: Argatroban is a small-molecule, direct thrombin inhibitor that reversibly binds to the thrombin active site. Its mechanism of action is distinct from heparin, an indirect thrombin inhibitor, which requires the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin- catalyzed or induced reactions, including fibrin formation; activation of coagulation factor XIII, factor V, factor VIII, and protein C; and platelet aggregation.

Argatroban is highly selective for thrombin with an inhibitory constant (Ki) of 5-39 nM. At therapeutic concentrations, Argatroban has no or minimal effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein) .

Argatroban is also capable of inhibiting the action of clot-associated thrombin. In contrast, the heparin-antithrombin III complex is incapable of inhibiting clot-associated thrombin.

Experience in a limited number of patients who received multiple doses of Argatroban indicates no antibody formation.

Metabolism, Excretion, and Protein Binding: Using human liver microsomes and whole cell preparations in vitro, four oxidative metabolites were detected (M1, M2, M3 and trace amounts of M4). The formation of each of these metabolites was catalyzed in vitro by the human liver microsomal cytochrome P450 enzymes CYP3A4/5. The M1 oxidative metabolite was not quantifiable in plasma of volunteers who received drug. These data together with the lack of effect of erythromycin (a potent CYP3A4/5 inhibitor) on Argatroban pharmacokinetics suggest that CYP3A4/5 mediated metabolism is not an important elimination pathway in vivo.

The major route of excretion of Argatroban is via fecal elimination, presumably via biliary secretion. In a study in which [14C]Argatroban (5 ug/kg/min) was infused for 4 hours to healthy subjects, the majority of the radioactivity was recovered in the feces (approximately 65% of the administered dose) over 7 days and urine (approximately 22% of the administered

dose) within 6 days. Unchanged Argatroban accounted for the majority (approximately 16% of the administered dose) of the radioactivity in urine. The precise composition of the remainder of the radioactivity in urine and feces was not fully evaluated. Plasma radioactivity was undetectable by 24 hours. Argatroban is 54% bound to human serum proteins, with binding to albumin and "1-acid glycoprotein being 20% and 34%, respectively.

: The pharmacokinetic profile of Argatroban is well characterized by a two compartment model with first-order elimination. Total body clearance is approximately 5.1 mL/min/kg (0.31 L/hr/kg) for infusion doses up to 40

ug/kg/min, and the volume of the central compartment and the volume of distribution are approximately 84 and 174 mL/kg, respectively. Upon cessation of Argatroban infusion, plasma Argatroban concentrations rapidly decline with " and $ elimination half-lives of approximately 7 and 54 minutes, respectively. After four hours, little or no Argatroban remains in plasma.

The plasma clearance of the R and S stereoisomers is similar. In vivo, the plasma concentration ratio of R to S stereoisomers remains essentially constant over time and is approximately equal to the dose ratio (65:35). Hepatic impairment appears to equally affect the plasma concentration of the R and S stereoisomers since their ratio in plasma remains unchanged relative to that observed in healthy subjects. The less common S isomer is approximately twice as potent as the R isomer.

When Argatroban is administered by continuous infusion, anticoagulant effects and plasma concentrations of Argatroban follow similar, predictable temporal response profiles, with low intersubject variability. Immediately upon initiation of Argatroban infusion, anticoagulant effects are produced as plasma Argatroban concentrations begin to rise. Steady-state levels of both drug and anticoagulant effect are typically attained in 1-3 hours and are maintained until the infusion is discontinued or the dosage adjusted. Steady-state Argatroban plasma concentrations increase proportionally with dose (for infusion doses up to 40 ug/kg/min in healthy subjects) and are well-correlated with steady-state anticoagulant effects. For infusion doses up to 40 ug/kg/min, Argatroban increases, in a dose-dependent fashion, the activated partial thromboplastin time (aPTT), the activated clotting time (ACT), the prothrombin time (PT) and International Normalized Ratio (INR), and the thrombin time (TT). Representative steady-state plasma Argatroban concentrations and anticoagulant effects are shown in Figure 1 for Argatroban infusion doses up to 10 ug/kg/min.

Figure 1. Relationship at Steady State between Argatroban Dose, Plasma Argatroban Concentration and Anticoagulant Effect

: Because Argatroban is a direct thrombin inhibitor, co-administration of Argatroban and warfarin produces a combined effect on the laboratory measurement of the INR. However, concurrent therapy, compared to warfarin monotherapy, exerts no additional effect on vitamin-K-dependent factor Xa activity. It is anticipated that there will be no enhanced bleeding risk resulting from the combined effect on INR lab value.

The relationship between INR on co-therapy and warfarin alone is dependent on both the dose of Argatroban and the thromboplastin reagent used. This relationship is 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 (Thromboplastin C Plus, Dade) are presented in Figure 2 for an Argatroban dose of 2 ug/kg/min. Thromboplastins with higher ISI values than shown result in higher INRs on combined therapy of warfarin and Argatroban. These data are based on results obtained in normal individuals (see DOSAGE AND ADMINISTRATION, Conversion to Oral Anticoagulant Therapy).

Figure 2. Relationship of Argatroban and Warfarin on International Normalized Ratio (INR)

Predicted INR for warfarin alone from a co-therapy INR of 4.0 is demonstrated by Figure 2. To calculate INR for warfarin alone (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 ug/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). Solving for an INRWA value of

4.0 on combined therapy: INRw =0.19 +0.57 (4)=2.47 as the value for INR on warfarin alone. The error associated with

Age/Gender: The pharmacokinetics of Argatroban have been evaluated by age and gender in healthy subjects and in special populations including those with renal impairment, hepatic impairment, unstable angina, or patients undergoing coronary interventional procedures. There are no effects of age or gender on the pharmacokinetic parameters of Argatroban, with exception of clearance in elderly males being about 80% of that in elderly females.

Renal Impairment: Renal dysfunction did not affect the pharmacokinetic or pharmacodynamic parameters of Argatroban.

Hepatic Impairment: Moderate hepatic impairment is associated with a four-fold decreased clearance for Argatroban as well as an increased elimination half-life of 2.5 hours (see DOSAGE AND ADMINISTRATION).

Contraindications

Argatroban is contraindicated in patients with active major bleeding, or in patients hypersensitive to Argatroban injection concentrate.

Warnings

Argatroban is intended for intravenous administration. All parenteral anticoagulants must be discontinued before administration of Argatroban.

: Hemorrhage can occur at virtually any site in the body in patients receiving Argatroban. An unexplained fall in hematocrit, fall in blood pressure, or any other unexplained symptom should lead to serious consideration of a hemorrhagic event.

Argatroban should be used with extreme caution in disease states and other circumstances in which there is an increased danger of hemorrhage. These include severe hypertension; immediately following lumbar puncture; spinal anesthesia; major surgery especially involving the brain, spinal cord, or eye; hematologic conditions associated with increased bleeding tendencies such as hemophilia; gastrointestinal lesions such as ulcerations.

: There are no adequate and well controlledstudies in which preganant women have received Argatroban. Although animal reproductive studies have not revealed harm to the fetus (see Toxicology), these studies are not always predictive of the effects of a drug in humans. Argatroban should only be used in pregnancy if the benefits outweigh the risks.

should discontinue breast feeding while taking Argatroban because of the potential risk for serious adverse reactions in nursing infants. Although it is not known whether this drug is excreted in human milk, experiments in rats show that Argatroban is detected in milk.

: The safety and effectiveness of Argatroban in patients below the age of 18 years have not been established.

Precautions

: Caution should be exercised when administering Argatroban to patients with hepatic disease, by starting with a lower dose and carefully titrating until the desired level of anticoagulation is achieved. Also, upon cessation of Argatroban infusion in patients with hepatic impairment, full reversal of anticoagulant effects may require longer than 4 hours due to decreased clearance and increased elimination half-life of Argatroban (see DOSAGE AND ADMINISTRATION).

: Anticoagulation effects associated with Argatroban infusion at doses up to 40 ug/kg/min are well-correlated with the activated partial thromboplastin time (aPTT). If aPTT monitoring is problematic (such as for those having antiphospholipid antibodies), other global clot-based tests sensitive to Argatroban include the prothrombin time (PT), the International Normalized Ratio (INR), the activated clotting time (ACT) and thrombin time (TT). Plasma Argatroban concentrations also correlate well with anticoagulant effects (see ACTION AND CLINICAL PHARMACOLOGY).

The concomitant use of Argatroban and warfarin results in prolongation of the PT and INR beyond that produced by warfarin alone. Alternative approaches for monitoring concurrent Argatroban and warfarin therapy are described in a subsequent section (see DOSAGE AND ADMINISTRATION).

Heparin: Heparin is contraindicated in patients with heparin-induced thrombocytopenia; therefore, co-administration of Argatroban and heparin is unlikely. If Argatroban is to be initiated after cessation of heparin therapy, sufficient time should be allowed for the effects of heparin on the aPTT to decrease prior to the initiation of Argatroban therapy. As the half- life of heparin is highly variable, the maximum being about 2 hours, a period of time equal to two half-lives, or 4 hours, is recommended. Nevertheless, because of the variability in heparin metabolism, aPTT should always be the primary indicator as to when Argatroban therapy may be initiated.

Aspirin/Acetaminophen: There are no pharmacokinetic or pharmacodynamic drug-drug interactions between Argatroban and concomitantly administered aspirin or acetaminophen.

Oral anticoagulant agents: There are no pharmacokinetic drug-drug interactions between Argatroban and warfarin. However, the concomitant use of Argatroban and warfarin results in prolongation of the prothrombin time (PT) and International Normalized Ratio (INR), therefore, previously established relationships between PT/INR and bleeding risk no longer apply (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Thrombolytic agents: Argatroban at doses up to 3ug/kg/min has been administered in two clinical studies with either rt-PA or streptokinase. No clinically significant safety concerns were noted in these studies.

Digoxin: In 12 healthy volunteers, a 5 day intravenous infusion of Argatroban (2 ug/kg/min) did not affect the steady-state pharmacokinetics of oral digoxin (0.375 mg daily for 15 days).

Lidocaine: Argatroban (1.5 ug/kg/min for 16 hours), did not inhibit the metabolism of concomitantly administered lidocaine (a CYP3A4/5 substrate) using a 1.5 mg/kg bolus plus 2 mg/kg/hour infusion for 16 hours.

Erythromycin: In 10 healthy subjects, orally administered erythromycin (both a substrate for and a potent inhibitor of CYP3A4/5) at 500 mg QID for 7 days had no effect on the pharmacokinetics of Argatroban at a dose of 1 ug/kg/min for 5 hours. These data suggest oxidative metabolism by CYP3A4/5 is not an important elimination pathway in vivo for Argatroban. Based on these results, other CYP3A4/5 inhibitors such as ketoconazole and itraconazole are unlikely to inhibit the metabolism of Argatroban. As there has been no clinical experience with the co-adminstration of Argatroban and other CYP3A4/5 - metabolized drugs, such as fluconazole, indinavir, ritonavir, cyclosporine, simvastatin, nefazodone or their analogues, the potential for possible interaction is unknown.

: In the prospective study in HIT and HITTS, the effectiveness of Argatroban was not affected by patient age.

Adverse Reactions

The following safety information is based upon the 568 patients treated with Argatroban in the prospective pivotal clinical studies in patients with heparin-induced thrombocytopenia with and without thrombosis syndrome.

Serious Adverse Events: Study Days 0-37

: Table 1 shows the incidence of the primary efficacy endpoints [death (all cause), amputations (all cause), or new thrombosis, during study days 0 - 37; recorded as the most severe event] in the prospective and follow-on trials combined. These events qualify as "Serious Adverse Events". Table 1 illustrates the safety profile of Argatroban with regard to these serious outcomes as compared to a historical control group.

Table 1 Serious Adverse Events

	HIT		HITTS
	Argatroban	Historical Control	Argatroban	Historical Control
	N=285	N=147	N=283	N=46
Death, N(%)	48 (17)	32 (22)	61 (22)	13 (28)
Amputation, N(%)	9 (3)	3 (2)	32 (11)	4 (9)
New Thrombosis, N(%)	16 (6)	22 (15)	27 (10)	9 (20)

Bleeding Event Frequency

: In the first prospective pivotal trial, no statistically significant differences in the incidence of major bleeding were observed between the historical control group and the Argatroban group in either the HIT arm (8.2% versus 3.1%; p=0.0784) or HITTS arm (2.2% versus 10.4%; p=0.124). In the second pivotal trial, no statistically significant differences in the incidence of major bleeding were observed between the historical control group and the Argatroban group in either the HIT arm (8.2% vs. 3.2%; p=0.1190) or HITTS arm (2.2% vs. 4.3%; p=0.683). No clinically significant difference in minor bleed incidence was observed in either trial comparing Argatroban treated patients to historical controls. There were no cases of drug-related intracranial hemorrhage noted in either trials.

Most Common Reported Adverse Events in the Prospective Pivotal Clinical Trials

The adverse events reported in this section are consistent with those which would be anticipated for a severely-ill patient population who present with HIT/HITTS syndrome. In general, these patients had a mean age of 60+ years and were on complex concomitant medications. No clinically significant safety trends with regard to Argatroban exposure are apparent from both pivotal trials adverse event data. There may be some evidence of a clinical trend for treated patients to experience more mild gastrointestinal disturbances, such as nausea, or diarrhea.

Comparative Summary of Adverse Events Events for Prospective Pivotal Clinical Trials

: The following is a comparative summary of non-hemorrhagic adverse events in pivotal studies that

were experienced in heparin-induced thrombocytopenia (HIT) patients treated with Argatroban. All adverse events occurring with frequency of $5% in treated patients, in either trial, are listed in descending order of frequency as they occurred in the first pivotal trial.

Table 2 Comparative Summary of Adverse Events - HIT

Adverse Event	ARG-911 n = 160	ARG-915 n = 125	Historic Control; n = 147
$ 5%	%	%	%
Diarrhea	11	2	2
Dyspenia	8	9	9
Hypotension	7	5	3
Apnea	6	0	5
Chest Pain	6	2	2
Sepsis	6	3	14
Dizziness	5	2	0
Vomiting	5	3	0
Fever	4	6	2
Nausea	4	6	0
Tachycardia Ventricualr	3	7	3

The following is a comparative summary of non-hemorrhagic adverse events in pivotal studies that were experienced in heparin-induced thrombocytopenia with thrombotic syndrome (HITTS) patients treated with Argatroban. All adverse events occurring with frequency of $5% in treated patients, in either trial, are listed in descending order of frequency as they occurred in the first pivotal trial.

Table 3 Comparative Summary of Adverse Events - HITTS

Adverse Event	ARG-911 n = 149	ARG-915 n = 139	Historic Control n = 46
$ 5%	%	%	%
Hypotension	9	8	0
Pain	9	3	4
Apnea	8	0	7
Cardiac Arrest	8	8	9
Constipation	8	1	2
Fever	8	9	2
Peripheral Ischemia	8	6	7
Urinary Tract Infection	8	4	4
Infection	7	4	4
Pulmonary Embolism	7	4	13
Rash	7	4	2
Thrombophlebitis	7	0	2
Confusion	6	1	0
Sepsis	6	8	9
Thrombophlebitis (Deep)	6	4	15
Vomiting	6	3	0
Peripheral Gangrene	5	1	4
Pleural Effusion	5	3	4
Dyspena	4	12	9
Diarrhea	4	7	0
Tachycardia Ventricualr	4	5	4
Acute Renal Failure	3	5	7
Nausea	3	6	2
Pneumonia	2	5	15
Respiratory Insufficiency	1	6	0
Cardiac Failure	0	5	0

Adverse Events Resulting from Repeated or Chronic Administration

: Adverse event rates in patients receiving multiple courses of Argatroban were similar to rates observed in patients receiving short courses of the drug. Patients receiving chronic administration (greater than 14 days of continuous therapy) of argatrban had adverse event rates at a similar frequency to those receiving shorter courses of Argatroban.

Symptoms and Treatment of Overdosage

: Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing Argatroban or by decreasing the Argatroban infusion dosage. In clinical trials, anticoagulation parameters generally return to baseline within 2 to 4 hours after discontinuation of the drug (although this may take longer for those with hepatic impairment). Argatroban infusion doses of up to 40 ug/kg/min have been administered to healthy subjects up to four hours without drug-related adverse events.

No specific antidote to Argatroban is available; if life-threatening bleeding occurs and excessive plasma levels of Argatroban are suspected, the following steps should be followed:

Dosage and Administration

Argatroban, as supplied, is a concentrated drug which must be diluted prior to its infusion. Argatroban should not be mixed with other drugs prior to dilution in a suitable intravenous fluid

: Argatroban should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose injection, USP or Lactated Ringer's Injection, USP; to a final concentration of 1 mg/mL. Use 1 vial (for 2.5 mL total) per 250 mL diluent bag, or 2 vials (for 5.0 mL total) per 500 mL diluent bag. The constituted solution must be mixed by repeated inversion of the diluent bag for one minute. Upon preparation, the solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing. The pH of the intravenous solution prepared as recommended is 3.2-7.5.

: Discontinue heparin therapy and obtain baseline aPTT. The recommended initial dose of Argatroban for adult patients without hepatic impairment is 2 ug/kg/min, administered as a continuous infusion (see Table 4).

: In general, therapy with Argatroban is monitored using the aPTT. Anticoagulant effects (including the aPTT) typically attain steady-state levels within 2.5 hours following initiation of Argatroban or with dosage adjustment. Check the aPTT two hours after initiation of therapy to confirm that the patient has attained the desired therapeutic range.

: The dose can be adjusted as clinically indicated (not to exceed 10 ug/kg/min), until the steady-state aPTT is 1.5 to 3.0 times the initial baseline value (not to exceed 100 seconds).

: For patients with heparin-induced thrombocytopenia with hepatic impairment, the initial dose of Argatroban should be reduced. For patients with moderate hepatic impairment, an initial dose of 0.5 ug/kg/min is recommended, based on the approximate four-fold decrease in Argatroban clearance relative to those with normal hepatic function. The aPTT should be monitored closely and the dosage should be adjusted as clinically indicated.

: In a study of over 20 patients with renal impairment, and some who required dialysis, dosage adjustment was not necessary and dosages up to 5.0 ug/kg/min were administered with no medically significant safety concerns.

Initiating Oral Anticoagulant TherapyWhen converting to oral anticoagulant therapy, a loading dose of warfarin should not be used because of the potential for combined effects on INR by the combination of Argatroban and warfarin. Initiate therapy using the expected daily dose of warfarin

Co-Administration of Warfarin and Argatroban at Doses up to 2 uglkg/min: The concommitant use of Argatroban with warfarin results in prolongation of INR beyond that produced by warfarin alone. Therefore, the previously established relationship between INR and bleeding risk are altered (for details, see ACTION AND CLINICAL PHARMACOLOGY). INR should be measured daily while Argatroban and warfarin are co-administered. In general, with doses of Argatroban up to 2 ug/kg/min, Argatroban can be discontinued when the INR is >4.0. After Argatroban is discontinued, repeat the INR measurement in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the infusion of Argatroban and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached. The relationship between INR on combined therapy and warfarin alone is dependent on both the dose of Argatroban and the thromboplastin reagent used.

: For doses greater than 2 ug/kg/min, the relationship between INR on warfarin alone, and warfarin plus Argatroban is less predictable. In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of Argatroban to a dose of 2 ug/kg/min. Repeat the INR on Argatroban and warfarin 4 to 6 hours after Argatroban reduction and follow the process outlined above for dosing Argatroban at up to 2 ug/kg/min.

Pharmaceutical Information

: 1-[5-[(aminoiminomethyl)amino]-1-oxo-2[[(1 ,2,3,4-tetrahydro-3-methyl-8- quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate.

Molecular Formula: C23H36N6O5S.H20 Molecular Weight: 526.66 Description: Argatroban is a synthetic, small-molecule, direct thrombin inhibitor derived from L-arginine. Argatroban has 4 asymmetric carbons. One of the asymmetric 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 at a ratio of approximately 65:35. 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.

: Argatroban injection concentrate is a sterile clear, colorless to pale yellow, slightly viscous solution. Each mL of sterile, nonpyrogenic solution contains 100 mg Argatroban. Inert ingredients: D-sorbitol JP, dehydrated alcohol, USP and water for injection.

: Vials of Argatroban injection concentrate are stable until the date indicated on the package when stored at 15- 25degC. If the solution is cloudy, or if an insoluble precipitate is noted, the vial should be discarded.

Store the vials in original cartons at room temperature (15-25degC, 59-77degF). Do not refrigerate. Store in carton until use. PROTECT FROM LIGHT.

*The constituted solution must be mixed by repeated inversion of the diluent bag for one minute.

: Solutions prepared as recommended (see Dosage and Administration) are stable at 15-25degC in ambient indoor light for 24 hours; therefore, light resistant measures such as foil protection for intravenous lines are unnecessary. Solutions are physically and chemically stable for up to 48 hours when stored at 2 to 8degC in the dark. Prepared solutions should not be exposed to direct sunlight. No significant potency losses have been noted following simulated delivery of the solution through intravenous tubing.

: As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

Availability of Dosage Form

Injection Concentrate is supplied in 2.5 mL solution in single-use vials at the concentration of 100 mg/ml. Each vial contains 250 mg of Argatroban.

Information to the Patient

Pharmacology

: Argatroban is a potent and selective thrombin inhibitor with anticoagulant properties both "in vitro" and "in vivo". Its activity does not depend upon the presence of antithrombin III. Unlike heparin, Argatroban is able to inhibit both the amidolytic and platelet activities of clot-associated thrombin. Pharmacological studies have shown that Argatroban is a potent antithrombotic agent when administered as an intravenous infusion in a wide variety of animal models both of erythrocyte-rich (venous) and platelet-rich (arterial) thrombosis, although the doses required to inhibit arterial thrombosis are higher than those necessary to inhibit venous thrombosis in experimental models. In addition, Argatroban has been shown to enhance experimental thrombolysis and maintain vascular recanalization when administered with either rt-PA, streptokinase or sc-UPA (Saruplase).

Argatroban is highly specific in that it has no effect on a battery of other serine proteases or other platelet activating agents except at concentrations several orders of magnitude greater than those required to inhibit thrombin. Argatroban caused a slight increase in the largely predominant anticoagulant effect of heparin using the aPTT as the coagulant parameter, but the effect of the combination was not statistically significant when compared to heparin alone, and is not relevant in the context of the use of Argatroban in the indication HIT/HITTS. When coadministered with anticoagulant doses of Argatroban via the same venous catheter in the rat, rt-PA has no inhibitory effect on the anticoagulant effect of Argatroban. Moreover, there is no significant loss of fibrinolytic activity of rt-PA. Moreover, the concomitant administration of Argatroban with aspirin, indomethacine, sulfinpyrazone, quinidine, ouabain, tolbutamide, clofibrate, furosemide or ticlopidine did not affect the anticoagulant properties of Argatroban in the rat. However, administration of Argatroban to rats 24 hours after oral warfarin, increased the anticoagulant effect of the latter. None of the general pharmacological tests suggest that Argatroban has any potential adverse effects at pharmacologically relevant doses.

Toxicology

IP= Intraperitoneally; IV = Intravenous; PO = Oral; SC = Subcutaneous; NOEL = No- observable-effect-level NS = Not specified

AE = Adverse events; IP= Intraperitoneally; IV = Intravenous; PO = Orally; NOEL = No- observable-effect-level

Carcinogenesis, Mutagenesis, Impairment of Fertility: In vitro assays designed to assess the mutagenic potential of Argatroban in bacteria (Ames, rec-A), effects on DNA synthesis (W1-38 cells), or the ability of Argatroban to induce chromosomal aberrations were conducted both in the presence or absence of metabolic activation. The results indicate that Argatroban does not possess mutagenic potential.

Reproduction studies in rats and rabbits at doses up to two times the recommended dose in man have revealed no evidence of impaired fertility or harm to the fetus due to Argatroban. Overall, in reproductive studies with Argatroban in animals, there were no indications of impaired parental reproductive capacity, embryotoxicity, fetotoxicity, teratogenicity, or effects on weaning, lactation, normal development, or reproductive competence of progeny. The parental "no-effect doses" were 54.9 mg/m2 in rats and 127.4 mg/m2 in rabbits; fetal "no-effect doses" were 164.7 mg/m2 in rats and 127.4 mg/m2 in rabbits.

: Reproduction studies performed in rats and rabbits at doses up to two times the recommended dose in man have revealed no evidence of impaired fertility or harm to the fetus due to Argatroban.

: Experiments in rats show that Argatroban is detected in milk. It is not known whether this drug is excreted in human milk.

ID = Intradermal; IM = Intramuscular; IP = Intraperitoneal; SC = Subcutaneous; PV = Perivenous

Selected Bibliography

Arnoletti JP, Whitman GJ. Heparin-induced thrombocytopenia in coronary bypass surgery. Ann Thorec Surg 1999; 68 (2): 576-8. Boeve TJ, Reed GL, de Oliveira NC et al. Comparison of argatroban and hirudin for the reperfusion of thrombotic arterial occlusion by tissue plasminogen activator. J Thromb Thrombolysis 1998; 6: 103-108. Bush LR. Argatroban, a selective potent thrombin inhibitor. Cardiovascular Drug reviews 1991; 9 (3): 247-263. Fenton JW 2nd, Ofosu FA, Brezniak DV et al. Thrombin and antithrombotics. Semin Thromb Hemost 1998; 24 (2): 87-91. Hantgan RR, Jerome WG, Hursting MJ. No effect of clot age or thrombolysis on argatroban's inhibition of thrombin. Blood 1998; 92 (6): 2064-74. Hursting MJ, Zehnder JL, Joffrion JL et al. The International Normalized Ratio during concurrent warfarin and argatroban anticoagulation: differential contributions of each agent and effects of the choice of thromboplastin used. Clin Chem 1999; 45 (3): 409-12. Imura Y, Stassen JM, Collen D. Comparative antithrombotic effects of heparin, recombinant hirudin and argatroban in a hamster femoral vein platelet-rich mural thrombosis model. J Pharmacol Exp Ther 1992; 261 (3): 895-898. Jang I, Gold HK, Leinbach RC et al. Persistent inhibition of arterial thrombosis by a 1-hour intravenous infusion of argatroban, a selective thrombin inhibitor. Coronary Artery Disease 1992; 3 (5): 407-414. Jang I, Gold HK, Ziskind AA et al. Prevention of platelet-rich arterial thrombosis by selective thrombin inhibition. Circulation 1990; 81 (1): 219-225. Januzzi JL jr, Jang IK. Heparin induced thrombocytopenia: diagnosis and contemporary antithrombin management. J Thromb Thrombolysis 1999; 7 (3): 259-64. Kawada T, Okada Y, Hoson M et al. Argatroban, an attractive anticoagulant, for left heart bypass with centrifugal pump for repair of traumatic aortic rupture. Jpn J Thorac Cardiovasc Surg 1999; 47 (3): 104-9. Kelton JG. The clinical management of heparin-induced thrombocytopenia. Semin Hematol 1999; 36 (1 suppl 1): 17-21. Koza M, Lewis B, Walenga J et al. Antithrombin agents in the management of HIT. Chapter 20: 309-324. Laposata M, Green D, Van Cott E, et al. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 1998; 122 (9): 799-807. Lewis BE, Rangel Y, Fareed J. The first report of successful carotid stent implant using argatroban anticoagulation in a patient with heparin-induced thrombocytopenia and thrombosis syndrome: a case report. Angiology 1998; 49 (1): 61-7. Lewis B, Walenga J, Wallis D. Anticoagulation with Novastan in patients with HIT and HITTS. Sem Throm Hem 1997; 23 (2): 197-202. Lewis B, Ferguson J, Grassman E et al. Successful coronary interventions performed with argatroban anticoagulation in patients with HITTS. J. of Invasive Cardiology 1996; 8 (9): 410- 17. Lewis B, Walenga J, Pifarre R et al. Argatroban in the management of HIT and HITTS. Chapter 15: 223-229. Matthai WH jr. Use of argatroban during percutaneous coronary interventions in patients with heparin-induced thrombocytopenia. Semin Thromb Hemost 1999; 25 (suppl 1): 57-60. Nguyen P, de Maistre E, Cornillet-Lefebvre E et al. Heparin-induced thrombocytopenia in France, 1980-1998. Semin Thromb Hemost 1999; 25 (suppl 1): 9-15. Ortel TL, Chong BH. New treatment options for heparin-induced thrombocytopenia. Semin Hematol 1998; 35 (4 suppl 5): 26-34. Schwartz R, Becker JC, Brooks R et al. The preclinical and clinical pharmacology of Novastan: a small molecule, direct, thrombin inhibitor. Clin Appl Thromb / Haem 1997; 3 (1): 1-15. Tran JO, Di Cicco RA, Sheth SS et al. Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban. J Clin Pharmacol 1999; 39 (5): 513-9. Walenga JM, Jeske WP, Wallis DE et al. Clinical experience with combined treatment of thrombin inhibitors and GPIIb/IIIa inhibitors in patients with HIT. Semin Thromb Hemost 1999; 25 (suppl 1): 77-81. Walenga JM, Koza M, Khenkina Y et al. Argatroban anticoagulation with warfarin or heparin administration. Department of Thoracic and Cardiovascular Surgery. Loyola University Medical Center. April 1995. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998; 97: 251-6.

N x Vial size	Volume of diluent	Recommended diluents *	Concentration
1 x 2.5 mL (100 mg/mL)	250 mL	0.9% Sodium Chloride Injection, USP; or 5% Dextrose injection, USP; or Lactated Ringer's Injection	1 mg/mL
2 x 2.5 mL (100 mg/mL)	500 mL	Same recommended diluents	1 mg/mL

Species/ strains	No. per group	Route	Compound	Dose level (mg/kg)	Observations
Mice: ddY	10 4-5 4-5	IV PO IP	Argatroban	174-230 NS NS	LD 50 : 211.4 mg/kg LD 50 : 6200 mg/kg LD 50 : 600-800 mg/kg
Rat: Wistar	29 4-5 4-5	IV PO IP	Argatroban	100-200 NS NS	LD 50 : 138 mg/kg
Dog: Beagle	3 4	IV PO	Argatroban	30-65.8 NS	LD 50 : >65.8 mg/kg LD 50 : > 1000 mg/kg
Rabbit: Japanese White	9	IV	Argatroban	100-200	LD 50 : 100-150 mg/kg
Mice: ddY	10	PO	Argatroban	15 g/kg	LD 50 : > 15 g/kg
		IV		81	LD 50 : > 81 mg/kg
		IP		167-1307	LD 50 : M: 474 mg/kg F: 640 mg/kg
		SC		108-14860	LD 50 : M: 3750 mg/kg F: 3900 mg/kg
Rat: Wistar	10	PO	Argatroban	15 g/kg	LD 50 : > 15 g/kg
		IV		81	LD 50 : >81 mg/kg
		IP		68-726: M	LD 50 : M: 320 mg/kg
				141-726: F	F: 409 mg/kg
		SC		50-7000: M	LD 50 : M: 620 mg/kg
		SC		50-5000: F	F: 1565 mg/kg
Rat: Sprague- Dawley	5	IV	Argatroban	16.7, 50, 150	Dose related increase in aPTT and PT reversible by end of study.
Rat: Wistar-slc	5	IV	Argatroban	180-540	LD 50 : 304 mg/kg
Rat: Wistar-slc	5	IV	Product G Product H	450 60	LD 50 : > 450 mg/kg LD 50 : > 60 mg/kg
Dog: Beagle	1	IV	Argatroban	100, 200	1 M and 1 F died at 200 mg/kg Hind limb paralysis at 100 and 200 mg/kg Increase in WBC, GPT, GOT
Dog: Beagle	2	IV	Argatroban	M: 3.3, 9.6, 28.9 F: 3.3, 10.4, 27.7	No deaths NOEL: < 3.3 mg/kg Dose related increase in aPTT and PT reversible within 24-48 hrs.

Species/ strains	No. per group	Route	Compound	Dose levels (mg/kg)	Duration	Key observations
Rat: Sprague- Dawley	15	IV	Argatroban	C, 3, 9, 27	1X daily / 6 months	Minimal variations in aPTT and PT levels for duration of study Nontoxic dose: 9 mg/kg
Dog: Beagle	4	IV	Argatroban	3, 10, 30	24 hr/day /28days	No overt toxicity 30 mg/kg/day: No AE dose level
Dog: Beagle	4	IV	Argatroban	1, 3, 9	1X daily/ 6 months	Occasional vomiting after admin. in 3 mg/kg or more groups Non toxic dose: 1 mg/kg
Rat: Sprague- Dawley	8	IV	Argatroban	60/day	24 hr/day /14 days	No adverse systemic effects. Argatroban caused modest irritation at site of catheter implantation.
Dog: Beagle	1-2	IV	Argatroban	60/day	24 hr/day / 13 days	Hepatic Kupffer cell pigmentation attributed to test compound
Dog: Beagle	3	IV	Argatroban	2.5/day	1 injection /day for 1 month	2.5 mg/kg/day considered, systemically a no- effect dose.
Rat: Sprague- Dawley	12	IV	Argatroban	5/day	1X Daily /30 days	Slight perivenous hemorrhage related to antithrombotic action of drug. NOEL: 5 mg/kg/day
Rat : Sprague- Dawley	15	IV	Argatroban	15, 30, 60	24 hr/day /1 month	Well tolerated at all doses. Spleen weights for F increased. Pneumonia and histiocytic proliferation increased in all groups.
Dog: Beagle	4	IV	Argatroban	15, 30, 60	24 hr/day /1 month	No overt toxicity. NOEL: 60 mg/kg/day
Dog: Beagle	3	IV	Argatroban	3, 9, 27	1X daily/ 1 month	No abnormalities in clinical signs or pathology Non toxic dose = 3 mg/kg
Dog: Beagle	4	IV	Argatroban	3, 10, 30	24 hr/day /28 days	No overt toxicity. NOEL = 30 mg/kg/day
Rat: Wistar-slc	10	IV	Argatroban	3, 9, 27	1X daily/ 1 month	Increase in F hematocrit and decrease in F body weight gain at 27 mg/kg/day Non toxic dose = 9 mg/kg
Rat: Sprague- Dawley	10	IV	Argatroban	3, 10, 30	1X daily / 28 days	No deaths or remarkable finding NOEL = 30 mg/kg

Species/ strains	Route	Compound	Concentrations ( : g/ml)	Duration	Key observations
CHO cells (Chromosome test)	In vitro	Argatroban	1,3,10,30,100, 300, 1000	16 hrs incubation	No Chromosomal aberrations
Human normal diploid culture cells (UDS test)	In vitro	Argatroban	1,3,10,30,100, 300, 1000	5.5 hrs incubation	No increase in DNA synthesis
B. Subtilis (Rec-Assay)	In vitro	Argatroban	6250, 12500, 25000, 50000	18 hrs incubation	Weak positive response at 12500 : g/ml or more Possible DNA damaging effect on B. subtilis.
S.typhimurium; E. Coli	In vitro	Argatroban	200 : g/plate 500 : g/plate 1000 : g/plate	45 hrs incubation	Argatroban was not mutagenic with or without metabolic activation.
S.typhimurium; E. Coli	In vitro	Argatroban	5, 10, 50, 100, 500, 1000, 5000 : g/plate	48 hrs incubation	Argatroban was not mutagenic with or without metabolic activation.
CHO cells	In vitro	Argatroban	10, 25, 50, 100, 250, 500, 1000, 2500	24 or 48 hrs exposure	Argatroban was not clastogenic.
CHO cells	In vitro	Argatroban	500, 750, 1000, 1500, 2000, 2500, 3000	-	Argatroban was not cytotoxic either in the absence or presence of rat liver S-9 mix.
Mouse	IV	Argatroban	27 mg/kg	24 or 48 hrs	No induction of cytogenic damage to mouse bone marrow cells
Rat hepatocyte (Sprague-Dawley)	In vitro	Argatroban	1.5, 4.74, 15, 47.4, 150, 474, 1500	24 hrs incubation	Induction of Unscheduled DNA Synthesis (UDS)
Rat hepatocyte (Fischer 344)	In vitro	Argatroban	1 mg/ml - 10 - 8 mg/ml	18-20 hrs	Test material precipitated at 1 mg/ml. No induction of DNA repair at # 5 x 10 - 1 mg/ml

Species/ strains	No. per group	Route	Compound	Dose levels (mg/kg)	Duration	Key observations
Rat: SPF Wistar	28	IV	Argatroban	3, 9, 27	M: daily 60 days prior to mating F: daily 14 days prior to mating to day 7 of gestation	NOEL (toxicity) = 9 mg/kg NOEL (fetal devel.) = 27 mg/kg
Rat: SPF Wistar	40-45	IV	Argatroban	3, 9, 27	F: Daily days 7-17 of gestation	No significant toxic effects on dams or pups.
Rat: SPF Wistar	23	IV	Argatroban	3, 9, 27	Daily day 17 of gestation to day 21 post partum	NOEL (maternal rats) = 9 mg/kg NOEL (maternal reproductive performance and F1 generation development) = 27 mg/kg
Rabbit: NZW	17	IV	Argatroban	0.5, 1.0, 2.0	Daily days 6-18 of gestation	NOEL (maternal rabbits) = 0.5 mg/kg NOEL (fetal rabbits) 1.0 mg/kg No teratogenic effects.
Rabbit: NZW	18	IV	Argatroban	10.8	Daily days 6-18 of gestation	NOEL (maternal rabbits) = 10.8 mg/kg NOEL (fetal rabbits) 10.8 mg/kg No teratogenic effects.

PRODUCT MONOGRAPH

Action and Clinical Pharmacology

Indications and Clinical Use