CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`RESEARCH
`
`APPLICA TION NUMBER:
`APPLICATION NUMBER:
`APPLICA TION NUMBER:
`20-873
`20-873
`20-8 73
`
`APPROVED LABELING
`APPROVED LABELING
`APPROVED LABELING
`
`MYLAN - EXHIBIT 1058
`
`0001
`
`0001
`
`MYLAN - EXHIBIT 1058
`
`

`

`NDA 20-873
`NDA 20-873
`Page 4
`Page 4
`
`ANGIOMAX™ (bivalirudin) Injection
`ANGIOMAX114 (bivalirudin) Injection _
`
`DESCRIPTION
`DESCRIPTION
`
`Angiomax™ (bivalirudin) is a specific and reversible direct thrombin inhibitor. The active substance is a synthetic,
`AngiomaxTM (bivalirudin) 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-glycyl-glycyl-glycyl-glycyl-
`20 amino acid peptide. The chemical name 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-isoIeucyl-L-prolyl-L-gkiiamyl-L-glutamyl-L-
`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 ef Angiomax ™ is 2180 daltons
`tyrosyl-L-leucine trifluoroacetate (salt) hydrate (Figure 1). The molecular weight of Angiomax TM is 2180 daltons
`(anhydrous free base peptide). Angiomax ™ is supplied in single-use vials as a white lyophilized cake, which is sterile.
`(anhydrous free base peptide). Angiomax TM 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 to 6 (equivalent
`Each vial contains 250 mg bivalirudin, 125 mg mannitol, and sodium hydroxide to adjust the pH to 5 to 6 (equivalent
`of approximately 12.5 mg sodium). When reconstituted with Sterile Water for Injection the product yields a clear to
`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.
`opalescent. colorless to slightly yellow solution, pH 5-6.
`
`Figure 1. Structural Formula for Bivalirudin
`Figure 1. Structural Formula for Bivalirudin
`
`O
`O
`O
`O
`O
`O
`O
`O
`0
`o
`O
`O
`O
`0
`O
`0— 0
`0
`0
`0
`0
`0
`0
`0
`II-
`II
`II
`11
`11
`11
`11
`II
`II
`11
`II-
`II
`H,N-CH-C-N-CH-C-NH-CH-C-N-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-
`H2N-CH-P-N-CH-C-NH-CH-C-N-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-
`1
`1
`I
`1
`1
`I
`I
`I
`/ \
`I
`\
`i
`I
`i
`'
`‘`2
`I
`\
`I
`H
`CHJ CHJ CH2
`H
`H
`CH2 CHJ CHJ
`H
`H
`CHJ
`CHj
`CHj
`CH2 CH2 CH2
`CH2 CH2 CH2
`H
`H
`H
`H
`CH2
`CH2
`H
`CH2
`I
`I
`I
`\
`/
`I
`I
`I
`n \
`CHj CHJ
`C
`C
`CH2 CH2
`c
`C
`I
`// \
`// \
`CHj
`O OH
`O NHj
`CH2
`0 NH2
`0 OH
`1
`NH
`NH
`
`u \
`
`CHJ
`CH2
`
` C
`
`C / w
`HjN NH
`H2N NH
`
`o
`o
`o
`o
`o
`O
`O
`O
`o
`O
`O
`0
`0
`0
`0
`0
`II
`J
`'I
`Il
`II
`II
`li
`-NH-CH-C-NH-CH-C-NH-CH-C-N-CH-C-N
`H-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-OH
`-NH-CH-C-NH-CH-C-NH-CH-j-N-CH-d-NH-CH-C-NH-CH-C-NH-CH-C-NH-CH-C-OH
`/ \
`1
`1
`I
`I
`I
`I
`/
`\
`QH CHj CHj -CHJ
`CHJ
`CH?
`CHj
`CHj
`pH CH2 CH2 __CH2
`CH2
`CH2
`CH2
`CH2
`/\
`\
`/
`I .
`I
`I
`I
`I
`CHJ
`CHJ
`CHJ CHJ CHj CHj
`CH
`CH2 CH3 CH2 CH2
`CH2 — CH2
`CH
`/ \
`I
`I
`_c_
`CH3 CHj
`C
`a
`C
`c
`C
`CH3 CH3
`e \
`f\
`// \
`// \
`--
`.
`0_ OH O OH
`O OH O OH _OH
`0 OH 0 OH
`0 OH 0 OH
`OH
`
`CHj
`CH2
`
`CHJ
`CH2
`
`CH3
`CHj
`
`CLINICAL PHARMACOLOGY
`CLINICAL PHARMACOLOGY
`
`.
`General:
`General:
`Angiomax™ directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding
`AngiomaxTM 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
`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 Xm to Factor XIDa,
`thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor
`allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates
`allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates
`Factors V and Vm, promoting further thrombin generation, and activates platelets, stimulating aggregation and
`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-
`granule release. The binding of Angiomax Tm to thrombin is reversible as thrombin slowly cleaves the Angiomax-
`Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.
`Argr Proa bond, resulting in recovery of thrombin active site functions.
`
`'r. in vitro studies, bivalirudin inhibited both soluble (free) and clot-bound thrombin, was not neutralized by products
`Tr. in vitro studies, bivalirudin 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),
`of the platelet release reaction, and prolonged the activated partial thromboplastin time (aPTT), thrombin time (TT),
`
`0002
`
`0002
`
`

`

`NDA 20-873
`NDA 20-873
`Page 5
`Page 5
`
`and prothrombin time (PT) of norma] human plasma in a concentration-dependent manner. The clinical relevance
`and prothrombin time (PT) of normal human plasma in a concentration-dependent manner. The clinical relevance
`of these findings is unknown.
`of these findings is unknown.
`
`Pharmacokinetics: —
`Pharmacokinetics:
`Bivalirudin exhibits linear pharmacokinetics following intravenous (IV) adriiinistration to patients undergoing
`Bivalirudin exhibits linear pharmacokinetics following intravenous (IV) administration to patients undergoing
`.
`percutaneous transluminal coronary angioplasty (PTCA). In these patients, a mean steady state bivalirudin
`percutaneous transluminal coronary angioplasty (PICA). In these patients, a mean steady state bivalirudin
`concentration of 12.3 ± 1.7 mcg/mL is achieved following an FV bolus of 1 mg/kg and a 4-hour 2.5 mg/kg/h FV
`-
`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. Bivalirudin is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage, with
`infusion. Bivaliru—din 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 minutes. The disposition of bivalirudin was studied in
`— a half-life in patients with normal renal function of 25 minutes. The disposition of bivalirudin was studied in
`PTCA patients with mild and moderate renal function and in patients with severe renal function. Drug
`PICA patients with mild and moderate renal function and in patients with severe renal function. Drug
`elimination was related to glomerular filtration rate (GFR). Total body clearance was similar for patients with
`elimination was related to glomerular filtration rate (GFR). Total body clearance was similar for patients with
`normal renal function and with mild renal impaiiment (60-89mL/min). Clearance was reduced approximately
`normal renal function and with mild renal impairment (60-89mUrnin). Clearance was reduced approximately
`20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-
`20% in patients with moderate and severe renal impairment and was reduced approximately 80% in dialysis-
`dependent patients. See Table 1 for pharmacokinetic parameters and dose reduction recommendations. For
`dependent patients. _See Table 1 for pharmacokinetic parameters and dose reduction recommendations. For
`patients with renal impairment the activated clotting time (ACT) should be monitored. Bivalirudin is
`patients withrenal impairment the activated clotting time (ACT) should be monitored. Bivalirudin is
`hemodialyzable. Approximately 25% is cleared by hemodialysis.
`hemodialyzable. Approximately 25% is cleared by hemodialysis.
`
`Bivalirudin does not bind to plasma proteins (other than thrombin) or to red blood cells.
`Bivalirudin does not bind to plasma proteins (other than thrombin) or to red blood cells.
`
`Table 1. PK parameters and dose adjustments in renal impairment
`Table 1. PK parameters and dose adjustments in renal impairment
`Half-life % reduction in
`Renal Function
`Clearance
`Renal Function
`Clearance
`Half-life % reduction in
`(minutes)
`infusion dose
`(GFR, ml/min)
`(mL/min/kg)
`(GFR, ml/min)
`(minutes)
`infusion dose
`(mL/min/kg)
`
`-
`
`Normal renal^ function
`Normal renal function
`(>90 ml/min)
`(.?_90 m1/min)
`Mild renal impairment
`Mild renal impairment
`(60-90 ml/min)
`(60-90 ml;min)
`Moderate renal impairment
`Moderate renal impairment
`(30-59 ml/min)
`(30-59 ml/min)
`Severe renal impairment
`Se‘ ere renal impairment
`(10-29 ml/min)
`(10-29 ml!min)
`Dialysis-dependent
`Dialysis-dependent
`patients (off dialysis)
`patients (off dialysis)
`
`3.4
`3.4
`
`3.4
`3.4
`
`2.7
`2.7
`
`2.8
`2.8
`
`1.0
`1.0
`
`25
`25
`
`22
`2-2
`
`34
`34
`
`57
`57
`
`3.5 hours
`3.5 hours
`__
`
`* The ACT should be menitored in renally-impaired pari ents
`* The ACT should be—Menitored in renally-impaired patients
`
`0
`0
`--
`0
`0
`
`20
`20
`
`60
`60
`
`90
`90
`
`~
`—
`Pharmacodynamics:
`Pha rmacodynamics:
`In healthy volunteers and patients (with > 70% vessel occlusion undergoing routine angioplasty), bivalirudin exhibits
`In healthy volunteers and patients (with 70% vessel occlusion undergoing routine angioplasty), bivalirudin exhibits
`linear dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT,
`linear dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of the ACT, aPTT, PT,
`and TT. Intraveiious administration of Angiomax ™ produces an immediate anticoagulant effect. Coagulation times
`and TT. Intravenous administration of Angiomax TM produces an immediate anticoagulant effect. Coagulation times
`return to baseline approximately 1 hour following cessation of Angiomax ™ administration.
`return to baseline approximately 1 hour following cessation of Angiomax TM administration.
`
`In 291 patients with > 70% vessel occlusion undergoing routine angioplasty, a positive correlation was observed
`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 of300 sec or 350 sec. At an
`between the dose of Angiomax Trti 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
`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. .
`patients reached maximal ACT values > 300 sec.
`
`Clinical Trials:
`Clinical Trials:
`Angiomax™ was evaluated in patients with unstable angina undergoing PTCA in two randomized, double-blind,
`Angiomax-Tm was evaluated in patients with unstable angina undergoing PICA in two randomized, double-blind,
`
`0003
`
`0003
`
`

`

`NDA 20-873
`_ NDA 20-873
`Page 6
`Page 6
`
`multicenter studies with identical protocols. Patients must have had unstable angina defined as: (1) a new onset of
`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 j study entry or (2) angina or ischemic rest pain
`severe or accelerated angina or rest pain within the month prior
`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
`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 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
`with Angiomax n4 or heparin. Patients ranged in age from 29 —90 (median 63) years, their weight was a median of
`80 kg (39-120kg), 68% were male, and 91% were Caucasian. Twenty-three percent of patients were treated with
`80 kg (39-120kg), 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
`heparin within one hour prior to randomization. All patients were administered aspirin 300-325 mg prior to PICA
`and daily thereafter. Patients randomized to Angiomax ™ were started on an intravenous infusion of Angiomax ™
`and daily thereafter. Patients randomized to Angiomax TM were started on an intravenous infusion of Angiomax TM
`(2.5 mg/kg/h). Within 5 minutes after starting the infusion, and prior to PTCA, a 1 mg/kg loading dose was
`(2.5 mg/kg/h). Within 5 minutes 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
`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
`double-blinded conditions to Angiomax TM (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-minutes and at 45-minutes following
`infusion for an average of 14 hours). The ACT was checked at 5-minutes and at 45-minutes following
`commencement. If on either occasion the ACT was <350 seconds, an additional double-blinded bolus of placebo
`commencement. If on either occasion the ACT was <350 seconds, an additional double-blinded bolus of placebo
`was-administered. The Angiomax™ dose was not titrated to ACT. Median ACT values were: ACT in seconds (5 ^
`wasadministered. The Angiomaxml dose was not titrated to ACT. Median ACT values were: ACT in seconds (5 th
`percentile's"1 percentile): 345 sec (240 - 595 seconds) at 5 min and 346 sec (range 269- 583 sec) at 45 mirt after
`percentile-95th percentile): 345 sec (240 — 595 seconds) 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 lU/kg) as an intravenous bolus
`initiation Gf dosing. Patients randomized to heparin were given a loading dose (175 IU/kg) as an intravenous bolus
`5-minutes before the planned procedure, with immediate commencement of an infusion of heparin (15 lU/kg/h). The
`5-minutes-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-
`infusion was continued for 4 hours. After 4-hours of infusion, the heparin infusion was changed under double-
`blinded conditions to heparin (15 lU/kg/hour) for up to 20 additional hours. The ACT was checked at 5-minutes and
`blinded conditions to heparin (15 IU/kg/hour) for up to 20 additional hours. The ACT was checked at 5-minutes and
`at 45 minutes following commencement. If on either occasion the ACT was <350 seconds, an additional double-blind
`at 45 minutes following commencement. If on either occasion the ACT was <350 seconds, an additional double-blind
`bolus of heparin (60 lU/kg) was administered. Once the target ACT was achieved for heparin patients, no further
`bolus of heparin (60 Ri/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
`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,
`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
`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).
`between Angiomax TM 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
`The studies were designed to demonstrate the safety and efficacy of Angiomax Tm in patients undergoing PICA as
`a treatment for unstable angina as compared with a control group of similar patients receiving heparin during and
`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
`up to 24 hours after initiation of PICA. The primary protocol endpoint was a composite endpoint called
`procedural failure, which included both clinical and angiographic elements measured during hospitalization. The
`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
`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
`conditions. The angiographic elements were: impending or abrupt vessel closure. The protocol-specified safety
`endpoint was rrnjor hemorrhage.
`endpoint was nrijor hemorrhage.
`
`The median duration of hospitalization was 4 days for both the Angiomax ™ treatment group and the heparin
`The median duration of hofffitalization was 4 days for both the Angiomax TM treatment group and the heparin
`treatment group. The rates of procedural failure were similar in the Angiomax ™ and heparin treatment groups.
`treatment group. The rates of procedural fo ire were similar in the Angiomax TM and d heparin treatment groups.
`•
`Study outcomes are shown in Table 2.
`Study outcomes are shown in Table 2.
`
`0004
`
`0004
`
`

`

`NDA 20-873
`NDA 20-873
`Page 7
`Page 7
`
`Table 2. Incidences of In-hospital Clinical Endpoints In Randomized Clinical Trials
`Table 2. Incidences of In-hospital Clinical Endpoints In Randomized Clinical Trials
`Occurring Within 7 Days
`Occurring Within 7 Days
`ANGIOMAX™
`ANGIOMAXIm
`
`HEPARIN
`HEPARIN
`
`All Patients
`AU Patients
`
`Efficacy Endpoints:
`Efficacy Endpoints:
`
`Procedural Failure'
`Procedural Failurel_
`
`Death. MI, Revascularization
`Death. MI, Revascularization
`
`Death
`Death
`
`MI2
`
`Revascularization3
`Revascularization3
`
`•
`
`Safety Endpoint:
`Safety Endpoint:
`
`Major Hemorrhage4
`Major Hemorrhage 4
`
`n=2161
`n=2161
`
`N=2151
`N=2151
`
`-
`
`7.9%
`7.9%
`
`6.2%
`6.2%
`
`0.2%
`0.2%
`
`3.3%
`3.3%
`
`4.2%.
`4.2%
`
`3.5%
`3.5%
`
`9.3%
`9.3%
`
`7.9%
`7.9%
`
`0.2%
`0.2%
`
`4.2%
`4.2%
`
`5.6%
`5.6%
`
`9.3%
`9.3%
`
`-
`
`.
`
`The protocol specified primary endpoint (a composite of death or MI or clinical deterioration of cardiac origin requiring
`' 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).
`revascularization or placement of an aortic balloon pump or angiographic evidence of abrupt vessel closure).
`" Defmedas: Q-wave Ml; CK-MB elevation > 2xULN, new ST- or T-wave abnormality, and chest pain >30 mins; OR new
`2 Defined-as:_Q-wave Ml; CK-MB elevation > 2xULN, new ST- or T-wave abnormality, and chest pain 230 mins; OR new
`LBBB with chest pain >30 mins and/or elevated CK-MB enzymes; OR elevated CK-MB and new ST- or T-wave
`LBBB with chest pain
`mins and/or elevated CK-MB enzymes; OR elevated CK-MB and_new ST- or T-wave
`-
`abnormality without chest pain; OR elevated CK-MB
`abnormality without chest pain; OR elevated CK-MB
`3 Defined as: any revascularization procedure, including angioplasty, CABG, stenting, or placement of an intra-aortic
`3 Defined as: any revascularization procedure, including angioplasty, CABG, stenting, or placement of an intra-aortic
`balloon pump.
`balloon pump.
`4 Defined as the occurrencepf any of the following: intracranial bleeding, retroperitoneal bleeding, clinically overt bleeding
`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.
`with a decrease in hemoglobin 23 g/dL or leading to a transfusion of 22 units of blood.
`_
`-
`INDICATIONS AND USAGE
`INDICATIONS AND USAGE
`
`Angiomax™ is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous
`AneiomaxTm is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous
`transluminal coronary angioplasty (PTCA). Angiomax ™ is intended for use with aspirin and has-been studied only
`transluminal coronary angioplasty (PTCA). Angiomax TM is intended for use with aspirin and has-been studied only
`in patients receiving concomitant aspirin (see CLINICAL TRIALS and DOSAGE AND ADMINISTRATION).
`in patients feceiving concomitant aspirin (see CLINICAL TRIALS and DOSAGE AND ADMINISTRATION).
`
`The safety and effectiveness of Angiomax™ have not been established when used in conjunction with platelet
`The safety and effectiveness of Angiomax II" have not been established when used in conjunction with platelet
`inhibitors other than aspirin, such as glycoprotein Db/IIIa inhibitors. (See PRECAUTIONS, Drug-Interactions).
`inhibitors other than aspirin, such as glycoprotein IM/Ma inhibitors. (See PRECAUTIONS, Drug-Interactions).
`
`The safety and effectiveness of Angiomax™ have not been established in patients with unstable angina who are not
`The safety and effectiveness of Angiomax TM have not been established in patients with unstable angina who are not
`undergoing PTCA or in patients with other acute coronary syndromes.
`undergoing PTCA or in patients with other acute coronary syndromes.
`
`CONTRAINDICATIONS
`CONTRAINDICATIONS
`
`0005
`
`0005
`
`

`

`NDA 20-873
`NDA 20-873
`Page 8
`Page 8
`
`Angiomax™ is contraindicated in patients with:
`AngiomaxTM is contraindicated in patients with:
`active major bleeding;
`-
`-
`active major bleeding;
`hypersensitivity to Angiomax™ or its components.
`-
`-
`hypersensitivity to AngiomaxTM or its components.
`
`WARNINGS
`WARNINGS
`
`Angiomax™ is not intended for intramuscular administration. Although most bleeding associated with the use of
`AngiomaxTM is not intended for intramuscular administration. Although most bleeding associated with the use of
`Angiomax™ in PTCA occurs at the site of aiterial puncture, hemorrhage can occur at any site." An unexplained fall
`• AngiomaxlM in PTCA 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 hemonhagic
`in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic
`event and cessation of Angiomax™ administration.
`event and cessation of AngiomaxTM administration.
`
`There is no known antidote to Angiomax™. Angiomax™ is hemodialyzable (See CLINICAL PHARMACOLOGY,
`There is no known antidote to Angiomax TM. Angiomaxn" is hemodialyzable (See CLINICAL PHARMACOLOGY,
`Pharmacokinetics).
`Pharmacokinetics).
`
`PRECAUTIONS
`PRECAUTIONS
`
`General:
`General:
`Clinical trials have provided limited informaiion for use ofAngiomax ™ in patients with heparin-induced
`Clinical trials have provided limited information for use ofAngiomax TM in patients with heparin-induced
`thrombocytopenia/heparin-induced thrombocytopenia-thrombosis syndrome (HIT/HITTS) undergoing PTCA.
`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
`The number of HIT/HITTS patients treated isin-adequate to reliably assess efficacy and safety in these patients
`undergoing PTCA. Angiomax™ was administered to a small number of patients with a history of HIT/HITTS or
`undergoing PTCA. Angiomax TM was administered to a small number of patients with a history of HIT/HITTS or
`active HIT/HITTS and undergoing PTCA in an uncontrolled, open-label study and in an emergency treatment
`active HIT/HITTS and undergoing PTCA in an uncolitiolled, open-label study and in an emergency treatment
`program and appeared to provide adequate anticoagulation in these patients. In in vitro studies, bivalirudin
`program and appeared to provide adequate anticoagulation in these patients. In in vitro studies, bivalirudin
`exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS.
`exhibited no platelet aggregation response against sera from patients with a history of HIT/HITTS.
`
`Drug Interactions:
`Drug Interactions:
`_
`r
`Bi\ alirudin does not exhibit binding to plasma proteins (other than thrombin) or red blood cells.
`Bivalirudin does not exhibit binding to plasma proteins (other than thrombin) or red blood cells.
`
`Drug-drug interaction studies have been conducted with the adenosine diphosphate (ADP) antagonist, ticlopidine,
`Drug-drug interaction studies have been conducted with the adenosine diphosphate (ADP) antagonist, ticlopidine,
`and the glycoprotein Hb/IIIa inhibitor, abcixuna&Tand with low molecular weight heparin. Although data are
`and the glycoprotein Ilb/lBa inhibitor, abcixirnaband with low molecular weight heparin. Although data are
`limited. precluding conclusions regarding efficacy and safety in combination with these agents, the results do not
`limited.-precluding conclusions regarding efficacy and safety in combination with these agents-, the results do not
`suggest pharmacodynamic interactions. In patients treated with low molecular weight heparin, low molecular
`suggest pharmacodynamic interactions. In patients treated with low molecular weight heparin, low molecular
`weight heparin was discontinued at least 8 hours prior to the procedure and administration of Angiomax ™.
`weight heparin was discontinued at least 8 hours prior to the procedure and administration of Angiomax TM .
`-
`-
`. _
`The safety and effectiveness of Angiomax™ have not been established when used in conjunction with platelet
`The safety and effectiveness of Angiomax_Tm have not been established when used in conjunction with platelet
`inhibitors other than aspirin, such as glycoprotein Hb/IIIa inhibitors.
`inhibitors other than aspirin, such as glycoprotein
`inhibitors.
`
`In clinical trials in patients undergoing PTCA, co-administration of Angiomax ™ with heparin, warfarin or
`In clinical trials in patients undergoing PTCA, co-administration of Angiomax TM with heparin, warfarin or
`thromboKtics was associated with increased risks of major bleeding events compared to patients not receiving these
`thrombolvtics 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
`concomitant medications. There is no experience with co-administration of Angiornax TM and plasma expanders such
`asdextran. Angiomax™ should be used with caution in patients with disease states associated with an increased risk
`as•dextran. AngiomaxTM should be used with caution in patients with disease states associated with an increased risk
`—
`ofbleeding.
`of bleeding.
`
`Pediatric Use:
`Pediatric Use:
`_The safety and effectiveness ofAngiomax™ in pediatric patients have not been established.
`__The safety and effectiveness of Angiomax TM in pediatric patients have not been established.
`
`'
`Inimunogenicity/Re-exposure:
`I n im u nogen icity/Re- exposure:
`.Among 494 subjects who received Angiomax™ in clinical trials and were tested for antibodies, 2 subjects had
`Among 494 subjects who received Angiomax n4 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
`treatment-emergent positive bivalirudin antibody tests. Neither subject demonstrated clinical evidence of allergic or
`rnaphylactic reactions and repeat testing was not performed. Nine additional patients who had initial positive tests
`znaphylactic reactions and repeat testing was not performed. Nine additional patients who had initial positive tests
`
`0006
`
`0006
`
`

`

`NDA 20-873
`NDA 20-873
`Page 9
`Page 9
`
`were negative on repeat testing. -
`were negative on repeat testing. -
`
`Carcinogenesis, mutagenesis, and impairment of fertility:
`Carcinogenesis, mutagenesis, and impairment of fertility:
`No long-term studies in animals have been performed to evaluate the carcinogenic potential of Angiemax ™.
`No long-term studies in animals have been performed to evaluate the carcinogenic potential of Angiomax
`Bivalirudin displayed no genotoxic potential in the in vitro bacterial cell reverse mutation assay (Ames test), the in
`Bivalirudin 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
`vitro Chinese hamster ovary cell forward gene mutation test (CHO/HGPRT), the -in vitro human lymphocyte
`chromosomal abenation assay, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the in vivo
`chromosomal aberration assay, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay, and the in vivo
`rat micronucleus assay. Fertility and general reproductive perfoimance in rats were unaffected by subcutaneous doses
`rat micronucleus assay. Fertility and general reproductive performance in rats were unaffected by subcutaneous doses
`of bivalirudin 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
`of bivalirudin 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.
`given the maximum recommended dose of 15 mg/kg/day.
`
`Pregnancy:
`Pregnancy:
`Angiomax™ is intended for use with aspirin (see INDICATIONS AND USAGE). Because of possible adverse
`AngiomaxT 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,
`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.
`Angiomax TM and aspirin should be used together during pregnancy only if clearly needed.
`
`_
`Pregnancy Category B:
`— Pretnancy Category B:
`Teratogenicity studies have been performed in rats at subcutaneous doses up to 150 mg/kg/day, (1.6 times the
`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
`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
`mgkg/da