Drug: Angiomax

Angiomax is a specific and reversible direct thrombin inhibitor. The active substance is a synthetic, 20 amino acid peptide. The chemical name is D-phenylalanyl-L-prolyl-L-arginyl-L-prolyl-glycylglycyl-glycyl-glycyl-L-asparagyl-glycyl-L-aspartyl-L-phenylalanyl-L-glutamyl-L-glutamyl-L-isoleucyl-L-prolyl-L-glutamyl-L-glutamyl-L-tyrosyl-L-leucine trifluoroacetate (salt) hydrate (Figure 1). The molecular weight of Angiomax is 2180 daltons (anhydrous free base peptide). Angiomax is supplied in single-use vials as a white lyophilized cake, which is sterile. Each vial contains 250 mg bivalirudin, 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. Figure 1: Structural Formula for Bivalirudin

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Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Bleeding In 6010 patients undergoing PCI treated in the REPLACE-2 trial, Angiomax patients exhibited statistically significantly lower rates of bleeding, transfusions, and thrombocytopenia as noted in Table 2. Table 2: Major Hematologic Outcomes REPLACE-2 Study (Safety Population)
  Angiomax with “provisional” GPI1
( n=2914) HEPARIN + GPI
(n=2987) p-value Protocol defined major hemorrhage2 (%) 2.30% 4.00% < 0.001 Protocol defined minor hemorrhage3 (%) 13.60% 25.80% < 0.001 TIMI defined bleeding4 -Major 0.60% 0.90% 0.259 -Minor 1.30% 2.9 < 0.001 Non-access site bleeding -Retroperitoneal bleeding 0.20% 0.50% 0.069 -Intracranial bleeding < 0.1% 0.10% 1 Access site bleeding -Sheath site bleeding 0.90% 2.40% < 0.001 Thrombocytopenia5

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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 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] 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 by a continuous infusion at a rate of 1.75 mg/kg/h for the duration of the procedure. For ongoing treatment post procedure Continuation of the Angiomax infusion following PCI/PTCA for up to 4 hours post-procedure is optional, at the discretion of the treating physician. 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]. 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. Each reconstituted vial should be further diluted in 50 mL of 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 bag, reconstitute the 250 mg vial with 5 mL of Sterile Water for Injection, USP. Gently swirl until all material is dissolved. Each reconstituted vial should be further diluted in 500 mL of 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. Table 1 : Dosing Table
Weight (kg) Using 5 mg/mL Concentration Using 0.5 mg/mL Concentration Subsequent Low-rate Infusion 0.2 mg/kg/h (mL/h) Bolus 0.75 mg/k (mL) Infusion 1.75 mg/kg/h (mL/h) 43-47 7 16 18 48-52 7.5 17.5 20 53-57 8 19 22 58-62 9 21 24 63-67 10 23 26 68-72 10.5 24.5 28 73-77 11 26 30 78-82 12 28 32 83-87 13 30 34 88-92 13.5 31.5 36 93-97 14 33 38 98-102 15 35 40 103-107 16 37 42 108-112 16.5 38.5 44 113-117 17 40 46 118-122 18 42 48 123-127 19 44 50 128-132 19.5 45.5 52 133-137 20 47 54 138-142 21 49 56 143-147 22 51 58 148-152 22.5 52.5 60 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 2-8oC 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.

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In clinical trials in patients undergoing PCI/PTCA, co-administration of Angiomax with heparin, warfarin, thrombolytics, or GPIs was associated with increased risks of major bleeding events compared to patients not receiving these concomitant medications. There is no experience with co-administration of Angiomax and plasma expanders such as dextran. Read the Angiomax Drug Interactions Center for a complete guide to possible interactions Learn More »

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Percutaneous Transluminal Coronary Angioplasty (PTCA) Angiomax® (bivalirudin) is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). Percutaneous Coronary Intervention (PCI) Angiomax with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as listed in the REPLACE-2 trial [see Clinical Studies] is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). Angiomax is indicated for patients with, or at risk of, heparin induced thrombocytopenia (HIT) or heparin induced thrombocytopenia and thrombosis syndrome (HITTS) undergoing PCI. Use with Aspirin Angiomax in these indications is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin [see DOSAGE AND ADMINISTRATION and Clinical Studies]. Limitation of Use The safety and effectiveness of Angiomax have not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.

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Angiomax is contraindicated in patients with:
  • Active major bleeding;
  • Hypersensitivity (e.g., anaphylaxis) to Angiomax or its components [see ADVERSE REACTIONS].
Last reviewed on RxList: 6/3/2013
This monograph has been modified to include the generic and brand name in many instances.

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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]. 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].

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Dosage Forms And Strengths Angiomax is supplied as a sterile, lyophilized powder in single-use, glass vials. After reconstitution, each vial delivers 250 mg of Angiomax. Storage And Handling Angiomax is supplied as a sterile, lyophilized powder in single-use, glass vials. After reconstitution, each vial delivers 250 mg of Angiomax. NDC 65293-001-01 Store Angiomax dosage units at 20-25°C (68-77°F). Excursions to 15-30°C permitted. [See USP Controlled Room Temperature.] Marketed by: The Medicines Company Parsippany, NJ 07054, For information call: (800) 264-4662. Revised: May 2013 Last reviewed on RxList: 6/3/2013
This monograph has been modified to include the generic and brand name in many instances.

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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]. Angiomax should be used with caution in patients with disease states associated with an increased risk of bleeding. 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]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate the carcinogenic potential of Angiomax. Angiomax displayed no genotoxic potential in the in vitro bacterial cell reverse mutation assay (Ames test), the in vitro Chinese hamster ovary cell forward gene mutation test (CHO/HGPRT), the in vitro human lymphocyte chromosomal aberration assay, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the in vivo rat micronucleus assay. Fertility and general reproductive performance in rats were unaffected by subcutaneous doses of Angiomax up to 150 mg/kg/day, about 1.6 times the dose on a body surface area basis (mg/m²) of a 50 kg person given the maximum recommended dose of 15 mg/kg/day. Use In Specific Populations 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 Angiomax. 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]. 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]. The infusion dose of Angiomax may need to be reduced, and anticoagulant status monitored in patients with renal impairment [see DOSAGE AND ADMINISTRATION]. Last reviewed on RxList: 6/3/2013
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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