with STEMI undergoing PCI

Acute stent thrombosis (AST) (<4 hours) has been observed at a greater frequency in Bivalirudin treated patients (1.2%, 36/2,889) compared to heparin treated patients (0.2%, 6/2,911) with STEMI undergoing primary PCI. Among patients who experienced an AST, one fatality (0.03%) occurred in a Bivalirudin treated patient and one fatality (0.03%) in a heparin treated patient. These patients have been managed by Target Vessel Revascularization (TVR). Patients should remain for at least 24 hours in a facility capable of managing ischemic complications and should be carefully monitored following primary PCI for signs and symptoms consistent with myocardial ischemia.

Coronary Artery Brachytherapy

An increased risk of thrombus formation, including fatal outcomes, has been associated with the use of Bivalirudin in gamma brachytherapy.

If a decision is made to use Bivalirudin during brachytherapy procedures, maintain meticulous catheter technique, with frequent aspiration and flushing, paying special attention to minimizing conditions of stasis within the catheter or vessels [see Adverse Reactions (6.3)].

5.4 Laboratory Test Interference

Bivalirudin affects International Normalized Ratio (INR), therefore INR measurements made in patients who have been treated with Bivalirudin may not be useful for determining the appropriate dose of warfarin.

PCI/PTCA

Bivalirudin has been evaluated in five randomized, controlled interventional cardiology trials reporting 11,422 patients. Stents were deployed in 6,062 of the patients in these trials – mainly in trials performed since 1995. Percutaneous transluminal coronary angioplasty, atherectomy or other procedures were performed in the remaining patients.

REPLACE-2 Trial

This was a randomized, double-blind, multicenter study reporting 6,002 (intent-to-treat) patients undergoing PCI. Patients were randomized to treatment with Bivalirudin with the "provisional" use of platelet glycoprotein IIb/IIIa inhibitor (GPI) or heparin plus planned use of GPI. GPIs were added on a "provisional" basis to patients who were randomized to Bivalirudin in the following circumstances:

During the study, one or more of these circumstances occurred in 10.9% of patients in the Bivalirudin with provisional GPI arm. GPIs were administered to 7.2% of patients in the Bivalirudin with provisional GPI arm (66.8% of eligible patients).

Patients ranged in age from 25-95 years (median, 63); weight ranged from 35-199 kg (median 85.5); 74.4% were male and 25.6% were female. Indications for PCI included unstable angina (35% of patients), myocardial infarction within 7 days prior to intervention (8% of patients), stable angina (25%), positive ischemic stress test (24%), and other not specified indications (8%). Stents were deployed in 85% of patients. Ninety-nine percent of patients received aspirin and 86% received thienopyridines prior to study treatment.

Bivalirudin was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for the duration of the procedure. The activated clotting time (ACT – measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. If the ACT was <225 seconds, an additional bolus of 0.3 mg/kg was given. At investigator discretion, the infusion could be continued following the procedure for up to 4 hours. The median infusion duration was 44 min. Heparin was administered as a 65 U/kg bolus. The activated clotting time (ACT – measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. If the ACT was <225 seconds, an additional bolus of 20 units/kg was given. GPIs (either abciximab or eptifibatide) were given according to manufacturers' instructions. Both randomized groups could be given "provisional" treatments during the PCI at investigator discretion, but under double-blind conditions. "Provisional" treatment with GPI was requested in 5.2% of patients randomized to heparin plus GPI (they were given placebo) and 7.2% patients randomized to Bivalirudin with provisional GPI (they were given abciximab or eptifibatide according to pre-randomization investigator choice and patient stratification).

The percent of patients reaching protocol-specified levels of anticoagulation was greater in the Bivalirudin with provisional GPI group than in the heparin plus GPI group. For patients randomized to Bivalirudin with provisional GPI, the median 5 min ACT was 358 sec (interquartile range 320-400 sec) and the ACT was <225 sec in 3%. For patients randomized to heparin plus GPI, the median 5 min ACT was 317 sec (interquartile range 263-373 sec) and the ACT was <225 sec in 12%. At the end of the procedure, median ACT values were 334 sec (Bivalirudin group) and 276 sec (heparin plus GPI group).

For the composite endpoint of death, MI, or urgent revascularization adjudicated under double-blind conditions, the frequency was higher (7.6%)(95% confidence interval 6.7%-8.6%) in the Bivalirudin with "provisional" GPI arm when compared to the heparin plus GPI arm (7.1%)(95% confidence interval 6.1%-8.0%). However, major hemorrhage was reported significantly less frequently in the Bivalirudin with provisional GPI arm (2.4%) compared to the heparin plus GPI arm (4.1%). Study outcomes are shown in Table 7.

At 12 months' follow-up, mortality was 1.9% among patients randomized to Bivalirudin with "provisional" GPIs and 2.5% among patients randomized to heparin plus GPI.

Bivalirudin Angioplasty Trial (BAT)

Bivalirudin was evaluated in patients with unstable angina undergoing PTCA in two randomized, double-blind, multicenter studies with identical protocols. Patients must have had unstable angina defined as: (1) a new onset of severe or accelerated angina or rest pain within the month prior to study entry or (2) angina or ischemic rest pain which developed between four hours and two weeks after an acute myocardial infarction (MI). Overall, 4,312 patients with unstable angina, including 741 (17%) patients with post-MI angina, were treated in a 1:1 randomized fashion with Bivalirudin or heparin. Patients ranged in age from 29-90 (median 63) years, their weight was a median of 80 kg (39-120 kg), 68% were male, and 91% were Caucasian. Twenty-three percent of patients were treated with heparin within one hour prior to randomization. All patients were administered aspirin 300-325 mg prior to PTCA and daily thereafter. Patients randomized to Bivalirudin were started on an intravenous infusion of Bivalirudin (2.5 mg/kg/h). Within 5 min after starting the infusion, and prior to PTCA, a 1 mg/kg loading dose was administered as an intravenous bolus. The infusion was continued for 4 hours, then the infusion was changed under double-blinded conditions to Bivalirudin (0.2 mg/kg/h) for up to an additional 20 hours (patients received this infusion for an average of 14 hours). The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blinded bolus of placebo was administered. The Bivalirudin dose was not titrated to ACT. Median ACT values were: ACT in sec (5th percentile-95th percentile): 345 sec (240-595 sec) at 5 min and 346 sec (range 269-583 sec) at 45 min after initiation of dosing. Patients randomized to heparin were given a loading dose (175 IU/kg) as an intravenous bolus 5 min before the planned procedure, with immediate commencement of an infusion of heparin (15 IU/kg/h). The infusion was continued for 4 hours. After 4 hours of infusion, the heparin infusion was changed under double-blinded conditions to heparin (15 IU/kg/h) for up to 20 additional hours. The ACT was checked at 5 min and at 45 min following commencement. If on either occasion the ACT was <350 sec, an additional double-blind bolus of heparin (60 IU/kg) was administered. Once the target ACT was achieved for heparin patients, no further ACT measurements were performed. All ACTs were determined with the Hemochron® device. The protocol allowed use of open-label heparin at the discretion of the investigator after discontinuation of blinded study medication, whether or not an endpoint event (procedural failure) had occurred. The use of open-label heparin was similar between Bivalirudin and heparin treatment groups (about 20% in both groups).

The studies were designed to demonstrate the safety and efficacy of Bivalirudin in patients undergoing PTCA as a treatment for unstable angina as compared with a control group of similar patients receiving heparin during and up to 24 hours after initiation of PTCA. The primary protocol endpoint was a composite endpoint called procedural failure, which included both clinical and angiographic elements measured during hospitalization. The clinical elements were: the occurrence of death, MI, or urgent revascularization, adjudicated under double-blind conditions. The angiographic elements were: impending or abrupt vessel closure. The protocol-specified safety endpoint was major hemorrhage.

The median duration of hospitalization was 4 days for both the Bivalirudin and the heparin treatment groups. The rates of procedural failure were similar in the Bivalirudin and heparin treatment groups. Study outcomes are shown in Table 8.

AT-BAT Trial

This was a single-group open-label study which enrolled 51 patients with heparin-induced thrombocytopenia (HIT) or heparin induced thrombocytopenia and thrombosis syndrome (HITTS) undergoing PCI. Evidence for the diagnosis of HIT/HITTS was based on a clinical history of a decrease of platelets in patients after heparin administration [new diagnosis or history of clinically suspected or objectively documented HIT/HITTS defined as either: 1) HIT: positive heparin-induced platelet aggregation (HIPA) or other functional assay where the platelet count has decreased to <100,000/mL (minimum 30% from prior to heparin), or has decreased to <150,000/mL (minimum 40% from prior to heparin), or has decreased as above within hours of receiving heparin in a patient with a recent, previous exposure to heparin; 2) HITTS: thrombocytopenia as above plus arterial or venous thrombosis diagnosed by physician examination/laboratory and/or appropriate imaging studies]. Patients ranged in age from 48-89 years (median 70); weight ranged from 42-123 kg (median 76); 50% were male and 50% were female. Bivalirudin was administered as either 1 mg/kg bolus followed by 2.5 mg/kg/h (high dose in 28 patients) or 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion (lower dose in 25 patients) for up to 4 hours. Ninety-eight percent of patients received aspirin, 86% received clopidogrel and 19% received GPIs.

The median ACT values at the time of device activation were 379 sec (high dose) and 317 sec (lower dose). Following the procedure, 48 of the 51 patients (94%) had TIMI grade 3 flow and stenosis <50%. One patient died during a bradycardic episode 46 hours after successful PCI, another patient required surgical revascularization, and one patient experienced no flow requiring a temporary intra-aortic balloon.

Two of the fifty-one patients with the diagnosis of HIT/HITTS developed thrombocytopenia after receiving Bivalirudin and GPIs.

10 x 250 mg Single-dose
ADD-Vantage™ Vials

NDC 0409-8300-15

Rx only

Bivalirudin For Injection

250 mg/vial

INTRAVENOUS USE ONLY
WARNING: This package is intended for institutional use only.

Hospira

Refer to adult dosing. No dosage adjustment is needed in elderly patients with normal renal function. Puncture site hemorrhage and catheterization site hemorrhage were seen in more patients ≥65 years of age than in patients <65 years of age.

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Avoid combination

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification

Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Avoid combination

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

Depends upon indication for use of bivalirudin: ACT or aPTT

Applies to bivalirudin: intravenous powder for solution

Along with its needed effects, bivalirudin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking bivalirudin:

• Abdominal pain or swelling
• arm, back, or jaw pain
• black, tarry stools
• blood in the eyes
• blood in the urine
• blurred vision
• bruising or purple areas on the skin
• chest pain or discomfort
• chest tightness or heaviness
• confusion
• coughing up blood
• decreased alertness
• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly
• headache
• joint pain or swelling
• nausea
• nervousness
• nosebleeds
• pounding in the ears
• shortness of breath
• slow, fast, or irregular heartbeat
• sweating
• unusual tiredness or weakness

• Decrease in frequency of urination
• decrease in urine volume
• difficulty in passing urine (dribbling)
• lightheadedness or fainting
• painful urination

• Blue lips and fingernails
• changes in skin color
• cold hands and feet
• cough or hoarseness
• coughing that sometimes produces a pink frothy sputum
• difficult, fast, noisy breathing, sometimes with wheezing
• fever or chills
• increased blood pressure
• increased thirst
• loss of appetite
• lower back or side pain
• pain, redness, or swelling in the arm or leg
• pale skin
• paralysis of the face
• rapid, shallow breathing
• severe numbness, especially on one side of the face or body
• swelling in the legs and ankles
• swelling of the face, fingers, or lower legs
• troubled breathing
• vomiting
• weight gain

• Bleeding gums
• difficulty in swallowing
• hives
• increased menstrual flow or vaginal bleeding
• irritation
• itching
• joint stiffness
• pains in the chest, groin, or legs, especially calves of legs
• paralysis
• prolonged bleeding from cuts
• rash
• red or dark brown urine
• redness of the skin
• severe headaches of sudden onset
• sudden loss of coordination
• sudden onset of shortness of breath for no apparent reason
• sudden onset of slurred speech
• sudden vision changes
• swelling of the eyelids, lips, hands, or feet
• wheezing

Some side effects of bivalirudin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Fear or nervousness
• pain where the needle is placed
• pelvic pain
• sleeplessness
• trouble sleeping
• unable to sleep

• Acid or sour stomach
• belching
• heartburn
• indigestion
• stomach discomfort, upset, or pain

Applies to bivalirudin: intravenous powder for injection

Cardiovascular

Common (1% to 10%): Atrial fibrillation, ventricular tachycardia, angina pectoris, bradycardia, hypertension, hypotension, chest pain
Rare (less than 0.1%): Myocardial infarction, cardiac tamponade, pericardial hemorrhage, coronary artery thrombosis, coronary stent thrombosis (including reports with fatal outcome), arteriovenous fistula, catheter thrombosis, vascular pseudoaneurysm
Postmarketing reports: Cardiac tamponade, ventricular fibrillation[Ref]

Respiratory

Uncommon (0.1% to 1%): Epistaxis, hemoptysis, pharyngeal hemorrhage
Rare (less than 0.1%): Pulmonary hemorrhage, dyspnea[Ref]

Dermatologic

Uncommon (0.1% to 1%): Rash, urticaria[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, vomiting, dyspepsia
Uncommon (0.1% to 1%): GI hemorrhage (i.e., hematemesis, melena, esophageal hemorrhage, anal hemorrhage), retroperitoneal hemorrhage, gingival hemorrhage
Rare (less than 0.1%): Retroperitoneal hematoma[Ref]

Genitourinary

Uncommon (0.1% to 1%): Hematuria[Ref]

Hematologic

Very common (10% or more): Minor hemorrhage at any site (22%)
Common (1% to 10%): Hemoglobin decreased, major hemorrhage at any site (including fatal outcomes)
Uncommon (0.1% to 1%): Thrombocytopenia, anemia, hematoma
Rare (less than 0.1%): INR increased
Postmarketing reports: Catheter thrombosis, arteriovenous fistula, compartment syndrome[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Anaphylaxis (including fatal shock)[Ref]

Local

Common (1% to 10%): Access site hemorrhage, vessel puncture site hematoma (5 cm or less), vessel puncture site hematoma (greater than 5 cm), injection site pain
Rare (less than 0.1%): Injection site reactions (i.e., injection site discomfort, injection site pain, puncture site reaction)[Ref]

Musculoskeletal

Very common (10% or more): Back pain
Common (1% to 10%): Chest pain[Ref]

Nervous system

Common (1% to 10%): Headache, insomnia
Rare (less than 0.1%): Intracranial hemorrhage[Ref]

Ocular

Rare (less than 0.1%): Intraocular hemorrhage[Ref]

Other

Rare (less than 0.1%): Ear hemorrhage[Ref]

Psychiatric

Common (1% to 10%): Nervousness[Ref]

Some side effects of bivalirudin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Data not available