CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`RESEARCH
`
`APPLICA HON NUMBER:
`APPLICATION NUMBER:
`APPLICA TION NUMBER:
`20-883
`20-883
`20-8 83
`
`APPROVED LABELING
`APPROVED LABELING
`APPROVED LABELING
`
`MYLAN - EXHIBIT 1059
`
`0001
`
`0001
`
`MYLAN - EXHIBIT 1059
`
`

`

`NDA 20-883
`NDA 20-883
`Page 4
`Page 4
`
`ACOVA™ (argatroban) Injection
`ACOVATM (argatroban) Injection
`
`DESCRIPTION
`DESCRIPTION
`
`Argatroban is a synthetic direct thrombin inhibitor derived from L-arginine. The
`Argatroban is a synthetic direct thrombin inhibitor derived from L-arginine. The
`chemical name for argatroban is 1-[5-[(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-
`chemical name for argatroban is 145-[(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-
`tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic
`tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]penty1]-4-methyl-2-piperidinecarboxylic
`acid, monohydrate. Argatroban has 4 asymmetric carbons. One of the asymmetric
`acid, monohydrate. Argatroban has 4 asymmetric carbons. One of the asymmetric
`carbons has an R configuration (stereoisomer Type I) and an S configuration
`carbons has an R configuration (stereoisomer Type I) and an S configuration
`(stereoisomer Type II). Argatroban consists of a mixture of R and S stereoisomers in a
`(stereoisomer Type II). Argatroban consists of a mixture of R and S stereoisomers in a
`ratio of approximately 65:35.
`ratio of approximately 65:35.
`
`The molecular formula of argatroban is C23H36N605S*H20. Its molecular weight is
`The molecular formula of argatroban is C23H36N60 5S.1-120. Its molecular weight is
`526.66. The structural formula is shown below:
`526.66. The structural formula is shown below:
`
`HN
`
`H/4
`
`Figure 1
`Figure 1
`O
`0
`
`CO2H
`CO2H
`
`H
`
`• H2O
`
`NH
`0/
`
`H
`N
`
`I
`
`• /
`
`'fcH,
`
`H,
`
`Argatroban is a white, odorless crystalline powder that is freely soluble in glacial acetic
`Argatroban is a white, odorless crystalline powder that is freely soluble in glacial acetic
`acid, slightly soluble in ethanol, and insoluble in acetone, ethyl acetate and ether.
`acid, slightly soluble in ethanol, and insoluble in acetone, ethyl acetate and ether.
`ACOVA™ (argatroban) Injection is a sterile clear, colorless to pale yellow, slightly
`ACOVATM (argatroban) Injection is a sterile clear, colorless to pale yellow, slightly
`viscous solution. ACOVA™ is available in 250 mg (in 2.5 mL) single-use amber vials,
`viscous solution. ACOVATM is available in 250 mg (in 2.5 mL) single-use amber vials,
`with gray flip-top caps. Each mL of sterile, nonpyrogenic solution contains 100 mg
`with gray flip-top caps. Each mL of sterile, nonpyrogenic solution contains 100 mg
`argatroban. Inert ingredients: D-sorbitol, dehydrated alcohol.
`argatroban. Inert ingredients: D-sorbitol, dehydrated alcohol.
`
`CLINICAL PHARMACOLOGY
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`Mechanism of Action
`
`Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site.
`Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site.
`Argatroban does not require the co-factor antithrombin III for antithrombotic activity.
`Argatroban does not require the co-factor antithrombin III for antithrombotic activity.
`Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or induced
`Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or induced
`reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII;
`reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII;
`
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`

`NDA 20-883
`NDA 20-883
`Page 5
`Page 5
`
`protein C; and platelet aggregation.
`protein C; and platelet aggregation.
`
`Argatroban is highly selective for thrombin with an inhibitory constant (KJ of 0.04
`At
`Argatroban is highly selective for thrombin with an inhibitory constant (K,) of 0.04 µM. At
`therapeutic concentrations, argatroban has little or no effect on related serine proteases
`therapeutic concentrations, argatroban has little or no effect on related serine proteases
`(trypsin, factor Xa, plasmin, and kailikrein).
`(trypsin, factor Xa, plasmin, and kallikrein).
`
`Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.
`Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.
`
`Argatroban does not interact with heparin-induced antibodies. Evaluation of sera from
`Argatroban does not interact with heparin-induced antibodies. Evaluation of sera from
`12 healthy subjects and 8 patients who received multiple doses of argatroban did not
`12 healthy subjects and 8 patients who received multiple doses of argatroban did not
`reveal antibody formation to argatroban (see CLINICAL STUDIES).
`reveal antibody formation to argatroban (see CLINICAL STUDIES).
`
`Pharmacokinetics
`Pharmacokinetics
`Distribution
`Distribution
`Argatroban distributes mainly in the extracellular fluid as evidenced by an apparent
`Argatroban distributes mainly in the extracellular fluid as evidenced by an apparent
`steady state volume of distribution of 174 ml/kg (12.18L in a 70 kg adult). Argatroban
`steady state volume of distribution of 174 mUkg (12.18L in a 70 kg adult). Argatroban
`is 54% bound to human serum proteins, with binding to albumin and a^acid
`is 54% bound to human serum proteins, with binding to albumin and a1-acid
`glycoprotein being 20% and 34% respectively.
`glycoprotein being 20% and 34% respectively.
`
`Metabolism
`Metabolism
`The main route of argatroban metabolism is hydroxylation and aromatization of the 3-
`The main route of argatroban metabolism is hydroxylation and aromatization of the 3-
`methyltetrahydroquinoline ring in the liver. The formation of each of the four known
`methyltetrahydroquinoline ring in the liver. The formation of each of the four known
`metabolites is catalyzed in vitro by the human liver microsomal cytochrome P450
`metabolites is catalyzed in vitro by the human liver microsomal cytochrome P450
`enzymes CYP3A4/5. The primary metabolite (M1) exerts 3 to 5-fold weaker
`enzymes CYP3A4/5. The primary metabolite (M1) exerts 3 to 5-fold weaker
`anticoagulant effects than argatroban. Unchanged argatroban is the major component
`anticoagulant effects than argatroban. Unchanged argatroban is the major component
`in plasma. The plasma concentrations of M1 range between 0 - 20% of that of the
`in plasma. The plasma concentrations of M1 range between 0 — 20% of that of the
`parent drug. The other metabolites (M2 - 4) are found only in very low quantities in the
`parent drug. The other metabolites (M2 — 4) are found only in very low quantities in the
`urine and have not been detected in plasma or feces. These data, together with the
`urine and have not been detected in plasma or feces. These data, together with the
`lack of effect of erythromycin (a potent CYP3A4/5 inhibitor) on argatroban
`lack of effect of erythromycin (a potent CYP3A4/5 inhibitor) on argatroban
`pharmacokinetics suggest that CYP3A4/5 mediated metabolism is not an important
`pharmacokinetics suggest that CYP3A4/5 mediated metabolism is not an important
`elimination pathway in vivo.
`-
`elimination pathway in vivo.
`
`Total body clearance is approximately 5.1 mL/min/kg (0.31 L/hr/kg) for infusion doses
`Total body clearance is approximately 5.1 mUmin/kg (0.31 Uhr/kg) for infusion doses
`up to 40 ^tg/kg/min. The terminal elimination half-life of argatroban ranges between 39
`up to 40 µg/kg/min. The terminal elimination half-life of argatroban ranges between 39
`and 51 minutes.
`and 51 minutes.
`
`There is no interconversion of the 21-(R): 21-(S) diastereoisomers. The plasma ratio
`There is no interconversion of the 21—(R): 21—(S) diastereoisomers. The plasma ratio
`of these diastereoisomers is unchanged by metabolism or hepatic impairment,
`of these diastereoisomers is unchanged by metabolism or hepatic impairment,
`remaining constant at 65:35 (+2%).
`remaining constant at 65:35 (±2%).
`
`Excretion
`Excretion
`Argatroban is excreted primarily in the feces, presumably through biliary secretion. In a
`Argatroban is excreted primarily in the feces, presumably through biliary secretion. In a
`study in which 14C-argatroban (5 ng/kg/min) was infused for 4 hours into healthy
`study in which "C-argatroban (5 µg/kg/min) was infused for 4 hours into healthy
`
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`NDA 20-883
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`Page 6
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`
`subjects, approximately 65% of the radioactivity was recovered in the feces within 6
`subjects, approximately 65% of the radioactivity was recovered in the feces within 6
`days of the start of infusion with little or no radioactivity subsequently detected.
`days of the start of infusion with little or no radioactivity subsequently detected.
`Approximately 22% of the radioactivity appeared in the urine within 12 hours of the start
`Approximately 22% of the radioactivity appeared in the urine within 12 hours of the start
`of infusion. Little or no additional urinary radioactivity was subsequently detected.
`of infusion. Little or no additional urinary radioactivity was subsequently detected.
`Average percent recovery of unchanged drug, relative to total dose, was 16% in urine
`Average percent recovery of unchanged drug, relative to total dose, was 16% in urine
`and at least 14% in feces.
`and at least 14% in feces.
`Pharmacokinetic/Phannacodynamic Relationship
`PharmacokineticlPharmacodynamic Relationship
`When ACOVA™ is administered by continuous infusion, anticoagulant effects and
`When ACOVATM is administered by continuous infusion, anticoagulant effects and
`plasma concentrations of argatroban follow similar, predictable temporal response
`plasma concentrations of argatroban follow similar, predictable temporal response
`profiles, with low intersubject variability. Immediately upon initiation of ACOVA™
`profiles, with low intersubject variability. Immediately upon initiation of ACOVATM
`infusion, anticoagulant effects are produced as plasma argatroban concentrations begin
`infusion, anticoagulant effects are produced as plasma argatroban concentrations begin
`to rise. Steady-state levels of both drug and anticoagulant effect are typically attained
`to rise. Steady-state levels of both drug and anticoagulant effect are typically attained
`within 1-3 hours and are maintained until the infusion is discontinued or the dosage
`within 1-3 hours and are maintained until the infusion is discontinued or the dosage
`adjusted. Steady-state plasma argatroban concentrations increase proportionally with
`adjusted. Steady-state plasma argatroban concentrations increase proportionally with
`dose (for infusion doses up to 40 ng/kg/min in healthy subjects) and are well correlated
`dose (for infusion doses up to 40 µg/kg/min in healthy subjects) and are well correlated
`with steady-state anticoagulant effects. For infusion doses up to 40 iig/kg/min,
`with steady-state anticoagulant effects. For infusion doses up to 40 µg/kg/min,
`ACOVA™ increases in a dose-dependent fashion, the activated partial thromboplastin
`ACOVATM increases in a dose-dependent fashion, the activated partial thromboplastin
`time (aPTT), the activated clotting time (ACT), the prothrombin time (PT) and
`time (aPTT), the activated clotting time (ACT), the prothrombin time (PT) and
`International Normalized Ratio (INR), and the thrombin time (TT) in healthy volunteers
`International Normalized Ratio (INR), and the thrombin time (TT) in healthy volunteers
`and cardiac patients. Representative steady-state plasma argatroban concentrations
`and cardiac patients. Representative steady-state plasma argatroban concentrations
`and anticoagulant effects are shown below for ACOVA™ infusion doses up to
`and anticoagulant effects are shown below for ACOVATM infusion doses up to
`10 ng/kg/min (See Figure 2).
`1014/kg/min (See Figure 2).
`
`Figure 2
`Figure 2
`Relationship at Steady State between ACOVA™ Dose, Plasma Argatroban
`Relationship at Steady State between ACOVATM Dose, Plasma Argatroban
`Concentration and Anticoagulant Effect
`Concentration and Anticoagulant Effect
`
`0.4
`0.1
`
`Plasma AiyKEfcon ((igfrnL)
`Plaarra Azgatroban (ant.)
`0B
`1.2
`06
`1.2
`
`1.6
`1.6
`
`20
`T 300
`
`225
`
`iso
`
`75
`
`•
`
`q
`0
`3
`A
`
`•
`
`100
`100
`
`E 75
`I 75
`s
`•
`•
`I 50
`r s
`•
`• 25
`•
`
`50
`
`0
`0
`
`2
`
`6
`6
`4
`Irfuaan dne {Mgfcpftin)
`Irtusion tae ( pgigynin)
`
`6
`
`10
`
`0004
`
`0004
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`

`NDA 20-883
`NDA 20-883
`Page 7
`Page 7
`
`Effect on International Normalized Ratio (INR)
`Effect on International Normalized Ratio (INR)
`
`Because argatroban is a direct thrombin inhibitor, co-administration of ACOVA™ and
`Because argatroban is a direct thrombin inhibitor, co-administration of ACOVATM and
`warfarin produces a combined effect on the laboratory measurement of the INR.
`warfarin produces a combined effect on the laboratory measurement of the INR.
`However, concurrent therapy, compared to warfarin monotherapy, exerts no additional
`However, concurrent therapy, compared to warfarin monotherapy, exerts no additional
`effect on vitamin K dependent factor Xa activity.
`effect on vitamin K dependent factor Xa activity.
`
`The relationship between INR on co-therapy and warfarin alone is dependent on both
`The relationship between INR on co-therapy and warfarin alone is dependent on both
`the dose of ACOVA™ and the thromboplastin reagent used. This relationship is
`the dose of ACOVATM and the thromboplastin reagent used. This relationship is
`influenced by the International Sensitivity Index (ISI) of the thromboplastin. Data for two
`influenced by the International Sensitivity Index (ISI) of the thromboplastin. Data for two
`commonly utilized thromboplastins with ISI values of 0.88 (Innovin, Dade) and 1.78
`commonly utilized thromboplastins with ISI values of 0.88 (Innovin, Dade) and 1.78
`(Thromboplastin C Plus, Dade) are presented in Figure 3 for an ACOVA™ dose of 2
`(Thromboplastin C Plus, Dade) are presented in Figure 3 for an ACOVATM dose of 2
`ng/kg/min. Thromboplastins with higher ISI values than shown result in higher INRs on
`µg/kg/min. Thromboplastins with higher ISI values than shown result in higher INRs on
`combined therapy of warfarin and ACOVA™. These data are based on results obtained
`combined therapy of warfarin and ACOVATM. These data are based on results obtained
`in normal individuals (see DOSAGE AND ADMINISTRATION, Conversion to Oral
`in normal individuals (see DOSAGE AND ADMINISTRATION, Conversion to Oral
`Anticoagulant Therapy).
`Anticoagulant Therapy).
`
`Figure 3
`Figure 3
`INR Relationship of Argatroban plus Warfarin Versus Warfarin Alone
`INR Relationship of Argatroban plus Warfarin Versus Warfarin Alone
`
`TrhIrm't.briv,:sitcrflo::77:3
`
`Thromboplaslin A (ISI = 0 88]
`Thromboplastin B (ISI = 1 78]
`
`Data from 24 Subject
`Data from 24 Subject
`
`W=0ie*0 45*WA .
`W= 0 18 .0 45sWA..
`" ..
`r
`
`•
`
`' 44
`•-•••
`
`W « 0.19 • 0.57xWA
`W = 0.19. 0.57xWA
`
`Error (Confidence interval)
`Error (Confidence Interval)
`Associated with
`Associated with
`Prediction of Warfahn INR:
`Prediction of Warfann INR.
`* 0 4 units
`0.4 units
`
`3
`2
`INR Warfarin Alone (W)
`INR Warfarin Alone (W)
`
`4
`
`INR Warfarin Plus Argatroban (WA)
`
`5
`a
`
`£ &
`s
`%
`M
`
`! ^
`
`2
`
`0.
`
`0
`
`Figure 3 demonstrates the relationship between INR for warfarin alone and INR for warfarin co­
`Figure 3 demonstrates the relationship between INR for warfarin alone and INR for warfarin co-
`administered with argatroban at argatroban doses s2 pg/kg/min. To calculate INR for warfarin alone
`administered with argatroban at argatroban doses s2 µg/kg/min. To calculate INR for warfarin alone
`(INRw). based on INR for co-therapy of warfarin and argatroban (INRWA). use the equation next to the
`(INRW), based on INR for co-therapy of warfarin and argatroban (INRwA), use the equation next to the
`appropriate curve. Example: At a dose of 2 ng/kg/min and an INR performed with Thromboplastin A, the
`appropriate curve. Example: At a dose of 2 µg/kg/min and an INR performed with Thromboplastin A, the
`equation 0.19 + 0.57 (INRWA) = INRw would allow a prediction of the INR on warfarin alone (INRw)-
`equation 0.19 + 0.57 (INRWA) = INRW would allow a prediction of the INR on warfarin alone (INRW).
`Thus, using an INRWA value of 4.0 obtained on combined therapy: INRw =0.19 +0.57 (4)=2.47 as the
`Thus, using an INRWA value of 4.0 obtained on combined therapy: INRW =0.19 +0.57 (4)=2.47 as the
`value for INR on warfarin alone. The error (confidence interval) associated with a prediction is +0.4 units.
`value for INR on warfarin alone. The error (confidence interval) associated with a prediction is +0.4 units.
`Thus, for argatroban doses of 1 or 2 ng/kg/min, INRw can be predicted from INRwA- F01, argatroban
`Thus, for argatroban doses of 1 or 2 µg/kg/min, INRW can be predicted from INRWA. For argatroban
`doses greater than 2 ng/kg/min, the error associated with predicting INRw from INRWA's ±1 • Thus, INRw
`doses greater than 2 µg/kg/min, the error associated with predicting INRW from INRWA is +1. Thus, INRW
`cannot be reliably predicted from INRwA at closes greater than 2 ng/kg/min.
`cannot be reliably predicted from INRWA at doses greater than 2 µg/kg/min.
`
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`NDA 20-883
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`Page 8
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`
`SPECIAL POPULATIONS
`SPECIAL POPULATIONS
`
`Renal Impairment
`Renal Impairment
`No dosage adjustment is necessary in patients with renal dysfunction. The effect of
`No dosage adjustment is necessary in patients with renal dysfunction. The effect of
`renal disease on the pharmacokinetics of argatroban was studied in 6 subjects with
`renal disease on the pharmacokinetics of argatroban was studied in .6 subjects with
`normal renal function (mean Clcr = 95 + 16 mL/min) and in 18 subjects with mild (mean
`normal renal function (mean Clcr = 95 ± 16 mUmin) and in 18 subjects with mild (mean
`Clcr = 64 + 10 mL/min), moderate (mean Clcr = 41 + 5.8 mL/min), and severe (mean
`Clcr = 64 ± 10 mUmin), moderate (mean Clcr = 41 ± 5.8 mUmin), and severe (mean
`Clcr = 5 + 7 mL/min) renal impairment. The pharmacokinetics and pharmacodynamics
`Clcr =.5 ± 7 mUmin) renal impairment. The pharmacokinetics and pharmacodynamics
`of argatroban at dosages up to 5 jig/kg/min were not significantly affected by renal
`of argatroban at dosages up to 5 µg/kg/min were not significantly affected by renal
`dysfunction.
`dysfunction.
`Hepatic Impairment
`Hepatic Impairment
`The dosage of argatroban should be decreased in patients with hepatic impairment,
`The dosage of argatroban should be decreased in patients with hepatic impairment,
`(see DOSAGE AND ADMINISTRATION). Hepatic impairment is associated with
`(see DOSAGE AND ADMINISTRATION). Hepatic impairment is associated with
`decreased clearance and increased elimination half-life of argatroban (to 1.9 mL/min/kg
`decreased clearance and increased elimination half-life of argatroban (to 1.9 mUinin/kg
`and 181 minutes, respectively, for patients with a Child-Pugh score >6).
`and 181 minutes, respectively, for patients with a Child-Pugh score >6).
`
`Age, Gender
`Age, Gender
`
`There are no clinically significant effects of age or gender on the pharmacokinetics or
`There are no clinically significant effects of age or gender on the pharmacokinetics or
`pharmacodynamics (e.g., aPTT) of argatroban.
`pharmacodynamics (e.g., aPTT) of argatroban.
`
`Drug-Drug Interactions
`Drug-Drug Interactions
`
`Digoxin: In 12 healthy volunteers, intravenous infusion of argatroban (2 (ig/kg/min)
`Digoxin: In 12 healthy volunteers, intravenous infusion of argatroban (2 µg/kg/min)
`over 5 hours daily for 5 days did not affect the steady-state pharmacokinetics of oral
`over 5 hours daily for 5 days did not affect the steady-state pharmacokinetics of oral
`digoxin (0.375 mg daily for 15 days).
`digoxin (0.375 mg daily for 15 days).
`
`Erythromycin: In 10 healthy subjects, orally administered erythromycin (a potent
`Erythromycin: In 10 healthy subjects, orally administered erythromycin (a potent
`inhibitor of CYP3A4/5) at 500 mg four times daily for 7 days had no effect on the
`inhibitor of CYP3A4/5) at 500 mg four times daily for 7 days had no effect on the
`pharmacokinetics of argatroban at a dose of 1 ^g/kg/min for 5 hours. These data
`pharmacokinetics of argatroban at a dose of 1 µg/kg/min for 5 hours. These data
`suggest oxidative metabolism by CYP3A4/5 is not an important elimination pathway in
`suggest oxidative metabolism by CYP3A4/5 is not an important elimination pathway in
`vivo for argatroban.
`vivo for argatroban.
`
`CLINICAL STUDIES
`CLINICAL STUDIES
`
`Heparin-induced thrombocytopenia (HIT) is a potentially serious, immune-mediated
`Heparin—induced thrombocytopenia (HIT) is a potentially serious, immune—mediated
`complication of heparin therapy that is strongly associated with subsequent venous and
`complication of heparin therapy that is strongly associated with subsequent venous and
`arterial thrombosis. Whereas initial treatment of HIT is to discontinue administration of
`arterial thrombosis. Whereas initial treatment of HIT is to discontinue administration of
`all heparin, patients may require anticoagulation for prevention and treatment of
`all heparin, patients may require anticoagulation for prevention and treatment of
`thromboembolic events.
`thromboembolic events.
`
`The conclusion that ACOVA™ is an effective treatment for heparin-induced
`The conclusion that ACOVAT'a is an effective treatment for heparin—induced
`thrombocytopenia (HIT) and heparin-induced thrombocytopenia and thrombosis
`thrombocytopenia (HIT) and heparin—induced thrombocytopenia and thrombosis
`syndrome (HITTS) is based upon the data from an historically controlled efficacy and
`syndrome (HITTS) is based upon the data from an historically controlled efficacy and
`
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`NDA 20-883
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`
`safety study (Study 1) and a follow-on efficacy and safety study (Study 2). These
`safety study (Study 1) and a follow-on efficacy and safety study (Study 2). These
`studies were comparable with regard to study design, study objectives, dosing regimens
`studies were comparable with regard to study design, study objectives, dosing regimens
`as well as study outline, conduct and monitoring.
`as well as study outline, conduct and monitoring.
`
`In these studies, 568 adult patients were treated with ACOVA™ and 193 adult patients
`In these studies, 568 adult patients were treated with ACOVATM and 193 adult patients
`made up the historical control group. Patients were required to have a clinical diagnosis
`made up the historical control group. Patients were required to have a clinical diagnosis
`of heparin-induced thrombocytopenia, either without thrombosis (HIT) or with
`of heparin-induced thrombocytopenia, either without thrombosis (HIT) or with
`thrombosis (HITTS) and be males or non-pregnant females between the age of 18 and
`thrombosis (HITTS) and be males or non-pregnant females between the age of 18 and
`80 years old. HIT/HITTS was defined by a fall in platelet count to less than 100,000/^L
`80 years old. HIT/HITTS was defined by a fall in platelet count to less than 100,000/4
`or a 50% decrease in platelets after the initiation of heparin therapy with no apparent
`or a 50% decrease in platelets after the initiation of heparin therapy with no apparent
`explanation other than HIT. Patients with HITTS also had presence of an arterial or
`explanation other than HIT. Patients with HITTS also had presence of an arterial or
`venous thrombosis documented by appropriate imaging techniques or supported by
`venous thrombosis documented by appropriate imaging techniques or supported by
`clinical evidence such as acute myocardial infarction, stroke, pulmonary embolism, or
`clinical evidence such as acute myocardial infarction, stroke, pulmonary embolism, or
`other clinical indications of vascular occlusion. Patients who required anticoagulation
`other clinical indications of vascular occlusion. Patients who required anticoagulation
`with documented histories of positive HIT antibody test were also eligible in the absence
`with documented histories of positive HIT antibody test were also eligible in the absence
`of thrombocytopenia or heparin challenge (e.g., patients with latent disease).
`of thrombocytopenia or heparin challenge (e.g., patients with latent disease).
`Patients with documented unexplained aPTT >200% of control at baseline, documented
`Patients with documented unexplained aPTT >200% of control at baseline, documented
`coagulation disorder or bleeding diathesis unrelated to HITTS, a lumbar puncture within
`coagulation disorder or bleeding diathesis unrelated to HITTS, a lumbar puncture within
`the past 7 days or a history of previous aneurysm, hemorrhagic stroke, or recent
`the past 7 days or a history of previous aneurysm, hemorrhagic stroke, or recent
`thrombotic stroke, within the past 6 months, unrelated to HITTS were excluded from
`thrombotic stroke, within the past 6 months, unrelated to HITTS were excluded from
`these studies.
`these studies.
`
`The initial dose of argatroban was 2 ng/kg/min not to exceed 10 ng/kg/min. Two hours
`The initial dose of argatroban was 2 µg/kg/min not to exceed 10 lig/kg/min. Two hours
`after the start of the argatroban infusion, an aPTT level was obtained and dose
`after the start of the argatroban infusion, an aPTT level was obtained and dose
`adjustments were made to achieve a steady state aPTT value that was 1.5 to 3.0 times
`adjustments were made to achieve a steady state aPTT value that was 1.5 to 3.0 times
`the baseline value, not to exceed 100 seconds. In Study 1, the mean aPTT level for
`the baseline value, not to exceed 100 seconds. In Study 1, the mean aPTT level for
`HIT patients was 38 seconds prior to start of argatroban infusion. At first assessment*,
`HIT patients was 38 seconds prior to start of argatroban infusion. At first assessment*,
`during the argatroban infusion, mean aPTT level for HIT patients was 64 seconds.
`during the argatroban infusion, mean aPTT level for HIT patients was 64 seconds.
`Overall, the mean aPTT level during the argatroban infusion for HIT patients was 62.5
`Overall, the mean aPTT level during the argatroban infusion for HIT patients was 62.5
`seconds. In Study 1, the mean aPTT level for HITTS patients was 34 seconds prior to
`seconds. In Study 1, the mean aPTT level for HITTS patients was 34 seconds prior to
`start of argatroban infusion. At first assessment*, during the argatroban infusion, mean
`start of argatroban infusion. At first assessment*, during the argatroban infusion, mean
`aPTT level for HITTS patients was 70 seconds. Overall, the mean aPTT level during
`aPTT level for HITTS patients was 70 seconds: Overall, the mean aPTT level during
`the argatroban infusion for HITTS patients was 64.5 seconds (see DOSAGE AND
`the argatroban infusion for HITTS patients was 64.5 seconds (see DOSAGE AND
`ADMINISTRATION). (*First assessment was defined as occurring at least two hours
`ADMINISTRATION). (*First assessment was defined as occurring at least two hours
`post-infusion start time.)
`post-infusion start time.)
`
`The primary efficacy analysis was based on a comparison of event rates for a
`The primary efficacy analysis was based on a comparison of event rates for a
`composite endpoint that included death (all causes), amputation (all causes) or new
`composite endpoint that included death (all causes), amputation (all causes) or new
`thrombosis during the treatment and follow-up period (study days 0 to 37). Secondary
`thrombosis during the treatment and follow-up period (study days 0 to 37). Secondary
`analyses included evaluation of the event rates for the components of the composite
`analyses included evaluation of the event rates for the components of the composite
`endpoint as well as time-to-event analyses.
`endpoint as well as time-to-event analyses.
`
`In Study 1, 304 patients were enrolled having active HIT (129/304, 42%), active HITTS
`In Study 1, 304 patients were enrolled having active HIT (129/304, 42%), active HITTS
`(144/304, 47%) or latent disease (31/304, 10%). Among the 193 historical controls, 139
`(144/304, 47%) or latent disease (31/304, 10%). Among the 193 historical controls, 139
`(72%) had active HIT. 46 (24%) had active HITTS, and 8 (4%) had latent disease.
`(72%) had active HIT, 46 (24%) had active HITTS, and 8 (4%) had latent disease.
`Within each group, those with active HIT and those with latent disease were analyzed
`Within each group, those with active HIT and those with latent disease were analyzed
`
`0007
`
`0007
`
`

`

`NDA 20-883
`NDA 20-883
`Page *10
`Page•10
`
`together. Positive laboratory confirmation of HIT/HITTS by the heparin-induced platelet
`together. Positive laboratory confirmation of HIT/HITTS by the heparin-induced platelet
`aggregation test or serotonin release assay was demonstrated in 174 of 304 (57%)
`aggregation test or serotonin release assay was demonstrated in 174 of 304 (57%)
`argatroban-treated patients (i.e., in 80 with HIT or latent disease and 94 with HITTS)
`argatroban-treated patients (i.e., in 80 with HIT or latent disease and 94 with HITTS)
`and in 149 of 193 (77%) historical controls (i.e., in 119 with HIT or latent disease and 30
`and in 149 of 193 (77%) historical controls (i.e., in 119 with HIT or latent disease and 30
`with HITTS). The test results for the remainder of the patients and controls were either
`with HITTS). The test results for the remainder of the patients and controls were either
`negative or not determined.
`negative or not determined.
`
`A categorical analysis showed a significant improvement in the composite outcome in
`A categorical analysis showed a significant improvement in the composite outcome in
`patients with HIT and HITTS treated with ACOVA™ versus those in the historical control
`patients with HIT and HITTS treated with ACOVATm versus those in the historical control
`group (see Table 1). The components of the composite endpoint are shown in Table 2.
`group (see Table 1). The components of the composite endpoint are shown in Table 2.
`
`Table 1
`Table 1
`Efficacy Results of Study 1:
`Efficacy Results of Study 1:
`Composite Endpoint
`Composite Endpoint'
`
`HIT
`HIT
`
`HITTS
`HITTS
`
`HIT/HITTS
`HIT/HITTS
`
`Parameter, N (%)
`Parameter, N (%)
`
`Control
`Control
`n=147
`n=147
`
`Argatroban
`Argatroban
`n=160
`n=160
`
`Control
`Control
`n=46
`n=46
`
`Argatroban
`Argatroban
`n=144
`n=144
`
`Control
`Control
`n=193
`n=193
`
`Argatroban
`Argatroban
`n=304
`n=304
`
`Composite Endpoint
`Composite Endpoint
`
`57(38.8)
`57 (38.8)
`
`41(25.6)
`41(25.6)
`
`26 (56.5)
`26 (56.5)
`
`63 (43.8)
`63 (43.8)
`
`83 (43.0)
`83 (43.0)
`
`104 (34.2)
`104 (34.2)
`
`t Death (all causes), amputation (all causes) or new thrombosis within 37-<Jay study period
`t Death (all causes), amputation (all causes) or new thrombosis within 37-day study period.
`
`Table 2
`Table 2
`Efficacy Results of Study 1:
`Efficacy Results of Study 1:
`Components of the Composite Endpoint, Ranked by Severityt
`Components of the Composite Endpoint, Ranked by Severity'
`
`Parameter, N (%)
`hrjmntr. H (%)
`
`Control
`CoMrel
`«=l«7
`n=147
`
`mi
`NIT
`
`Arpirebin
`Arratroban
`•=IM
`n=160
`
`'
`•
`
`mm
`HIM
`
`Control
`(•Mrol
`a = «
`n= 46
`
`Argatroban
`Aijxnbu
`•=l«
`n=144
`
`mr/itim
`111/111TIS
`Arpmbn
`4r:indult
`•=304
`n=304
`
`Control
`(Mtltl
`•=IH
`n=193
`
`Dtuh
`Death
`
`Ampmrwn
`Amputation
`
`New Thrombosis
`NewThrombosti
`
`32(21 J)
`32 (21.1)
`
`J (2-0)
`3 (20)
`
`22(15.0)
`22(15.0)
`
`27 (li t)
`27 (16.9)
`
`J (l.»)
`3 (1.9)
`II (W)
`II (6.9)
`
`13 m
`II (283)
`« (1.7)
`4 ($1)
`
`• (Mi)
`9 (194)
`
`It (II I)
`28 (111)
`
`li (II I)
`li (11.1)
`
`21 (I4i)
`II (144)
`
`4$(BJ)
`45 (233)
`
`7 Pi)
`7 (3.6)
`
`31 (li.l)
`31 (16.1)
`
`S) (17.4)
`S3 (11.4)
`
`If («)
`19 (6.2)
`
`32 (I0.S)
`32 (103)
`
`t Reported as the most severe outcome among the components of composite endpoint (severity ranking:
`t Reported as the most severe outcome among the components of composite endpoint (severity ranking:
`death > amputation > new thrombosis); patients may have had multiple outcomes.
`death > amputation > new thrombosis); patients may have had multiple outcomes
`
`0008
`
`0008
`
`

`

`NDA 20-883
`NDA 20-883
`Page 11
`Page 11
`
`Time-to-event analyses showed significant improvements in the time-to-first event in
`Time-to-event analyses showed significant improvements in the time-to-first event in
`patients with HIT or HITTS treated with ACOVA™ versus those in the historical control
`patients with HIT or HITTS treated with ACOVATM versus those in the historical control
`group. The between-group differences in the proportion of patients