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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Bleeding events: Hemorrhage can occur at any site. Discontinue Angiomax for an unexplained fall in blood pressure or hematocrit. ( 5.1 ) • Coronary artery brachytherapy: Risk of thrombus formation, including fatal outcomes, in gamma brachytherapy. ( 5.2 ) 5.1 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. 5.2 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 )].
6 ADVERSE REACTIONS Most common adverse reaction was bleeding (28%). Other adverse reactions (incidence >0.5%) were headache, thrombocytopenia and fever. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact The Medicines Company at 1-800-264-4662 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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" GPI 1 (n=2914) HEPARIN + GPI (n=2987) p-value 1 GPIs were administered to 7.2% of patients in the Angiomax with provisional GPI group 2 Defined as the occurence of any of the following: intracranial bleeding, retroperitoneal bleeding, a transfusion of ≥2 units of blood/blood products, a fall in hemoglobin >4 g/dL, whether of not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in hemoglobin >3 g/dL 3 Defined as observed bleeding that does not meet the criteria for major hemorrhage 4 TIMI major bleeding is defined as intracranial, or a fall in adjusted Hgb >5 g/dL or Hct of >15%: TIMI minor bleeding is defined as a fall in adjusted Hgb of 3 to <5 g/dL or a fall in adjusted Hct of 9 to <15%, with a bleeding site such as hematuria, hematemesis, hematomas, retroperitoneal bleeding or a decrease in Hgb of >4 g/dL with no bleeding site 5 If <100,000 and >25% reduction from baseline, or <50,000 Protocol defined major hemorrhage 2 (%) 2.3% 4.0% <0.001 Protocol defined minor hemorrhage 3 (%) 13.6% 25.8% <0.001 TIMI defined bleeding 4 - Major 0.6% 0.9% 0.259 - Minor 1.3% 2.9 <0.001 Non-access site bleeding - Retroperitoneal bleeding 0.2% 0.5% 0.069 - Intracranial bleeding <0.1% 0.1% 1.0 Access site bleeding - Sheath site bleeding 0.9% 2.4% <0.001 Thrombocytopenia 5 <100,000 0.7% 1.7% <0.001 <50,000 0.3% 0.6% 0.039 Transfusions - RBC 1.3% 1.9% 0.08 - Platelets 0.3% 0.6% 0.095 In 4312 patients undergoing PTCA for treatment of unstable angina in 2 randomized, double-blind studies comparing Angiomax 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 3. The incidence of major bleeding was lower in the Angiomax group than in the heparin group. Table 3. Major Bleeding and Transfusions in BAT Trial (all patients) 1 Angiomax N=2161 Heparin N=2151 1 No monitoring of ACT (or PTT) was done after a target ACT was achieved. 2 Major hemorrhage was defined as the occurence of any of the following, intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin ≥3 g/dL or leading to a transfusion of ≥2 units of blood. This table includes data from the entire hospitalization period. No. (%) Patients with Major hemorrhage 2 79 (3.7) 199 (9.3) - with ≥3 g/dL fall in Hgb 41 (1.9) 124 (5.8) - with ≥5 g/dL fall in Hgb 14 (0.6) 47 (2.2) - retroperitoneal bleeding 5 (0.2) 15 (0.7) - intracranial bleeding 1 (<0.1) 2 (0.1) - Required transfusions 43 (2.0) 123 (5.7) In the AT-BAT study, of the 51 patients with HIT/HITTS, 1 patient who did not undergo PCI had major bleeding during CABG on the day following angiography. Nine patients had minor bleeding (mostly due to access site bleeding), and 2 patients developed thrombocytopenia. Other Adverse Reactions Adverse reactions, other than bleeding, observed in clinical trials were similar between the Angiomax treated patients and the control groups. Adverse reactions (related adverse events ) seen in clinical studies in patients undergoing PCI and PTCA are shown in Tables 4 and 5. Table 4. Most frequent (≥0.2%) treatment-related adverse events (reactions) (through 30 days) in the REPLACE-2 Safety population Angiomax with "provisional" GPI 1 (N = 2914) Heparin+GPI (N = 2987) Note: A patient could have more than one event in any category. Abbreviation: AE = adverse event. n (%) n (%) Patients with at least one treatment-related AE 78 (2.7) 115 (3.9) Thrombocytopenia 9 (0.3) 30 (1.0) Nausea 15 (0.5) 7 (0.2) Hypotension 7 (0.2) 11 (0.4) Angina pectoris 5 (0.2) 12 (0.4) Headache 6 (0.2) 5 (0.2) Injection site pain 3 (0.1) 8 (0.3) Nausea and vomiting 2 (0.1) 6 (0.2) Vomiting 3 (0.1) 5 (0.2) Table 5. Adverse Events Other Than Bleeding Occurring In ≥5% Of Patients In Either Treatment Group In BAT Trial Treatment Group EVENT Angiomax N=2161 Heparin N=2151 Number of Patients (%) CARDIOVASCULAR Hypotension 262 (12) 371 (17) Hypertension 135 (6) 115 (5) Bradycardia 118 (5) 164 (8) GASTROINTESTINAL Nausea 318 (15) 347 (16) Vomiting 138 (6) 169 (8) Dyspepsia 100 (5) 111 (5) GENITOURINARY Urinary retention 89 (4) 98 (5) MISCELLANEOUS Back pain 916 (42) 944 (44) Pain 330 (15) 358 (17) Headache 264 (12) 225 (10) Injection site pain 174 (8) 274 (13) Insomnia 142 (7) 139 (6) Pelvic pain 130 (6) 169 (8) Anxiety 127 (6) 140 (7) Abdominal pain 103 (5) 104 (5) Fever 103 (5) 108 (5) Nervousness 102 (5) 87 (4) 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 BAT trial, there was no causality assessment for adverse events. 6.2 Immunogenicity/Re-Exposure In in vitro studies, Angiomax exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS. 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. 6.3 Postmarketing Experience Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during postapproval use of Angiomax: fatal bleeding; hypersensitivity and allergic reactions including reports of anaphylaxis; lack of anticoagulant effect; thrombus formation during PCI with and without intracoronary brachytherapy, including reports of fatal outcomes.
adverse reactions table
<table ID="_Refid_41491323-cf8f-4613-923f-7e6447026" width="100%"> <caption> Table 2. Major Hematologic Outcomes REPLACE-2 Study (Safety Population) </caption> <col width="35%"/> <col width="25%"/> <col width="25%"/> <col width="15%"/> <thead> <tr> <th align="left" styleCode="Rrule Botrule Toprule " valign="bottom"/> <th align="center" styleCode="Rrule Botrule Toprule " valign="bottom"> <content styleCode="bold"> Angiomax with "provisional" GPI<sup>1</sup> </content> <content styleCode="bold">(n=2914) </content> </th> <th align="center" styleCode="Rrule Botrule Toprule " valign="bottom"> <content styleCode="bold"> HEPARIN + GPI</content> <content styleCode="bold">(n=2987) </content> </th> <th align="center" styleCode="Botrule Toprule " valign="bottom"> <content styleCode="bold"> p-value </content> </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4" styleCode="Botrule" valign="top"> <sup>1</sup> GPIs were administered to 7.2% of patients in the Angiomax with provisional GPI group <sup>2</sup> Defined as the occurence of any of the following: intracranial bleeding, retroperitoneal bleeding, a transfusion of ≥2 units of blood/blood products, a fall in hemoglobin >4 g/dL, whether of not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in hemoglobin >3 g/dL <sup>3</sup> Defined as observed bleeding that does not meet the criteria for major hemorrhage <sup>4</sup> TIMI major bleeding is defined as intracranial, or a fall in adjusted Hgb >5 g/dL or Hct of >15%: TIMI minor bleeding is defined as a fall in adjusted Hgb of 3 to <5 g/dL or a fall in adjusted Hct of 9 to <15%, with a bleeding site such as hematuria, hematemesis, hematomas, retroperitoneal bleeding or a decrease in Hgb of >4 g/dL with no bleeding site <sup>5</sup> If <100,000 and >25% reduction from baseline, or <50,000 </td> </tr> </tfoot> <tbody> <tr> <td styleCode="Toprule " valign="top"> <paragraph> <content styleCode="bold">Protocol defined major hemorrhage<sup>2</sup> (%)</content> </paragraph> </td> <td styleCode="Toprule " valign="top"> <paragraph> 2.3% </paragraph> </td> <td styleCode="Toprule " valign="top"> <paragraph> 4.0% </paragraph> </td> <td styleCode="Toprule " valign="top"> <paragraph> <0.001 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Protocol defined minor hemorrhage<sup>3</sup> (%)</content> </paragraph> </td> <td valign="top"> <paragraph> 13.6% </paragraph> </td> <td valign="top"> <paragraph> 25.8% </paragraph> </td> <td valign="top"> <paragraph> <0.001 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">TIMI defined bleeding<sup>4</sup> </content> </paragraph> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td valign="top"> <paragraph> - Major </paragraph> </td> <td valign="top"> <paragraph> 0.6% </paragraph> </td> <td valign="top"> <paragraph> 0.9% </paragraph> </td> <td valign="top"> <paragraph> 0.259 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> - Minor </paragraph> </td> <td valign="top"> <paragraph> 1.3% </paragraph> </td> <td valign="top"> <paragraph> 2.9 </paragraph> </td> <td valign="top"> <paragraph> <0.001 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Non-access site bleeding</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td valign="top"> <paragraph> - Retroperitoneal bleeding </paragraph> </td> <td valign="top"> <paragraph> 0.2% </paragraph> </td> <td valign="top"> <paragraph> 0.5% </paragraph> </td> <td valign="top"> <paragraph> 0.069 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> - Intracranial bleeding </paragraph> </td> <td valign="top"> <paragraph> <0.1% </paragraph> </td> <td valign="top"> <paragraph> 0.1% </paragraph> </td> <td valign="top"> <paragraph> 1.0 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Access site bleeding</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td valign="top"> <paragraph> - Sheath site bleeding </paragraph> </td> <td valign="top"> <paragraph> 0.9% </paragraph> </td> <td valign="top"> <paragraph> 2.4% </paragraph> </td> <td valign="top"> <paragraph> <0.001 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Thrombocytopenia<sup>5</sup> </content> </paragraph> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td valign="top"> <paragraph> <100,000 </paragraph> </td> <td valign="top"> <paragraph> 0.7% </paragraph> </td> <td valign="top"> <paragraph> 1.7% </paragraph> </td> <td valign="top"> <paragraph> <0.001 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <50,000 </paragraph> </td> <td valign="top"> <paragraph> 0.3% </paragraph> </td> <td valign="top"> <paragraph> 0.6% </paragraph> </td> <td valign="top"> <paragraph> 0.039 </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> <content styleCode="bold">Transfusions</content> </paragraph> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td valign="top"> <paragraph> - RBC </paragraph> </td> <td valign="top"> <paragraph> 1.3% </paragraph> </td> <td valign="top"> <paragraph> 1.9% </paragraph> </td> <td valign="top"> <paragraph> 0.08 </paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph> - Platelets </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph> 0.3% </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph> 0.6% </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph> 0.095 </paragraph> </td> </tr> </tbody> </table>
adverse reactions table
<table ID="_Refid_965ed720-f110-47e4-9a85-6191c9be3" width="100%"> <caption> Table 3. Major Bleeding and Transfusions in BAT Trial (all patients)<sup>1</sup> </caption> <col width="54%"/> <col width="23%"/> <col width="23%"/> <thead> <tr> <th align="left" styleCode="Rrule Botrule Toprule " valign="top"/> <th align="center" styleCode="Rrule Botrule Toprule " valign="top"> <content styleCode="bold"> Angiomax</content> <content styleCode="bold">N=2161 </content> </th> <th align="center" styleCode="Botrule Toprule " valign="top"> <content styleCode="bold"> Heparin</content> <content styleCode="bold">N=2151 </content> </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="7" styleCode="Botrule" valign="top"> <sup>1</sup> No monitoring of ACT (or PTT) was done after a target ACT was achieved. <sup>2</sup> Major hemorrhage was defined as the occurence of any of the following, intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in hemoglobin ≥3 g/dL or leading to a transfusion of ≥2 units of blood. This table includes data from the entire hospitalization period. </td> </tr> </tfoot> <tbody> <tr> <td styleCode="Toprule " valign="top"> <paragraph> No. (%) Patients with Major hemorrhage<sup>2</sup> </paragraph> </td> <td styleCode="Toprule " valign="top"> <paragraph> 79 (3.7) </paragraph> </td> <td styleCode="Toprule " valign="top"> <paragraph> 199 (9.3) </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> - with ≥3 g/dL fall in Hgb </paragraph> </td> <td valign="top"> <paragraph> 41 (1.9) </paragraph> </td> <td valign="top"> <paragraph> 124 (5.8) </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> - with ≥5 g/dL fall in Hgb </paragraph> </td> <td valign="top"> <paragraph> 14 (0.6) </paragraph> </td> <td valign="top"> <paragraph> 47 (2.2) </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> - retroperitoneal bleeding </paragraph> </td> <td valign="top"> <paragraph> 5 (0.2) </paragraph> </td> <td valign="top"> <paragraph> 15 (0.7) </paragraph> </td> </tr> <tr> <td valign="top"> <paragraph> - intracranial bleeding </paragraph> </td> <td valign="top"> <paragraph> 1 (<0.1) </paragraph> </td> <td valign="top"> <paragraph> 2 (0.1) </paragraph> </td> </tr> <tr> <td styleCode="Botrule " valign="top"> <paragraph> - Required transfusions </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph> 43 (2.0) </paragraph> </td> <td styleCode="Botrule " valign="top"> <paragraph> 123 (5.7) </paragraph> </td> </tr> </tbody> </table>