Angiomax

Serious side effects have been reported with Angiomax.

Common side effects of Angiomax include the following:

• bleeding
• headache
• fever
• thrombocytopenia (a low platelet count in your blood)

This is not a complete list of Angiomax side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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

Tell your doctor if you are using blood thinners or receiving any other medications to treat or prevent blood clots.

Bivalirudin can make it easier for you to bleed even from a minor injury.

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.

General

• Manufacturer states that bivalirudin is intended for use concomitantly with aspirin 300–325 mg daily.1 According to some experts, a lower dose of aspirin (e.g., 81–325 mg) may be administered prior to PCI in patients who are already receiving daily aspirin therapy.994

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by direct IV injection followed by IV infusion.1 Do not administer IM.1

Reconstitute vial containing 250 mg of lyophilized bivalirudin with 5 mL of sterile water for injection (swirl gently) to provide a solution containing 50 mg/mL.1

Discard any unused reconstituted solution.1

Dilute reconstituted solution in 50 mL of 5% dextrose or 0.9% sodium chloride injection to a final concentration of 5 mg/mL for direct IV injection and infusion.1

For low-rate infusion, further dilute the 5-mg/mL solution in 500 mL of 5% dextrose or 0.9% sodium chloride injection to a final concentration of 0.5 mg/mL.1 7

Dosage

Adults

0.75 mg/kg (5-mg/mL solution) by direct IV injection immediately before PCI, followed by 1.75 mg/kg per hour (5-mg/mL solution) by continuous IV infusion for the duration of the procedure.1 Obtain an activated clotting time (ACT) (as measured by a Hemochron device) 5 minutes after initial loading dose and administer an additional direct IV dose of 0.3 mg/kg if needed (e.g., if the ACT is <225 seconds).1 8

May continue infusion for up to 4 hours after the procedure if necessary.1 If needed, administer an additional IV infusion (0.5-mg/mL solution) at 0.2 mg/kg per hour for up to 20 hours.1

Consider administration of a GP IIb/IIIa-receptor inhibitor if procedural complications occur (“provisional use”).28 (See Acute Ischemic Complications of Percutaneous Coronary Intervention under Uses.)

0.75 mg/kg (5-mg/mL solution) by direct IV injection immediately before PCI, followed by 1.75 mg/kg per hour (5-mg/mL solution) by continuous IV infusion for the duration of the procedure.1

May continue infusion for up to 4 hours after the procedure if necessary.1 If needed, administer an additional IV infusion (0.5-mg/mL solution) at 0.2 mg/kg per hour for up to 20 hours.1

During “off-pump” cardiac surgery (i.e., without cardiopulmonary bypass), 0.75 mg/kg by direct IV injection, followed by 1.75 mg/kg per hour by continuous IV infusion to maintain an ACT >300 seconds has been used.26

During cardiopulmonary bypass, initially, 1 mg/kg by direct IV injection followed by 2.5 mg/kg per hour by continuous IV infusion has been used;24 if needed, additional direct IV doses of 0.1–0.5 mg/kg have been given to maintain a 2.5-fold or greater prolongation of the baseline ACT.24 In addition, 50 mg of bivalirudin is added to the recirculating priming fluid of the cardiopulmonary bypass circuit.24

Special Populations

Renal Impairment

Reduction of the initial loading dose not necessary in patients with moderate to severe renal impairment.1 7 Closely monitor ACT in patients with renal impairment.1 Reduce infusion rate to 1 mg/kg per hour in patients with severe renal impairment (Clcr <30 mL/minute).1 In dialysis-dependent patients, reduce off-dialysis infusion rate to 0.25 mg/kg per hour.1

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of bivalirudin in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of bivalirudin in the elderly. However, elderly patients are more likely to have bleeding problems than younger adults, which may require caution in patients receiving bivalirudin.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Defibrotide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab
• Aceclofenac
• Acemetacin
• Acenocoumarol
• Alipogene Tiparvovec
• Alteplase, Recombinant
• Amtolmetin Guacil
• Anagrelide
• Anistreplase
• Apixaban
• Argatroban
• Aspirin
• Bemiparin
• Betrixaban
• Bromfenac
• Bufexamac
• Cangrelor
• Celecoxib
• Chamomile
• Choline Salicylate
• Cilostazol
• Citalopram
• Clonixin
• Clopidogrel
• Collagenase, Clostridium histolyticum
• Dabigatran Etexilate
• Dalteparin
• Danaparoid
• Desvenlafaxine
• Dexibuprofen
• Dexketoprofen
• Diclofenac
• Diflunisal
• Dipyridamole
• Dipyrone
• Drotrecogin Alfa
• Droxicam
• Edoxaban
• Enoxaparin
• Epoprostenol
• Eptifibatide
• Escitalopram
• Etodolac
• Etofenamate
• Etoricoxib
• Felbinac
• Fenofibrate
• Fenofibric Acid
• Fenoprofen
• Fepradinol
• Feprazone
• Floctafenine
• Flufenamic Acid
• Fluoxetine
• Flurbiprofen
• Fluvoxamine
• Fondaparinux
• Garlic
• Ginkgo
• Heparin
• Ibuprofen
• Iloprost
• Indomethacin
• Ketoprofen
• Ketorolac
• Lepirudin
• Levomilnacipran
• Lornoxicam
• Loxoprofen
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Meloxicam
• Milnacipran
• Morniflumate
• Nabumetone
• Nadroparin
• Naproxen
• Nepafenac
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Nintedanib
• Orlistat
• Oxaprozin
• Oxyphenbutazone
• Papaya
• Parecoxib
• Paroxetine
• Pentosan Polysulfate Sodium
• Phenindione
• Phenprocoumon
• Phenylbutazone
• Piketoprofen
• Piracetam
• Piroxicam
• Pranoprofen
• Prasugrel
• Proglumetacin
• Propyphenazone
• Proquazone
• Reteplase, Recombinant
• Rivaroxaban
• Rofecoxib
• Selexipag
• Sertraline
• St John's Wort
• Streptokinase
• Sulfinpyrazone
• Sulindac
• Tan-Shen
• Tenecteplase
• Tenoxicam
• Tiaprofenic Acid
• Ticlopidine
• Tinzaparin
• Tirofiban
• Tolfenamic Acid
• Tolmetin
• Treprostinil
• Urokinase
• Valdecoxib
• Venlafaxine
• Vilazodone
• Vorapaxar
• Vortioxetine
• Warfarin

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Chondroitin
• Coenzyme Q10
• Curcumin
• Dong Quai
• Ginger
• Vitamin A

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Avocado

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bleeding problems, active—Should not be used in patients with this condition.

• Brachytherapy (a radiation treatment)—Use with caution. Your chance of having blot clots may be increased.

• Kidney disease—Use with caution. May require an adjustment of dosage for patients with this condition.

 Recommended Dose

Angiomax is for intravenous administration only.

Angiomax is intended for use with aspirin (300-325 mg daily) and has been studied only in patients receiving concomitant aspirin.

For patients who do not have HIT/HITTS

The recommended dose of Angiomax is an intravenous (IV) bolus dose of 0.75 mg/kg, followed immediately by an infusion of 1.75 mg/kg/h for the duration of the PCI/PTCA procedure. Five min after the bolus dose has been administered, an activated clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed.

GPI administration should be considered in the event that any of the conditions listed in the REPLACE-2 clinical trial description [see Clinical Studies (14.1)] is present.

For patients who have HIT/HITTS

The recommended dose of Angiomax in patients with HIT/HITTS undergoing PCI is an IV bolus of 0.75 mg/kg. This should be followed immediately by a continuous infusion at a rate of 1.75 mg/kg/h for the duration of the procedure.

For ongoing treatment post procedure

Angiomax infusion may be continued following PCI/PTCA for up to 4 hours post-procedure at the discretion of the treating physician.

In patients with ST segment elevation myocardial infarction (STEMI) continuation of the Angiomax infusion at a rate of 1.75 mg/kg/h following PCI/PTCA for up to 4 hours post-procedure should be considered to mitigate risk of stent thrombosis [see Warnings and Precautions (5.2)].

After four hours, an additional IV infusion of Angiomax may be initiated at a rate of 0.2 mg/kg/h (low-rate infusion), for up to 20 hours, if needed.

 Dosing in Renal Impairment

No reduction in the bolus dose is needed for any degree of renal impairment. The infusion dose of Angiomax may need to be reduced, and anticoagulant status monitored in patients with renal impairment. Patients with moderate renal impairment (30-59 mL/min) should receive an infusion of 1.75 mg/kg/h. If the creatinine clearance is less than 30 mL/min, reduction of the infusion rate to 1 mg/kg/h should be considered. If a patient is on hemodialysis, the infusion rate should be reduced to 0.25 mg/kg/h [see Use in Specific Population (8.6)].

 Instructions for Administration

Angiomax is intended for intravenous bolus injection and continuous infusion after reconstitution and dilution. To each 250 mg vial, add 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Next, withdraw and discard 5 mL from a 50 mL infusion bag containing 5% Dextrose in Water or 0.9% Sodium Chloride for Injection. Then add the contents of the reconstituted vial to the infusion bag containing 5% Dextrose in Water or 0.9% Sodium Chloride for Injection to yield a final concentration of 5 mg/mL (e.g., 1 vial in 50 mL; 2 vials in 100 mL; 5 vials in 250 mL). The dose to be administered is adjusted according to the patient's weight (see Table 1).

If the low-rate infusion is used after the initial infusion, a lower concentration bag should be prepared. In order to prepare this lower concentration, reconstitute the 250 mg vial with 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Next, withdraw and discard 5 mL from a 500 mL infusion bag containing 5% Dextrose in Water or 0.9% Sodium Chloride for Injection. Then add the contents of the reconstituted vial to the infusion bag containing 5% Dextrose in Water or 0.9% Sodium Chloride for Injection to yield a final concentration of 0.5 mg/mL. The infusion rate to be administered should be selected from the right-hand column in Table 1.

Angiomax should be administered via an intravenous line. No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets. The following drugs should not be administered in the same intravenous line with Angiomax, since they resulted in haze formation, microparticulate formation, or gross precipitation when mixed with Angiomax: alteplase, amiodarone HCl, amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, reteplase, streptokinase, and vancomycin HCl. Dobutamine was compatible at concentrations up to 4 mg/mL but incompatible at a concentration of 12.5 mg/mL.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Preparations of Angiomax containing particulate matter should not be used. Reconstituted material will be a clear to slightly opalescent, colorless to slightly yellow solution.

 Storage after Reconstitution

Do not freeze reconstituted or diluted Angiomax. Reconstituted material may be stored at 2-8°C for up to 24 hours. Diluted Angiomax with a concentration of between 0.5 mg/mL and 5 mg/mL is stable at room temperature for up to 24 hours. Discard any unused portion of reconstituted solution remaining in the vial.

 Bleeding Events

Although most bleeding associated with the use of Angiomax 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 Angiomax administration [see Adverse Reactions (6.1)]. Angiomax should be used with caution in patients with disease states associated with an increased risk of bleeding.

 Acute Stent Thrombosis in Patients with STEMI undergoing PCI

Acute stent thrombosis (AST) (<4 hours) has been observed at a greater frequency in Angiomax treated patients (1.2%, 36/2889) compared to heparin treated patients (0.2%, 6/2911) with STEMI undergoing primary PCI. Among patients who experienced an AST, one fatality (0.03%) occurred in an Angiomax 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 Angiomax in gamma brachytherapy.

If a decision is made to use Angiomax 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)].

 Laboratory Test Interference

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

 Pregnancy

Pregnancy Category B

Reproductive studies have been performed in rats at subcutaneous doses up to 150 mg/kg/day, (1.6 times the maximum recommended human dose based on body surface area) and rabbits at subcutaneous doses up to 150 mg/kg/day (3.2 times the maximum recommended human dose based on body surface area). These studies revealed no evidence of impaired fertility or harm to the fetus attributable to bivalirudin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Angiomax is intended for use with aspirin [see Indications and Usage (1.3)]. Because of possible adverse effects on the neonate and the potential for increased maternal bleeding, particularly during the third trimester, Angiomax and aspirin should be used together during pregnancy only if clearly needed.

 Nursing Mothers

It is not known whether bivalirudin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Angiomax is administered to a nursing woman.

 Pediatric Use

The safety and effectiveness of Angiomax in pediatric patients have not been established.

 Geriatric Use

In studies of patients undergoing PCI, 44% were ≥65 years of age and 12% of patients were ≥75 years old. Elderly patients experienced more bleeding events than younger patients. Patients treated with Angiomax experienced fewer bleeding events in each age stratum, compared to heparin.

 Renal Impairment

The disposition of Angiomax was studied in PTCA patients with mild, moderate and severe renal impairment. The clearance of Angiomax was reduced approximately 20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-dependent patients [see Clinical Pharmacology (12.3)]. The infusion dose of Angiomax may need to be reduced, and anticoagulant status monitored in patients with renal impairment [see Dosage and Administration (2.2)].

Cases of overdose of up to 10 times the recommended bolus or continuous infusion dose of Angiomax have been reported in clinical trials and in postmarketing reports. A number of the reported overdoses were due to failure to adjust the infusion dose of bivalirudin in persons with renal dysfunction including persons on hemodialysis [see Dosage and Administration (2.2)]. Bleeding, as well as deaths due to hemorrhage, have been observed in some reports of overdose. In cases of suspected overdosage, discontinue Angiomax immediately and monitor the patient closely for signs of bleeding. There is no known antidote to Angiomax. Angiomax is hemodialyzable [see Clinical Pharmacology (12.3)].

Angiomax is supplied as a sterile, lyophilized powder in single-dose, glass vials. Each vial contains 250 mg of bivalirudin equivalent to an average of 275 mg of bivalirudin trifluoroacetate*.

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

NDC 65293-001-01

Store Angiomax dosage units at 20 to 25°C (68 to 77°F). Excursions to 15 to 30°C permitted [see USP Controlled Room Temperature].

Advise patients to watch carefully for any signs of bleeding or bruising and to report these to their health care provider when they occur.

Advise patients to discuss with their health care provider their use of any other medications, including over-the-counter medications or herbal products, prior to Angiomax use. Examples of other medications that should not be taken with Angiomax are warfarin and heparin.

Marketed by:

The Medicines Company
Parsippany, NJ 07054

U.S. Patents 7,598,343; 7,582,727

Hemochron® is a registered trademark of International Technidyne Corporation, Edison, NJ.

PN1601-18

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

This drug should be used during pregnancy only if the benefit outweighs the risk. AU TGA pregnancy category: C US FDA pregnancy category: B

Animal studies have failed to reveal evidence of fetal harm or impaired fertility. There are no controlled data in human pregnancy. TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.