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Angiomax for Injection (The Medicines Company)
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Angiomax® (bivalirudin) is a specific and reversible direct thrombin inhibitor. The active substance is a synthetic, 20 amino acid peptide. The chemical name is D-phenylal-anyl-L-prolyl-L-arginyl-L-prolyl-glycyl-glycyl-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.
Angiomax directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of Angiomax to thrombin is reversible as thrombin slowly cleaves the Angiomax-Arg 3 -Pro 4 bond, resulting in recovery of thrombin active site functions.
In in vitro studies, Angiomax inhibited both soluble (free) and clot-bound thrombin, was not neutralized by products of the platelet release reaction, and prolonged the activated partial thromboplastin time (aPTT), thrombin time (TT), and prothrombin time (PT) of normal human plasma in a concentration-dependent manner. The clinical relevance of these findings is unknown.
Angiomax exhibits linear pharmacokinetics following intravenous (IV) administration to patients undergoing percutaneous transluminal coronary angioplasty (PTCA). In these patients, a mean steady state Angiomax concentration of 12.3 ± 1.7 mcg/mL is achieved following an IV bolus of 1 mg/kg and a 4-hour 2.5 mg/kg/h IV infusion. Angiomax is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage, with a half-life in patients with normal renal function of 25 min. The disposition of Angiomax was studied in PTCA patients with mild and moderate renal impairment and in patients with severe renal impairment. Drug elimination was related to glomerular filtration rate (GFR). Total body clearance was similar for patients with normal renal function and with mild renal impairment (60-89 mL/min). Clearance was reduced approximately 20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-dependent patients. See Table 1 for pharmacokinetic parameters. For patients with renal impairment the activated clotting time (ACT) should be monitored. For dosing instructions, refer to the DOSAGE AND ADMINISTRATION section. Angiomax is hemodialyzable. Approximately 25% is cleared by hemodialysis.
Angiomax does not bind to plasma proteins (other than thrombin) or to red blood cells.
In healthy volunteers and patients (with >/= 70% vessel occlusion undergoing routine angioplasty), Angiomax exhibits linear dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT, and TT. Intravenous administration of Angiomax produces an immediate anticoagulant effect. Coagulation times return to baseline approximately 1 hour following cessation of Angiomax administration.
In 291 patients with >/= 70% vessel occlusion undergoing routine angioplasty, a positive correlation was observed between the dose of Angiomax and the proportion of patients achieving ACT values of 300 sec or 350 sec. At an Angiomax dose of 1.0 mg/kg IV bolus plus 2.5 mg/kg/h IV infusion for 4 hours, followed by 0.2 mg/kg/h, all patients reached maximal ACT values > 300 sec.
Angiomax has been evaluated in five randomized, controlled interventional cardiology trials reporting 11,422 patients. Stents were deployed in 6062 of the patients in these trials - mainly in trials performed since 1995. Percutaneous transluminal coronary angioplasty (PTCA), atherectomy or other procedures were performed in the remaining patients.
This was a randomized double-blind multicenter study reporting 6002 (intent-to-treat) patients undergoing percutaneous coronary intervention (PCI). Patients were randomized to treatment with Angiomax® (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 Angiomax in the following circumstances:
During the study, one or more of these circumstances occurred in 12.7% of patients in the Angiomax with provisional GPI arm. GPIs were administered to 7.2% of patients in the Angiomax with provisional GPI arm (62.2% 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 included unstable angina (35% of patients), myocardial infarction within 7 days prior to intervention (8% of patients), stable angina (25%) and positive ischemic stress test (24%). Stents were deployed in 85% of patients. Ninety-nine percent of patients received aspirin and 86% received thienopyridines prior to study treatment.
Angiomax was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for the duration of the procedure. At investigator discretion, the infusion could be continued the procedure for up to 4 hours. The median infusion duration was 44 min. Heparin was administered as a 65 U/kg bolus. 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 Angiomax with provisional GPI (they were given abciximab or eptifibatide according to pre-randomization investigator choice and patient stratification).
The activated clotting time (ACT - measured by a Hemochron® device) was measured 5 min after the first bolus of study medication. The percent of patients reaching protocol-specified levels of anticoagulation was greater in the Angiomax with provisional GPI group than in the heparin plus GPI group. For patients randomized to Angiomax 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 (Angiomax 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 Angiomax 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 Angiomax with provisional GPI arm (2.4%) compared to the heparin plus GPI arm (4.1%). Study outcomes are shown in Table 2.
At 12 months follow-up, mortality was 1.9% among patients randomized to Angiomax with "provisional" GPIs and 2.5% among patients randomized to heparin plus GPI.
Bivalirudin Angioplasty Trial (BAT):
Angiomax 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, 4312 patients with unstable angina, including 741 (17%) patients with post-MI angina, were treated in a 1:1 randomized fashion with Angiomax 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 Angiomax were started on an intravenous infusion of Angiomax (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 Angiomax (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 Angiomax dose was not titrated to ACT. Median ACT values were: ACT in sec (5 th percentile-95 th 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 Angiomax and heparin treatment groups (about 20% in both groups).
The studies were designed to demonstrate the safety and efficacy of Angiomax 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 Angiomax and the heparin treatment groups. The rates of procedural failure were similar in the Angiomax and heparin treatment groups. Study outcomes are shown in Table 3.
INDICATIONS AND USAGE
Angiomax® (bivalirudin) is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).
Angiomax with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as listed in the CLINICAL TRIAL REPLACE-2 section is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI).
Angiomax is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin (see CLINICAL TRIALS and DOSAGE AND ADMINISTRATION ).
The safety and effectiveness of Angiomax have not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.
Angiomax is contraindicated in patients with:
-active major bleeding;
-hypersensitivity to Angiomax or its components.
Angiomax is not intended for intramuscular administration. Although most bleeding associated with the use of Angiomax in PCI occurs at the site of arterial puncture, hemorrhage can occur at any site. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of Angiomax administration.
An increased risk of thrombus formation has been associated with the use of Angiomax in gamma brachytherapy, including fatal outcomes.
There is no known antidote to Angiomax. Angiomax is hemodialyzable (see CLINICAL PHARMACOLOGY , Pharmacokinetics ).
Clinical trials have provided limited information for use of Angiomax in patients with heparin-induced thrombocytopenia/heparin-induced thrombocytopenia-thrombosis syndrome (HIT/HITTS) undergoing PTCA. The number of HIT/HITTS patients treated is inadequate to reliably assess efficacy and safety in these patients undergoing PCI. Angiomax was administered to a small number of patients with a history of HIT/HITTS or active HIT/HITTS and undergoing PCI in an uncontrolled, open-label study and in an emergency treatment program and appeared to provide adequate anticoagulation in these patients. In in vitro studies Angiomax exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS.
Caution should be used when Angiomax is used as the anti-thrombin during brachytherapy procedures. Operators are advised to maintain meticulous catheter technique, with frequent aspiration and flushing, paying special attention to minimizing conditions of stasis within the catheter or vessels (see WARNINGS and Post-marketing Events ).
Angiomax does not exhibit binding to plasma proteins (other than thrombin) or red blood cells.
In clinical trials in patients undergoing PTCA/PCI, co-administration of Angiomax with heparin, warfarin, thrombolytics or glycoprotein IIb/IIIa inhibitors 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. Angiomax should be used with caution in patients with disease states associated with an increased risk of bleeding.
The safety and effectiveness of Angiomax in pediatric patients have not been established.
Among 494 subjects who received Angiomax in clinical trials and were tested for antibodies, 2 subjects had treatment-emergent positive bivalirudin antibody tests. Neither subject demonstrated clinical evidence of allergic or anaphylactic reactions and repeat testing was not performed. Nine additional patients who had initial positive tests were negative on repeat testing.
Carcinogenesis, Mutagenesis, and 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/m 2 ) of a 50 kg person given the maximum recommended dose of 15 mg/kg/day.
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.
Pregnancy Category B:
Teratogenicity 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.
It is not known whether Angiomax 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.
In studies of patients undergoing PCI, 44% were >/=65 years of age, and 12% 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.
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 4.
In 4312 patients undergoing PTCA for treatment of unstable angina in 2 randomized, double-blind studies comparing Angiomax® (bivalirudin) to heparin, Angiomax patients exhibited lower rates of major bleeding and lower requirements for blood transfusions. The incidence of major bleeding is presented in Table 5. The incidence of major bleeding was lower in the Angiomax group than in the heparin group.
Other Adverse Events:
Adverse events observed in clinical trials are similar between the Angiomax-treated patients and the control groups. Adverse events seen are those typical of PCI trials, see Tables 6 and 7. Table
Serious, non-bleeding adverse events were experienced in 2% of 2161 Angiomax-treated patients and 2% of 2151 heparin-treated patients. The following individual serious non-bleeding adverse events were rare (>0.1% to <1%) and similar in incidence between Angiomax- and heparin-treated patients. These events are listed by body system: Body as a Whole: fever, infection, sepsis; Cardiovascular: hypotension, syncope, vascular anomaly, ventricular fibrillation; Nervous: cerebral ischemia, confusion, facial paralysis; Respiratory: lung edema; Urogenital: kidney failure, oliguria.
In the double-blind, randomized REPLACE-2 trial comparing Angiomax with "provisional" GPI to Heparin plus GPI described above similar adverse events were reported in both treatment groups:
The following events have been reported: fatal bleeding; hypersensitivity and allergic reactions including very rare reports of anaphylaxis; thrombus formation during PCI with and without intracoronary brachytherapy, including reports of fatal outcomes.
Single bolus doses of Angiomax up to 7.5 mg/kg have been reported without associated bleeding or other adverse events.Discontinuation of Angiomax leads to a gradual reduction in anticoagulant effects due to metabolism of the drug. In cases of overdosage, treatment with Angiomax should be immediately discontinued and the patient monitored closely for signs of bleeding. Angiomax is hemodialyzable (see CLINICAL PHARMACOLOGY , Pharmacokinetics ). There is no known antidote to Angiomax.
DOSAGE AND ADMINISTRATION
The recommended dose of Angiomax is an intravenous (IV) bolus dose of 0.75 mg/kg. This should be followed by an infusion of 1.75 mg/kg/h for the duration of the PCI procedure. Five min after the bolus dose has been administered, an 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 any of the conditions listed in CLINICAL TRIALS -REPLACE-2 is present.
Continuation of the infusion for up to 4 hours post-procedure is optional, at the discretion of the treating physician. After 4 hours, an additional IV infusion of Angiomax may be initiated at a rate of 0.2 mg/kg/h for up to 20 hours, if needed. Angiomax is intended for use with aspirin (300-325 mg daily) and has been studied only in patients receiving concomitant aspirin.
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 1.75 mg/kg/h. If the creatinine clearance is less than 30 mL/min, reduction of the infusion rate to 1.0 mg/kg/h should be considered. If a patient is on hemodialysis, the infusion should be reduced to 0.25 mg/kg/h. No reduction in the bolus dose is needed. See Table 1 in CLINICAL PHARMACOLOGY for details regarding the half-life in patients with renal impairment.
Instructions for Administration:
Angiomax® (bivalirudin) is intended for intravenous injection and infusion after 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 8.
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 8.
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.
Angiomax® (bivalirudin) is supplied as a sterile, lyophilized product in single-use, glass vials. After reconstitution, each vial delivers 250 mg of Angiomax.
Store Angiomax dosage units at 20-25°C (68-77°F). Excursions to 15-30°C permitted. [See USP Controlled Room Temperature.]
Ben Venue Laboratories
THE MEDICINES COMPANY
Parsippany, NJ 07054
For information call: (800) 264-4662
U.S. Patent 5,196,404
Hemochron® is a registered trademark of International Technidyne Corporation, Edison, NJ.
TMC PN 1601-9 (June 14, 2005)