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SUMMARY .Drug Name

argatroban Company

Mitsubishi-Tokyo Pharmaceuticals Inc (Mitsubishi Chemical Holdings Corp)Highest Dev

Status

Launched FDA Approved Coronary Artery Thrombosis, In Patients With Or At Risk For Heparin-Induced

Thrombocytopenia; Prophylaxis - Percutaneous Coronary Intervention (Adult),

Heparin-Induced Thrombocytopenia; Treatment And Prophylaxis - Heparin-Induced

Thrombocytopenia With Thrombosis (Adult)

Therapy Areas Thrombosis; Heparin induced thrombocytopenia; Myocardial infarction; Angina;

Thromboembolism; Deep vein thrombosis; Cerebral infarction; Cerebrovascular ischemia

Actions Factor IIa antagonist; Platelet aggregation inhibitor; Coagulation inhibitor

Technologies Injectable formulation; Small molecule therapeutic; Parenteral formulation unspecified

Target Factor IIa

Update date 29-DEC-2010

Reason for

update

Minor Editorial Amendment OVERVIEW

Mitsubishi Pharma (formerly Mitsubishi-Tokyo, now Mitsubishi Tanabe) and Daiichi Seiyaku (now Daiichi Sankyo) developed and launched argatroban (MCI-9038, MD-805, Acova, Slonnon, Novastan, Argatra,

Arganova), a non-protein, arginine-related thrombin inhibitor. The product is indicated in Japan as an injectable treatment of chronic arterial obstruction caused by thromboembolism and for acute cerebral thrombosis

[423717]. Mitsubishi and licensees Encysive (formerly Texas Biotechnology, now part of Pfizer) and SmithKline Beecham (now GlaxoSmithKline) have also developed the drug for use in heparin-induced thrombocytopenia (HIT); in this market, the drug indicated as an anticoagulant for prophylaxis or treatment of thrombosis in

patients with heparin-induced thrombocytopenia (HIT), as well as in patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI) [1099746].

Argatroban has been available in Japan for thromboembolism since 1990 [166797]. By November 2000, the drug had been launched in the US for HIT [389484]. It was additionally made available for HIT in Japan in July 2008 [934660]; and in several European countries and Canada by 2009 [1009181], [999725]. Mitsubishi and licensee Hyundai launched the drug for cerebral infarction in Japan and Korea in 2001 [423717], [1009181].Phase II development for cerebral infarction was underway in the US [401857], [480851]. However, no further development for this indication has been reported.

Sanofi-Synthelabo (formerly Synthelabo) was previously developing argatroban for myocardial infarction

(MI) and HIT; by April 1997, phase II trials were underway [256381], [291369]; development was ongoing in December 1998 [328910]. However, by February 2000, the company had discontinued development due to portfolio synergy [326141], [359231].

PATENT AND GENERICS INFORMATION

By December 2007, Mitsubishi Tanabe, Encysive and GlaxoSmithKline had filed a patent infringement lawsuit against Barr Laboratories (now Teva) related to argatroban injection (see EP-0301970) [863995]. In January 2008, Barr confirmed its challenge of the patents listed by Encysive in connection with its argatroban 100 mg/ml, 2.5 ml vial. Barr believed it was the first to file an ANDA containing a Paragraph IV certification for argatroban [864221]. A two-week trial in the case was held in January 2010; final ANDA approval was stayed until May 2010 or resolution of the case [1085324]. In March 2010, Teva received tentative FDA approval for its generic argatroban injection (100 mg/ml) [1085455]. In March 2010, Pliva received tentative FDA approval for its generic 100 mg/ml argatroban injection [1110322].

REGULATORY INFORMATION

The US

Heparin-induced thrombocytopenia

In August 1997, Texas initially filed an NDA for the treatment of HIT and the submission received Priority Review status 1 month later [260071], [261682]. In January 1998, the FDA review was extended by the agency to allow time to consider new data from a follow-on study (ARG-915) in the same patient population as those participating in the pivotal study, ARG-911. The company received a non-approvable letter from the FDA in

May 1998; Texas resubmitted the application in March 1999 [286980], [289075], [319140], [317991], [338812]. Following discussion with the FDA, Texas further amended the NDA in August 1999. The FDA required Texas to amend the coding of patient endpoint data and dates on which they occurred, and involved 33 of 304 patients in the pivotal phase III trial. The amendments improved one of the efficacy analyses for argatroban, although had no clinically substantive effects on the data [337571]. In February 2000, an approvable letter was issued

to Texas by the FDA; approval was granted in June 2000 [356813], [372891]. The FDA approved argatroban under the name Acova; the FDA considered that the former name Novastan was too similar to Immunex's Novantrone [373279]. The drug was subsequently launched by Texas and SB for this indication in the US in November 2000 [389484].

In December 2000, Texas and SB filed an sNDA for argatroban with the FDA to expand the use of argatroban to patients who have or who are at risk of developing HIT and are undergoing PCI [394626]. The FDA issued

an approvable letter for this sNDA in July 2001 [416378], [416695]. The sNDA was approved in April 2002 [450159].

Europe

Heparin-induced thrombocytopenia

At the end of 1997, Synthelabo initially filed for regulatory approval for HIT in Europe. Synthelabo and Texas had previously reached an agreement whereby Texas would supply Synthelabo data from its argatroban trials

in HIT and thrombosis syndrome [195980], [275126]. The European authorities also requested additional methodological and statistical data, and by the end of 1998, Synthelabo expected to resubmit the NDA

in mid-1999 [326141]. However, by February 2000, Sanofi-Synthelabo had discontinued development of argatroban due to portfolio synergy [359231].

In December 2002, a market authorization filing was submitted in Europe for the treatment of HIT [503339]. Approval was still pending in January 2004, at which time, launch was expected during 2005 [520195]. By May 2006, the drug had been approved for HIT in Iceland, Denmark and Norway. Preparations for filing in other EU countries were ongoing [679875]. By May 2008, approval was obtained in Germany, Austria, Sweden, and the Netherlands. At that time, the company planned to submit filings for other countries in the region [904699]. By 2009, it was available in Germany, Austria, The Netherlands, Sweden, Denmark, Iceland, Norway and Italy [1009181]. In May 2009, Mitsubishi submitted a filing for HIT in patients undergoing percutaneous coronary intervention [1018718]; this was approved in September 2009 [1052986].

Japan

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Thromboembolism

In 1990, Mitsubishi-Tokyo (now Mitsubishi Tanabe) launched the drug in Japan as Novastan. In 1994, Daiichi was enlisted as a joint marketer, commercializing the drug as Slonnon [166797]. In 1995, Daiichi filed for the additional indication of cerebral thrombosis in Japan [192683].

Heparin-induced thrombocytopenia

By February 2000, Mitsubishi had filed the drug in Japan for HIT and heparin-induced thrombocytopenia thrombosis syndrome (HITTS) [365460]. In September 2007, Mitsubishi and Daiichi filed for the drug's approval for thrombosis in HIT patients in Japan [836303]. In May 2008, the Japanese CDFS's First Committee recommended approval of the drug for thrombosis in HIT patients, by that time, Orphan Drug status had also been granted [917838]. In July 2008, the drug was approved for HIT [934660], [929604].

In February 2004, the CDFS's First Committee on Drugs designated argatroban as an Orphan Drug for prevention and treatment of thrombosis and prevention of blood coagulation during percutaneous coronary intervention (PCI) or hemodialysis in patients with HIT [530606]. In August 2010, an sNDA was filed in Japan [1142772].

Rest of the world

Thromboembolism

By August 2002, an NDA had been filed in China for the treatment of chronic arterial obstruction [460177]; by January 2003, argatroban had been launched in China [477153].

By February 2001, the drug for chronicarterial occlusion and acute cerebral thrombosis had been approved

in Korea. Mitsubishi stated that it was to launch the drug through Hyundai; it was presumed that the drug was made available during that year [1009181].

Heparin-induced thrombocytopenia

In July 2001, argatroban was approved in Canada for HIT [417629].

Cerebral infarction

Mitsubishi had filed an sNDA in China for acute cerebral infarction by May 2006 [679875]; however, the filing was 'terminated' by January 2008 [901809]. The company stated that the authorities in China did not approve the drug since the control drug used in a clinical trial was not appropriate, and that conducting further trials was not beneficial since there was already competition in the market [937576].

PREMARKETING STUDIES

Heparin-induced thrombocytopenia

In March 2000, at the Annual Meeting of the American College of Cardiology, results from a phase III trial

for HIT conducted by Texas were presented. The pivotal trial involved 304 patients treated with argatroban injection, which were compared to 194 historical controls. The primary endpoint of the trial was the evaluation

of all-cause death, all-cause amputation or new thrombosis over a 37-day period. Argatroban significantly improved patient outcomes and provided rapid, adequate anticoagulation with no increase in bleeding as compared to the control group [359465]. Data from the study showed that all 30 patients met the primary endpoint of ability to successfully complete the procedure while using argatroban as the anticoagulant. Clinically significant bleeding was noted in only one patient [242926].

In June 1997, results from second phase III trial (ARG-911) were presented at the annual conference of the International Society of Thrombosis and Hemostasis. The multicenter study compared 304 patients treated

with argatroban for up to 14 days (160 with HIT and 144 with HITTS), with 217 historical control patients (108 with HIT and 109 with HITTS). The data demonstrated significance in the primary efficacy endpoint, assessed by an overall composite index [252042]. The index included evaluation of development of new thrombosis, amputation and death. The index was improved by 19.2% in the HIT population and by 20.3% in the HITTS population. Argatroban was effective in resolving the clinically significant thrombocytopenia by producing increases in platelet counts of 129% in HIT patients and 198% in HITTS patients. The thrombotic composite outcome, defined as development of new thrombosis, amputation due to ischemic complications and death due to thrombosis, was improved in the treated population by 73.4% in HIT patients and 43.8% in HITTS patients.

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Development of new thrombosis, a component of the thrombotic index, was reduced by 72.7% and 54.4% in

the HIT and HITTS populations, respectively [252042]. A second component of the thrombotic index, death

due to thrombosis, was reduced by 100% in the HIT population, and by 90.4% in the HITTS population. There was no change in the number of amputations due to ischemic complications, the third major component of the thrombotic composite. However, the data indicate that the majority of amputations were deemed necessary prior to a patient entering the trial. There was no increase in major bleeding in the argatroban-treated population. Minor bleeding, which was reported as slightly higher in the treated population, was both quickly resolved and not considered clinically serious [247484], [252553].

In March 1999, it was disclosed that the first US phase III trial (ARG-310) evaluated the use of argatroban in coronary interventional procedures in patients who experience allergic reactions to heparin. Patients enrolled

in the trial had HIT or HITTS and were unable to receive heparin. At that time, an additional phase III trial was scheduled to begin in the second half of 1999, in which oral heparin was to be compared to sc injected heparin [319077].

In August 2003, a prospective study of patients with HIT was published, which showed that argatroban reduced thrombosis, and deaths due to thrombosis, without increasing the risk of bleeding. The study compared 418 patients to 185 historical controls. Patients treated with argatroban showed an improvement in a composite endpoint that included death, amputation or new thrombosis formation. In the HIT arm of the study, the composite endpoint was significantly lower in argatroban-treated patients (28%) than in the historical controls (38.8%). No difference in bleeding rates was observed between the argatroban group and the historical control group [500820], [500813].

In July 2003, clinical data on the use of argatroban and lepirudin in the treatment of HIT were presented at the 19th ISTH conference in Birmingham, UK. In the randomized prospective study, lepirudin and argatroban were given intravenously to patients with HIT for thromboembolism prophylaxis; all patients had a lepirudin history and had developed IgG antibodies. 4 of 16 eligible patients were enrolled, 2 others had exclusion criteria and were treated with argatroban off label use. Patients (n = 2) on lepirudin received a daily dose of 90.7 mg or 122 mg (day 1) and 69.1 or 215 mg (day 7). Therapeutic median activated partial thromboplastin time (aPTT) was 97.9 s, median ecarin clotting time (ECT) was 182.9 s, and median international normalized ratio (INR) was

1.6. IgG anti-lepirudin antibodies increased from 7 mOD to 158.5 mOD. During therapy with argatroban, anti-lepirudin antibodies remained negative. The daily dose of argatroban was 237 mg at day 1 and 213 mg at day 7. aPTT, ECT and INR values were 73.2 s, 215.9 s and

2.4, respectively, during therapy. Both treatments were well tolerated. The anti-lepirudin antibodies re-appeared during re-exposure to lepirudin. Thromboembolic or bleeding complications, and allergic reactions did not occur [499646].

In February 2002, at the 27th International Stroke Conference, San Antonio, CA, a retrospective analysis of phase III studies was presented suggesting positive clinical effects for argatroban in acute ischemic stroke

in patients with HIT. The study involved 812 argatroban-treated HIT patients and 193 historical control HIT patients from three multi-center phase III studies evaluating argatroban as a treatment for HIT. The objective

of the analysis was to compare the incidence of stroke in HIT and to assess the effect of argatroban on HIT patients compared with historical control patients. Historical control patients were typically treated by heparin discontinuation and/or oral anticoagulation. In the argatroban-treated HIT patients, the incidence of stroke-related events was 2.6% compared to 4.1% in the historical control group. This decrease in overall stroke events in the argatroban-treated patients was considered to be clinically relevant. Stroke-associated mortality in the argatroban-treated patients was significantly different compared to the historical control patients: 1.0% and 3.1%, respectively [439144].

In October 2000, at the annual meeting of the American College of Chest Physicians, treatment with argatroban was shown to provide adequate anticoagulation in patients with HIT who underwent PCI, most frequently balloon angioplasty. These findings complemented data presented at the Transcatheter Cardiovascular Therapeutics Scientific Sessions, which showed repeated argatroban exposure was well tolerated, without increasing the dose or safety risk. Results from the trials indicated that, of 91 patients treated with argatroban, 97.8% had adequate anticoagulation, while 94.5% achieved satisfactory procedural outcomes. In patients

who received argatroban, acute procedural success was 98.9%, versus 94.3% in the control group. Similarly, major bleeding rates for argatroban patients compared favorably with historical controls (2.2% versus 3.1%,

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respectively). Unsatisfactory procedural outcomes occurred in 5 of 91 patients and were coronary artery dissection, emergent bypass surgery, acute hypotension, failure to revascularize and failure of the stent. No death or Q-wave myocardial infarction occurred. Major bleeding events, which occurred in 2 patients, were retroperitoneal and gastrointestinal [387036]. Similar results were reported at the Transcatheter Cardiovascular Therapeutics symposium in 2002 [465102].

Cerebral thrombosis/cerebral infarction

Phase IIIn October 2002, Texas stated that due to the high risk and costs associated with stroke trials, it was unlikely that the company would proceed independently with a full phase III program. If sub-group analyses were to demonstrate potential efficacy, Texas planned to pursue alternative means to fund further clinical development [465698]. In March 2004, the indication was still listed as being in phase II development [538366]. No further development has been reported.

In September 2002, Texas Biotechnology revealed that argatroban would be evaluated in combination with tissue plasminogen activator (t-PA) as a new approach to the treatment of cerebral infarction. The trial was one of five novel approaches being studied by the Stroke Program at the UT-Houston Medical School to treat or prevent ischemic stroke. The objective of the open-label 20 patient argatroban/t-PA pilot trial, was to assess the safety and efficacy of argatroban in combination with t-PA [464171].

In February 2001, Mitsubishi and Encysive were planning to initiate a phase II trial in stroke [399764]. In March 2001, enrollment in the multicenter, placebo-controlled phase II ARGIS-1 trial began in patients with acute ischemic stroke for the treatment of cerebral infarction. The trial was expected to include 180 stroke patients

in over 30 major stroke centers in North America and would explore a 0 to 12 h treatment window [401857], [464171]. In October 2002, Texas revealed that preliminary results from the ARGIS-1 trial highlighted a lack of overall efficacy. The trial involved 176 patients at 42 major stroke centers in North America, with the primary endpoint being safety assessed in terms of incidence of symptomatic intracranial hemorrhage. Initial results showed that argatroban met the primary endpoint, with no significant difference in symptomatic intracranial hemorrhage rates between argatroban and placebo. Positive results were also observed for the secondary safety endpoint, asymptomatic intracranial hemorrhage. Neurological assessments were also evaluated at intervals up to 90 days. Based on the preliminary analysis at 90 days, there were no significant effects or major trends observed in the measures used to determine efficacy including: the Modified Rankin Scale, Barthel Index and the NIH Stroke Scale. A full analysis of the trial was underway to determine whether there were any meaningful efficacy trends in specific patient sub groups, stroke types and/or treatment windows [465698]. In March 2003, full results showed the drug to be safe and well tolerated. No difference was observed between argatroban and placebo in symptomatic or asymptomatic intracranial hemorrhage. A total of 176 patients were given argatroban to achieve two different levels of anticoagulation, versus placebo, within 12 h from symptom onset. No differences were observed in secondary outcomes, including asymptomatic ICH, major systemic hemorrhage, minor systemic bleeding, and efficacy, for each group and stroke type [480851].

In July 2001, clinical data on argatroban were presented at the 18th ISTH meeting in Paris, France. In the study, 812 argatroban-treated patients from studies ARG-911/915/915X were compared to 193 historical controls. In the argatroban and control groups, the incidence of stroke events was 2.6% and 4.1%, respectively. Mortality associated with stroke complications of HIT was significantly lower among argatroban-treated patients versus controls (1.0% vs 3.1%, p = 0.035) [414356].

Myocardial infarction

Phase II

In April 1997, at a Texas Biotechnology-sponsored investigator's meeting in Anaheim, California, data were presented from the phase II ARG-231 trial (Myocardial Infarction Novastan t-PA, MINT). The double-blind randomized study assessed argatroban as an adjunctive therapy with t-PA for reperfusion acceleration in coronary arteries in 120 patients, who were to receive either heparin at 15 IU/kg or argatroban at 1 or 3 microg/ kg/min. Results demonstrated a safety benefit and a statistically significant improvement in coronary artery reperfusion by 29% at the highest dose, compared to heparin, based on the TIMI Frame Count (an objective measure of artery reperfusion) [238982].

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Also in April 1997, data were presented from the phase II ARG-230 trial (Argatroban Myocardial Infarction, AMI)) at the 46th Annual American College of Cardiology meeting in Anaheim, CA. This companion randomized, double-blind, placebo-controlled angiographic trial assessed safety, as well as effect on a 30-

day composite endpoint, which included recurrent MI, urgent angioplasty (PTCA) or coronary bypass (CABG), shock/congestive heart failure and death. It was conducted with streptokinase in 180 patients and demonstrated improvement of coronary artery reperfusion by 34% compared to placebo within a 6-h therapeutic window,

and by 52% if given within 3 h of symptom onset. Results of the ARG-230 trial demonstrated no evidence of increased bleeding risk versus placebo [238982].

By April 1997, two phase II heparin-comparator studies had recruited 1200 patients [256381]. Preliminary results from these studies showed that the overall efficacy on clinical cardiovascular events after 30 days was comparable to that of heparin. The argatroban-treated patients also showed a tendency towards better safety with a lower risk of bleeding [291369].

By July 1995, two phase II trials evaluating argatroban as an adjunct to thrombolytic therapy in patients with acute MI had commenced. Another trial was evaluating patients receiving argatroban and streptokinase

and a third study, involving 120 patients, was evaluating patients receiving tissue plasminogen activator and argatroban [252553].

In 1995, a phase II trial was initiated with argatroban as an adjunct to streptokinase in patients with acute MI receiving thrombolytic therapy. The trial was to be conducted at up to 16 sites in the US. Patients randomly received iv infusions of argatroban or placebo, in a double-blind trial [197174]. Initial results, from the study by Texas, showed that this combination improved reperfusion of coronary arteries by 52% [224135].

Other clinical

In July 2003, data on the use of argatroban during PCI procedures were presented at the 19th ISTH conference in Birmingham, UK. The generation of thrombin during PCI in regimen A (argatroban alone) and regimen B (argatroban plus GPIIb/IIIa inhibitor-treated patients) was investigated. For PCI, a bolus of 275/350 microg/kg, followed by an infusion of 25 microg/kg/min dosing had been found to produce adequate anticoagulation with an observed ACT range of 250/350 sec. The ACT reverted to near normal after the cessation of regimen A. The fibrinopeptide A (FPA), thrombin antithrombin complex (TAT), and prothrombin fragment F1.2 baseline values in both regimens were elevated in comparison to the normal values (30-300%). An initial increase was observed in all markers (20-60%), which was markedly reduced after treatment. The levels of these markers remained steady during the PCI. The baseline TFPI levels were high then normal in both groups (up to 200%), however, during treatment in both groups, TAFI levels were reduced and remained less than 100% during the treatment period. Blood samples collected 1-4 hours post-administration did not show any rebound elevation of thrombin generation [498048]. In September 2003, similar results were presented at the 15th Annual Transcatheter Cardiovascular Therapeutics meeting in Washington, DC [505054].

In April 2003, GSK and Texas presented results, at the Annual Scientific Session of the American College of Cardiology, of a feasibility study showing that argatroban in combination with glycoprotein IIb/IIIa inhibitors provided adequate anticoagulation with an acceptable risk of bleeding during percutaneous coronary interventions such as coronary angioplasty and stent placement. In a multicenter, prospective pilot study, 100% of the patients who received the argatroban/glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor combination achieved angiographic success and adequate anticoagulation, while only 2% of the patients had an incident of major bleeding. The study investigated the use of argatroban and the GP IIb/IIIa inhibitors, abciximab and eptifibatide, in 101 patients during PCI procedures. Investigators administered a bolus argatroban dose of 250 microg/kg followed by continuous dosing of 15 microg/kg per min during the procedure until an acceptable level of blood thinning was achieved (defined as an activated clotting time (ACT) of between 275 s and 325 s). Additional bolus doses of 150 micro/kg were allowed during the study [484447].

Miscellaneous studies

In July 2003, clinical data on the use of argatroban and the oral anticoagulant vitamin K antagonists, phenprocoumon (PH) and acencoumarol (AC), were presented at the 19th ISTH conference in Birmingham, UK. The effect of argatroban alone and during combined treatment with PH or AC was studied in 36 healthy volunteers. The volunteers received a 5 h infusion of 1, 2 and 3 microg/kg/min argatroban for 4 days (day 1,

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3, 4 and 5) before (day 1) and during initiation of the oral anticoagulants. The study concluded that argatroban could be discontinued at doses of up to 2 microg/kg/min, when the INR reaches 4 on combined therapy in

order to achieve an INR on an oral anticoagulant alone of between 2 and 3.5 with thromboplastins of ISI values of around 1 or 2. The interaction between argatroban and PH or AC is similar to that described for warfarin [497909]. Further data from the same volunteers on the effect of argatroban in combination with PH or AC on aPTT and ECT [497911], and on thrombin generation [497914], were presented at the same meeting. aPTT was prolonged by argatroban alone depending on its plasma level, and was further prolonged by 10-30 s during combined treatment with PH or AC. Within 2 to 4 h after the end of argatroban infusion, the aPTT was normalized or reduced to the pre-argatroban level. In contrast, the ECT was not affected by PH or AC, and

was prolonged during argatroban infusion and reached baseline levels within 2 h after the end of the infusion [497911]. Bleeding times ranged from 2 to 14 min, and were not prolonged under argatroban alone at any dose, or in combination with the oral anticoagulants. Under argatroban alone, the platelet-induced thrombin generation time (PITT) was significantly prolonged, and the endogenous thrombin potential (ETP) was significantly reduced by 20-40%, with the reduction strongest at 3 microg/kg/min argatroban. These effects on thrombin generation were significantly amplified with PH and AC [497914].

Also in July 2003, data on the use of argatroban in patients with end-stage renal disease (ESRD) undergoing chronic hemodialysis (HD), were presented at the 19th ISTH conference in Birmingham, UK. In this randomized, open-label, 3-way crossover study, patients underwent 3 dialysis sessions (each more than 3 h in duration, separated by more than 48 h) using high flux CT 190 membranes and a randomized argatroban regimen schedule. Dosing regimens were: (A) 250 microg/kg bolus administered into the dialysis circuit immediately after starting HD with an additional 250 microg/kg bolus allowed after 2 h if the activated clotting time (ACT) was less than 140% of baseline value; (B) 250 microg/kg bolus administered into the dialysis circuit immediately after starting HD, followed by a continuous, 2-3 h infusion of 2 microg/kg/min into the circuit; and (C) continuous 2 microg/kg/min infusion via catheter port initiated approximately 4 h before starting HD and maintained during HD via dialysis circuit. Patients (n = 13) were enrolled and 12 completed the study. ACTs increased from

132 +/- 32 s at baseline to 168 +/- 38, 195 +/- 39, and 189 +/- 36 s during regimens A, B and C, respectively. During regimen A, 11 patients received an additional bolus. In 38 HD sessions, there were no adverse events related to the drug, no serious adverse events, no bleeding events, and no clinically significant changes in

heart rate, blood pressure, or clinical laboratory values. No membrane required changing and only 1 session was shortened due to clotting. Saline flushing was used to prevent further coagulation after the appearance of fibrin strands in the dialysis system drip bulb was observed in 11, 6 and 7 patients during regimens A, B and C, respectively [497928]. In November 2003, similar data on argatroban in ESRD patients undergoing HD were presented at the 31st Annual Scientific Meeting of the American Society of Nephrology [513574].

In two pharmacokinetic studies, this direct thrombin inhibitor gave a more predictable anticoagulant dose response than heparin [172877]. An sc formulation for the prevention of deep-vein thrombosis entered phase I trials in 1998 [291369].

PRECLINICAL STUDIES

In May 2001, Texas presented data from a stroke model at the Society for Academic Emergency Medicine meeting, Atlanta, GA. Research demonstrated that argatroban and t-PA, when used in combination at 4 h after the onset of an embolic stroke, reduced ischemic lesion size without increasing gross cerebral hemorrhage rates in rats. There was a significant reduction in lesion size without any increase in bleeding in the argatroban plus t-PA treated rats versus the t-PA treated group [408485].

ADDITIONAL INFORMATION

Argatroban has been referred to as argipidine, DK-7419, GN-1600, OM-805 and Argatrovan. Key benefits to the drug include a fast onset and offset, predictable anticoagulation, no antibody reaction and less major bleeding [317991].

DRUG NAME

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Names associated with this drug

Name Type

argatroban INN

74863-84-6CAS RN

DK-7419Research Code

GN-1600Research Code MCI-9038Research Code

MD-805Research Code

OM-805Research Code Acova Trade Name Arganova Trade Name Argatra Trade Name Argatrovan Trade Name Novastan Trade Name Slonnon Trade Name argipidine

lonnon

MQPA

NEWS

Date Title

25-MAR-2010Teva Announces Tentative Approval of Generic Argatroban Injection

29-SEP-2009The Medicines Company Licenses Innovative New Formulation of Argatroban; Gains Strategic Complement to Angiomax Franchise and Potential Near Term Revenue

Opportunity

30-JUL-2009Summary of 1st Quarter Financial Results for year ended March 31, 2010

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29-JAN-2009Risk Factors for Major Bleeding in Patients With Heparin-induced Thrombocytopenia Treated With Argatroban: A Retrospective Study

05-JAN-2009Successful Use of Argatroban During the Third Trimester of Pregnancy: Case Report and Review of the Literature

Deals

Summary

Primary company Eagle Pharmaceuticals Inc

Partnering company The Medicines Company

Deal Type Drug - Commercialization License

Start date29-SEP-2009

Overview

In September 2009, The Medicines Company licensed rights in the US and Canada to a ready-to-use formulation of argatroban from Eagle Pharmaceuticals [1046063].

Summary

Primary company Mitsubishi-Tokyo Pharmaceuticals Inc

Partnering company Hyundai Pharmaceutical

Deal Type Drug - Commercialization License

Start date31-DEC-2001

Overview

By December 2001, Hyundai had been granted rights by Mitsubishi-Tokyo to commercialize argatroban in Korea [1009181].

Summary

Primary company Encysive Pharmaceuticals Inc

Partnering company SmithKline Beecham plc

Deal Type Drug - Development/Commercialization License

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Start date06-AUG-1997

Overview

In August 1997, Texas Biotechnology (now Encysive Pharmaceuticals) and SmithKline Beecham (SB; now GlaxoSmithKline) entered into a marketing and codevelopment agreement for argatroban in the US and Canada [258268]. This agreement was still in place in May 2003 [491163].

Summary

Primary company Mitsubishi-Tokyo Pharmaceuticals Inc

Partnering company Daiichi Seiyaku Co Ltd

Deal Type Drug - Commercialization License

Start date18-OCT-1994

Overview

By October 1994, Daiichi Seiyaku and Mitsubishi Tokyo Pharmaceuticals (now Mitsubishi Pharma) had a sales and comarketing agreement for argatroban [166797].

Summary

Primary company Mitsubishi Pharma Corp

Partnering company Synthelabo SA

Deal Type Drug - Development/Commercialization License

Start date17-OCT-1993

End date23-FEB-2000

Overview

By October 1993, Synthelabo (now Sanofi-Synthelabo) had a codevelopment and sales & marketing agreement with Mitsubishi (now Mitsubishi Pharma) for argatroban in Europe and francophone Africa [165246]. By February 2000, Sanofi-Synthelabo had dropped the compound from its pipeline [359231].

Summary

Primary company MannKind Corp

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Partnering company Encysive Pharmaceuticals Inc

Deal Type Technology - Delivery/Formulation

Start date31-JUL-1993

Overview

In July 1993, Texas Biotechnology (now Encysive Pharmaceuticals) entered into an agreement with MannKind (formerly known as PDC) to encapsulate argatroban using PDC's proprietary polymer encapsulation technology [177786].

Summary

Primary company MannKind Corp

Partnering company Encysive Pharmaceuticals Inc

Deal Type Technology - Delivery/Formulation

Start date31-JUL-1993

End date23-APR-1996

Overview

In July 1993, Texas Biotechnology (now Encysive Pharmaceuticals; a subsidiary of Pfizer), entered into

an agreement with MannKind (formerly known as PDC) to encapsulate antisense nucleotides using PDC's proprietary polymer encapsulation technology [177786]. However, in April 1996, development has been discontinued [205821].

Summary

Primary company Genentech Inc

Partnering company Encysive Pharmaceuticals Inc

Deal Type Drug - Commercialization License

Start date31-MAY-1993

Overview

In May 1993, Texas Biotechnology (now Encysive) agreed to sublicense Genentech's rights and technology relating to argatroban [163913]. As of May 2003, this agreement was still in place [491163].

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DEVELOPMENT STATUS .

Detailed status for Daiichi Sankyo Co Ltd Therapy Area Country Status Reference Date Heparin induced thrombocytopenia

Japan

Launched

934660

17-JUL-2008

Detailed status for Daiichi Seiyaku Co Ltd Therapy Area Country Status Reference Date Thromboembolism

Japan

Launched

166797

18-OCT-1994

Detailed status for Encysive Pharmaceuticals Inc Therapy Area Country Status Reference Date

Cerebral infarction

Development Reported null

14-MAY-2010

Heparin induced thrombocytopenia Canada Launched

99972501-JAN-2009

Heparin induced thrombocytopenia

US Launched 38948415-NOV-2000

Detailed status for GlaxoSmithKline plc Therapy Area Country Status Reference Date

Cerebral infarction

Development Reported null

14-MAY-2010

Heparin induced thrombocytopenia

Canada Launched

99972501-JAN-2009

Detailed status for Hyundai Pharmaceutical Therapy Area Country Status Reference Date Cerebral infarction South Korea Launched 100918131-DEC-2001Thromboembolism

South Korea

Launched

1009181

31-DEC-2001

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Detailed status for Mitsubishi Pharma Corp Therapy Area Country Status Reference Date Cerebral infarction Japan

Launched 42371701-OCT-2001Heparin induced thrombocytopenia Western Europe

Launched

1009181

31-DEC-2008

Thromboembolism China Launched 47715320-JAN-2003Thromboembolism Germany Launched 61582431-JUL-2005Thrombosis

China

Discontinued

901809

29-JAN-2008

Detailed status for Mitsubishi Tanabe Pharma Corp Therapy Area Country Status Reference Date Heparin induced thrombocytopenia

Japan

Launched

934660

17-JUL-2008

Detailed status for Mitsubishi-Tokyo Pharmaceuticals Inc Therapy Area Country Status Reference Date Thromboembolism

Japan

Launched

166797

01-JUN-1990

Detailed status for Sanofi-Synthelabo Therapy Area Country Status Reference Date

Heparin induced thrombocytopenia Western Europe

Discontinued

359231

01-MAR-2000

Myocardial infarction

Western Europe Discontinued 35923101-MAR-2000

Detailed status for SmithKline Beecham plc Therapy Area Country Status Reference Date

Heparin induced thrombocytopenia

Launched

389484

14-NOV-2000

DEVELOPMENT STATUS : HISTORY .

Detailed status for Daiichi Sankyo Co Ltd

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Therapy Area Country Status Reference Date Heparin induced thrombocytopenia

Japan

Registered

934660

16-JUL-2008

Detailed status for Encysive Pharmaceuticals Inc Therapy Area Country Status

Reference Date

Cerebral infarction US Phase 2 Clinical 40185706-MAR-2001Heparin induced thrombocytopenia Canada

Registered

417629

02-AUG-2001

Heparin induced thrombocytopenia North America Pre-registration 26007101-AUG-1997

Heparin induced thrombocytopenia North America Phase 3 Clinical 17698101-NOV-1995

Heparin induced thrombocytopenia North America Phase 2 Clinical 163913null

Heparin induced thrombocytopenia US Registered 37289130-JUN-2000

Thromboembolism North America Phase 3 Clinical 17698101-NOV-1995Thromboembolism

North America

Phase 2 Clinical

163913

null

Detailed status for GlaxoSmithKline plc Therapy Area Country Status

Reference Date

Cerebral infarction US Phase 2 Clinical 48085105-MAR-2003Heparin induced thrombocytopenia

Canada

Registered

417629

02-AUG-2001

Detailed status for Hyundai Pharmaceutical Therapy Area Country Status Reference Date Cerebral infarction South Korea Registered 100918119-FEB-2001Thromboembolism

South Korea

Registered

1009181

19-FEB-2001

Detailed status for Mitsubishi Pharma Corp

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Therapy Area Country Status

Reference Date Cerebral infarction US Phase 2 Clinical 42371705-OCT-2001Heparin induced thrombocytopenia Germany

Launched

615824

20-JUL-2005

Heparin induced thrombocytopenia Japan Pre-registration 42371705-OCT-2001

Heparin induced thrombocytopenia Netherlands Registered 61582420-JUL-2005

Heparin induced thrombocytopenia Sweden Registered 61582431-OCT-2004

Heparin induced thrombocytopenia Western Europe Registered 67987511-MAY-2006

Thromboembolism

China Pre-registration 67987511-MAY-2006

Detailed status for Mitsubishi-Tokyo Pharmaceuticals Inc Therapy Area Country Status Reference Date Cerebral infarction Japan Clinical 39976422-FEB-2001Cerebral infarction US Phase 2 Clinical 40090706-MAR-2001Cerebrovascular ischemia

Japan

Launched

401857

null

Heparin induced thrombocytopenia

Japan Pre-registration 36546001-JUN-2000

Detailed status for Sanofi-Synthelabo Therapy Area Country Status Reference Date Heparin induced thrombocytopenia Western Europe

Pre-registration

328910

24-JUN-1999

Myocardial infarction

Western Europe Phase 2 Clinical 32891024-JUN-1999

Detailed status for SmithKline Beecham plc Therapy Area

Country

Status

Reference

Date

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Heparin induced thrombocytopenia

US Discovery 258268null

Detailed status for Synthelabo Therapy Area Country Status

Reference Date Angina Western Europe Phase 3 Clinical 21323001-JUN-1995Angina

Western Europe Phase 2 Clinical 176452null

Deep vein thrombosis Western Europe Phase 1 Clinical 29136915-JUL-1998Heparin induced thrombocytopenia Western Europe

Pre-registration

275126

01-AUG-1997

Heparin induced thrombocytopenia Western Europe Phase 3 Clinical 21323001-JUN-1995

Myocardial infarction Western Europe Phase 3 Clinical 21323001-JUN-1995Myocardial infarction Western Europe Phase 2 Clinical 176452null

Thromboembolism Western Europe Phase 3 Clinical 21323001-JUN-1995Thromboembolism

Western Europe

Phase 2 Clinical

165246

null

THERAPEUTIC USE .

United States

Therapeutic uses (Source: DRUGDEX System. MICROMEDEX)Therapeutic category

FDA Approvals

Efficacy

Summary

Adult

Pediatric Adult Pediatric Cardiovascular surgical procedure

Evidence favors efficacy

-Limited studies suggest the usefulness of argatroban as an alternative to heparin for anticoagulation following cardiovascular surgical procedures (Kumon et al, 1984b).

See Drug Consult reference:ANTITHROMBOTIC AND

THROMBOLYTIC THERAPY - ACCP GUIDELINES

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Cerebral thrombosis

no no

Evidence favors efficacy

Argatroban was effective and safe in treating acute cerebral thrombosis,particularly when initiated early (within 48 hours) (Kobayashi & Tazaki, 1997).

See Drug Consult reference:ANTITHROMBOTIC AND

THROMBOLYTIC THERAPY - ACCP GUIDELINES

Coronary artery thrombosis, In patients with or at risk for heparin-induced thrombocytopenia;Prophylaxis -Percutaneous coronary intervention

yes no Effective -

Argatroban is indicated as an

anticoagulant in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention (Prod Info argatroban IV injection, 2008).

Among 91 patients receiving 112interventions, acute procedural success (no death, Q-wave MI,

emergent CABG) was 98.2% versus historical heparin control rate 94.3%(Prod Info argatroban IV injection,2008).

In a comparison of 27 patients with stable angina receiving heparin (n=15)or argatroban (n=12) as adjunctive drugs during and after percutaneous transluminal coronary angioplasty,argatroban produced more favorable effects on platelet activation, thrombin inhibition, and antithrombin III (Suzuki et al, 2000).

A review of previously published and unpublished preliminary data (1995 to 1997) on argatroban therapy in patients with heparin-induced thrombocytopenia

undergoing percutaneous coronary revascularization (n=50) reported a 98% angiographic success rate (Matthai, 1999).

Anticoagulation for percutaneous

coronary intervention was successfully accomplished with argatroban in ten patients (with a total of 14 lesions)

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with histories of heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) (Lewis et al, 1996).

Administration of a continuous infusion of argatroban (0.6 to 1

milligram/kilogram/hour) immediately after percutaneous transluminal

coronary angioplasty (PTCA) rapidly suppressed increases in plasma thrombin-antithrombin III complex (TAT) in a small study (Sakamoto et al, 1995a).

See Drug Consult reference:ANTITHROMBOTIC AND

THROMBOLYTIC THERAPY - ACCP GUIDELINES

Disseminated intravascular coagulation

no no

Evidence favors efficacy Evidence favors efficacy

Limited data indicates efficacy in disseminated intravascular coagulation (DIC) (Kumon et al,1984b; Yamada, 1983).

Extracorporeal circulation procedure

no no

Evidence favors efficacy Evidence favors efficacy

Argatroban has limited use as an alternative anticoagulant in left heart bypass with the centrifugal pump,percutaneous cardiopulmonary

support (PCPS), and extracorporeal membrane oxygenation (ECMO)(Kawada et al, 2000).

Hemodialysis no no

Evidence favors efficacy

Several case reports have described the successful use of argatroban as an alternative to heparin in

hemodialysis patients with heparin-induced thrombocytopenia (Matsuo et al, 1988; Matsuo et al, 1990; Matsuo et al, 1986a; Matsuo et al, 1992a;Matsuo et al, 1988; Matsuo et al,

1990; Matsuo et al, 1986a; Matsuo et al, 1992a; Koide et al, 1995; Matsuo et al, 1992a).

Heparin-induced

thrombocytopenia;

yes

no Effective Effective

Argatroban is indicated for prophylaxis or treatment of thrombosis in patients with heparin-induced

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Prophylaxis

- Heparin-

induced

thrombocytopenia with thrombosis thrombocytopenia (Prod Info argatroban IV injection, 2008).The use of weight-based argatroban dosing nomograms for the treatment of heparin-induced

thrombocytopenia (HIT) or heparin-

induced thrombocytopenia with

thrombosis (HITTS) in non-critically

ill and critically ill patients rapidly

achieved and maintained therapeutic

levels of anticoagulation, without

periods of excessive anticoagulation,

and without high risk of bleeding, in

a prospective, non-randomized, non-

blinded, phase 2 study (n=51) (Ansara

et al, 2009).

Critically ill patients (with single or

multiple organ failure) diagnosed with

heparin induced thrombocytopenia

(HIT) require lower therapeutic

dosages of argatroban than non-

critically ill HIT patients as evidenced

by the inverse and linear relationship

between the argatroban dosage and

Sequential Organ Failure Assessment

(SOFA) score, in a retrospective,

cohort study (n=53) (Keegan et al,

2009).

In a clinical trial, prophylaxis or

treatment of thrombosis with

argatroban in 304 patients with

heparin-induced thrombocytopenia

(HIT) produced a composite endpoint

(death (all causes), amputation (all

causes), and new thrombosis within

the 37-day treatment and follow-

up period) of 34.2% compared with

43.0% in an historical control group of

193 patients (Prod Info argatroban IV

injection, 2008).

Argatroban was safe and effective

when used in 18 seriously ill pediatric

patients with heparin-induced

thrombocytopenia (HIT) or suspected

HIT (Prod Info argatroban IV injection,

2008).

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Insertion of carotid artery stent

no no

Evidence favors efficacy

Argatroban was successfully substituted for heparin in one case report of heparin-induced thrombocytopenia in a patient

undergoing carotid stent placement (Lewis et al, 1998).

See Drug Consult reference:ANTITHROMBOTIC AND

THROMBOLYTIC THERAPY - ACCP GUIDELINES

Myocardial infarction

no no Effective -

The MINT (Myocardial Infarction with Novastan(R) and TPA) trial (n=125)demonstrated that argatroban was at least as effective and safe as

heparin as an adjunct to front-loaded,accelerated tissue plasminogen

activator (TPA) and aspirin (Jang et al,1999a; Jang et al, 1998a).

The multi-center ARGAMI Study

(n=127) demonstrated that argatroban was as effective and well-tolerated as heparin when given for adjunctive thrombolytic therapy with alteplase in patients within 6 hours of onset of acute myocardial infarction (AMI)(Vermeer et al, 2000a).

See Drug Consult reference:ANTITHROMBOTIC AND

THROMBOLYTIC THERAPY - ACCP GUIDELINES

Peripheral vascular disease no no

Evidence favors efficacy -

Preliminary data suggest possible short-term clinical benefit; further study is needed (Ueki et al, 1999).

Radiation injury

no no Evidence favors efficacy

Argatroban may have a role in

managing radiation injury based on a single case report (Nakagawa et al,1997).

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Rheumatoid arthritis,Malignant

no no