Angiomax

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Angiomax uses


Dosage and Administration (2.1) 03/2016
Warning and Precautions (5.2, 5.4) 03/2016

Angiomax is a direct thrombin inhibitor indicated for use as an anticoagulant in patients:


Limitation of use

Safety and effectiveness not established in patients with acute coronary syndromes who are not undergoing PTCA or PCI. (1.4)

1.1 Percutaneous Transluminal Coronary Angioplasty

Angiomax® (bivalirudin) is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).

1.2 Percutaneous Coronary Intervention

Angiomax with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as listed in the REPLACE-2 trial 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.

1.3 Use with Aspirin

Angiomax in these indications is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin .

1.4 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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2 DOSAGE AND ADMINISTRATION

For patients who do not have HIT/HITTS


For patients who have HIT/HITTS


For patients with STEMI

2.1 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 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 .

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.

2.2 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 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 .

2.3 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.

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.

Weight

(kg)

Using 5 mg/mL

Concentration

Using 0.5 mg/mL

Concentration

Bolus

0.75 mg/kg

(mL)

Infusion

1.75 mg/kg/h

(mL/h)

Subsequent

Low-rate Infusion

0.2 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.

2.4 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.

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3 DOSAGE FORMS AND STRENGTHS

For injection: 250 mg of Angiomax in a single-dose vial for reconstitution. Each vial contains 250 mg of Angiomax equivalent to an average of 275 mg Angiomax trifluoroacetate*. Following reconstitution with Sterile Water for Injection, the product is a clear to opalescent, colorless to slightly yellow solution, pH 5-6.

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

For injection: 250 mg of Angiomax in a single-dose vial for reconstitution. (3)

4 CONTRAINDICATIONS

Angiomax is contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

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 . Angiomax 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 (<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.

5.3 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 .

5.4 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.

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6 ADVERSE REACTIONS

Most common adverse reaction was bleeding. 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.

1 GPIs were administered to 7.2% of patients in the Angiomax with provisional GPI group

2 Defined as the occurrence 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 or 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

Angiomax with "provisional" GPI1

(n=2914)

HEPARIN + GPI

(n=2987)

Protocol defined major hemorrhage2 (%) 2.3% 4.0%
Protocol defined minor hemorrhage3 (%) 13.6% 25.8%
TIMI defined bleeding4
- Major 0.6% 0.9%
- Minor 1.3% 2.9%
Non-access site bleeding
- Retroperitoneal bleeding 0.2% 0.5%
- Intracranial bleeding <0.1% 0.1%
Access site bleeding
- Sheath site bleeding 0.9% 2.4%
Thrombocytopenia5
<100,000 0.7% 1.7%
<50,000 0.3% 0.6%
Transfusions
- RBC 1.3% 1.9%
- Platelets 0.3% 0.6%

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.

* No monitoring of ACT (or PTT) was done after a target ACT was achieved.

1 Major hemorrhage was defined as the occurrence 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.

Angiomax

(n=2161)

HEPARIN

(n=2151)

No. (%) Patients with Major hemorrhage1 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.

1 Note: A patient could have more than one event in any category.

Abbreviation: AE = Adverse Event

Angiomax with “provisional” GPI1

(n=2914)

HEPARIN+GPI

(n=2987)

Patients with at least one treatment-related AE n (%) n (%)
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)
Event Treatment Groups
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 Angiomax 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; pulmonary hemorrhage; cardiac tamponade; and INR increased.

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7 DRUG INTERACTIONS

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.

Heparin, warfarin, thrombolytics, or GPIs: Increased major bleeding risk with concomitant use. (7)

8 USE IN SPECIFIC POPULATIONS

Geriatric patients: Increased bleeding risk possible.

Renal impairment: Reduce infusion dose and monitor ACT. (2.2, 8.6)


8.1 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 . 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.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

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

8.5 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.

8.6 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 . The infusion dose of Angiomax may need to be reduced, and anticoagulant status monitored in patients with renal impairment .

10 OVERDOSAGE

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 Angiomax in persons with renal dysfunction including persons on hemodialysis . 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 .

11 DESCRIPTION

Angiomax contains Angiomax which is a specific and reversible direct thrombin inhibitor. Angiomax is a synthetic, 20 amino acid peptide, with the chemical name of D-phenylalanyl-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. The active pharmaceutical ingredient is in the form of Angiomax trifluoroacetate as a white to off-white powder. The chemical name for Angiomax trifluoroacetate is D-phenylalanyl-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 (Figure 1). The molecular weight of Angiomax is 2180 daltons (anhydrous free base peptide).

Figure 1: Structure formula for Angiomax trifluoroacetate

Angiomax is supplied as a sterile white lyophilized cake, in single-dose vials. Each vial contains 250 mg Angiomax, equivalent to an average of 275 mg of Angiomax 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 Angiomax trifluoroacetate is 270 mg to 280 mg based on a range of trifluoroacetic acid composition of 1.7 to 2.6 equivalents.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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 bivalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.

In in vitro studies, Angiomax inhibited both soluble 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.

12.2 Pharmacodynamics

In healthy volunteers and patients (with ≥70% vessel occlusion undergoing routine PTCA), Angiomax exhibited 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 PTCA, 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 a Angiomax dose of 1 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.

12.3 Pharmacokinetics

Angiomax exhibits linear pharmacokinetics following IV administration to patients undergoing 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 does not bind to plasma proteins (other than thrombin) or to red blood cells. 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, moderate, and 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 in patients with moderate and severe renal impairment and in dialysis-dependent patients.

Angiomax is hemodialyzable, with approximately 25% cleared by hemodialysis.

* The ACT should be monitored in renally-impaired patients
Renal Function (GFR, mL/min) Clearance

(mL/min/kg)

Half-life

(min)

Normal renal function (≥90 mL/min) 3.4 25
Mild renal impairment (60-89 mL/min) 3.4 22
Moderate renal impairment (30-59 mL/min) 2.7 34
Severe renal impairment (10-29 mL/min) 2.8 57
Dialysis-dependent patients (off dialysis) 1.0 3.5 hours

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

14.1 PCI/PTCA

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, atherectomy or other procedures were performed in the remaining patients.

REPLACE-2 Trial

This was a randomized, double-blind, multicenter study reporting 6002 (intent-to-treat) patients undergoing PCI. Patients were randomized to treatment with Angiomax 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 10.9% of patients in the Angiomax with provisional GPI arm. GPIs were administered to 7.2% of patients in the Angiomax 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.

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. 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 65U/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 Angiomax 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 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 7.

1 Defined as intracranial bleeding, retroperitoneal bleeding, a transfusion of ≥2 units of blood/blood products, a fall in Hgb >4 g/dL, whether or not bleeding site is identified, spontaneous or non-spontaneous blood loss with a decrease in Hgb >3 g/dL

2 p-value <0.001 between groups

Intent-to-treat Population ANGIOMAX with

"Provisional" GPI

(n=2994)

HEPARIN + GPI

(n=3008)

Efficacy Endpoints
Death, MI, or urgent revascularization 7.6% 7.1%
Death 0.2% 0.4%
MI 7.0% 6.2%
Urgent revascularization 1.2% 1.4%
Safety Endpoint
Major hemorrhage1,2 2.4% 4.1%

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.

Angiomax 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 (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 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 8.

1 The protocol-specified primary endpoint (a composite of death or MI or clinical deterioration of cardiac origin requiring revascularization or placement of an aortic balloon pump or angiographic evidence of abrupt vessel closure).

2 Defined as: Q-wave MI; CK-MB elevation ≥2 x ULN, new ST- or T-wave abnormality, and chest pain ≥30 min; OR new LBBB with chest pain ≥30 min and/or elevated CK-MB enzymes; OR elevated CK-MB and new ST- or T-wave abnormality without chest pain; OR elevated CK-MB.

3 Defined as: any revascularization procedure, including angioplasty, CABG, stenting, or placement of an intra-aortic balloon pump.

4 Defined as the occurrence of any of the following: intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding with a decrease in Hgb ≥3 g/dL or leading to a transfusion of ≥2 units of blood.

All Patients Angiomax

(n=2161)

HEPARIN

(n=2151)

Efficacy Endpoints
Procedural failure1 7.9% 9.3%
Death, MI, revascularization 6.2% 7.9%
Death 0.2% 0.2%
MI2 3.3% 4.2%
Revascularization3 4.2% 5.6%
Safety Endpoint
Major hemorrhage4 3.5% 9.3%

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. Angiomax 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 Angiomax and GPIs.

16 HOW SUPPLIED/STORAGE AND HANDLING

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

*The range of Angiomax 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.

17 PATIENT COUNSELING INFORMATION

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

Angiomax pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Angiomax available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Angiomax destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Angiomax Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Angiomax pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."ANGIOMAX (BIVALIRUDIN) INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION [THE MEDICINES COMPANY]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."BIVALIRUDIN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Bivalirudin". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Angiomax?

Depending on the reaction of the Angiomax after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Angiomax not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Angiomax addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Angiomax, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Angiomax consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

One visitor reported useful

How is the drug Angiomax useful in reducing or relieving the symptoms? How useful is it?
According to the survey conducted by the website sdrugs.com, there are variable results and below are the percentages of the users that say the medicine is useful to them and that say it is not helping them much. It is not ideal to continue taking the medication if you feel it is not helping you much. Contact your healthcare provider to check if there is a need to change the medicine or if there is a need to re-evaluate your condition. The usefulness of the medicine may vary from patient to patient, depending on the other diseases he is suffering from and slightly depends on the brand name.
Visitors%
Useful1
100.0%

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

Visitor reported doses

No survey data has been collected yet

One visitor reported time for results

What is the time duration Angiomax drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sdrugs.com website users needed 1 month to notice the result from using Angiomax drug. The time needed to show improvement in health condition after using the medicine Angiomax need not be same for all the users. It varies based on other factors.
Visitors%
1 month1
100.0%

Visitor reported administration

No survey data has been collected yet

Visitor reported age

No survey data has been collected yet

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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