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What are the uses of Argatroban?
Argatroban is the first and only anticoagulant approved as an anticoagulant
for prophylaxis or treatment of thrombosis in patients with heparin-induced
thrombocytopenia (HIT).[2] Argatroban
is also approved as an anticoagulant in patients with or at risk for HIT
undergoing PCI.[2] Effective anticoagulation
is achieved in patients with HIT undergoing PCI rapidly, usually within
10 minutes.
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What are the physical and chemical characteristics of Argatroban?
Physical description
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.[2]
Argatroban Injection is a sterile, nonpyrogenic solution that is clear,
colorless to pale yellow, and slightly viscous.[2]
It is available in 250-mg (2.5-mL), single-use, amber vials with gray flip-top
caps. Each milliliter contains 100 mg of Argatroban. Inert ingredients include
750 mg D-sorbitol and 1000 mg dehydrated alcohol.[2]
Chemical description
Argatroban is a synthetic direct thrombin inhibitor derived from L-arginine.[2]
The chemical name for Argatroban is 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.
Argatroban has four asymmetric carbons.[2]
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.[2]
The molecular formula of Argatroban is C23H36N6O5S·H2O.
Its molecular weight is 526.66 daltons.[2]
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What is the pharmacologic profile of Argatroban?
Argatroban was designed to directly inhibit the procoagulant enzyme thrombin.[2]
The following pharmacologic properties offer the potential for significant
benefits[2]:
| • |
Selectivity: Argatroban
is a highly selective direct thrombin inhibitor and binds to the catalytic
site on the thrombin molecule. At therapeutic concentrations, it has
little or no effect on related serine protease (trypsin, factor Xa,
plasmin, and kallikrein), and it does not require the cofactor antithrombin
III for antithrombotic activity. |
| Argatroban is able to inhibit
both free and clot-bound thrombin. |
| • |
Ability to inhibit clot-bound
thrombin: Argatroban is able to inhibit both free and clot-bound
thrombin. In addition to prevention of further thrombotic events,
it has been suggested that DTIs may reduce the extension of existing
thromboses. |
Pharmacologic Properties of Argatroban[2]
| Physical Property |
Argatroban |
| Type of manufacture |
Synthetic |
| Direct thrombin inhibitor |
Yes |
| Requires cofactor antithrombin III for activities |
No |
| Inhibition of free and clot-bound thrombin |
Yes |
| Steady-state levels |
1
to 3 hours |
| Terminal elimination half-life* |
39
to 51 minutes |
| Molecular weight |
526.66
daltons |
| Cross-reactive with heparin-dependent antibodies |
No |
| Antigenicity |
No |
| Convenient monitoring with aPTT or ACT |
Yes |
| Predictable dose response* |
Yes |
| Low intersubject variability* |
Yes |
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What is the effect on International Normalized Ratio (INR)?
Because Argatroban is a direct thrombin inhibitor, coadministration of Argatroban
and warfarin produces a combined effect on the laboratory measurement of
the INR.[4] However, concurrent
therapy, compared to warfarin monotherapy, exerts no additional effect on
vitamin K-dependent factor Xa activity.
The relationship between the INR on cotherapy 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 6 for a dose of Argatroban of 2 mcg/kg/min. In general,
with doses up to 2 mcg/kg/min, for thromboplastins with ISI values between
0.88 and 2.0 when the INR on combination therapy is >4, the INR on warfarin
alone will be within the target range.[2,26]
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 healthy subjects (see Conversion
to Oral Anticoagulant Therapy). [2,26]
See the figure below for a demonstration of the relationship between the
INR for warfarin alone and the INR for warfarin coadministered with Argatroban
at doses of Argatroban of 2 mcg/kg/min.[2]
To calculate the INR for warfarin alone (INRW), based on the INR for cotherapy
of warfarin and Argatroban (INRWA),
use the equation next to the appropriate curve. For example: At a dose of
2 mcg/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).
Thus, using an INRWA
value of 4.0 obtained on combined therapy: INRW
= 0.19 + 0.57 (4) = 2.47 as the value for the INRW.
The error (confidence interval) associated with a prediction is ±0.4
units. Similar linear relationships and prediction errors also occur when
warfarin is coadministered with Argatroban 1 mcg/kg/min. Thus, for doses
of Argatroban of 1 or 2 mcg/kg/min, the INRW
can be predicted from the INRWA.
For doses of Argatroban greater than 2 mcg/kg/min, the error associated
with predicting the INRW
from the INRWA is
±1 unit. Thus, the INRW
cannot be reliably predicted from the INRWA
at doses greater than 2 mcg/kg/min.[2,36]
INR Relationship of Argatroban Plus Warfarin vs
Warfarin Alone[2]
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What are the benefits of Argatroban?
| Argatroban does not interact
with or induce heparin-dependent antibodies and is thus an appropriate
alternative for HIT patients, including those heparin-sensitive patients
with coronary artery disease who require PCI. |
| • |
Rapid onset of action:
Steady-state levels and anticoagulant effects occur within 1 to 3
hours. |
| • |
Short half-life: The
half-life of Argatroban is short (39 to 51 minutes) in healthy subjects.
As a result, the anticoagulant effects are relatively short-lived
after the drug is discontinued. Clearance is significantly reduced
and therefore half-life is longer in patients with hepatic impairment
(see Dosing). |
| • |
Low molecular weight:
Argatroban is a synthetic molecule with a molecular weight of 526.66.
Low-molecular-weight compounds are typically less antigenic. Evaluations
of HIT patients and sera from HIT patients demonstrated that therapy
with Argatroban does not generate antibodies that alter its anticoagulant
activity.[2,5] |
| • |
Lack of cross-reactivity with
heparin-dependent antibodies: Argatroban does not interact
with or induce heparin-dependent antibodies and is thus an appropriate
alternative for HIT patients, including those heparin-sensitive patients
with coronary artery disease who require percutaneous coronary intervention
(PCI). |
| • |
Predictable dose response:
When administered by continuous infusion in healthy subjects, anticoagulant
effects follow similar, predictable temporal response profiles with
low inter-subject variability. |
| • |
aPTT or ACT: Allows for
convenient monitoring of anticoagulant effects. |
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What is the pharmacokinetic/pharmacodynamic relationship of Argatroban?
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 infusion of Argatroban, anticoagulant effects are produced as concentrations
of plasma argatroban begin to rise. Steady-state levels of both drug and
anticoagulant effect are typically attained within 1 to 3 hours and are
maintained until the infusion is discontinued or the dosage adjusted. Steady-state
concentrations of plasma argatroban increase proportionally with dose (for
infusion doses up to 40 mcg/kg/min in healthy subjects) and are well correlated
with steady-state anticoagulant effects. For infusion doses up to 40 mcg/kg/min,
Argatroban increases, in a dose-dependent fashion, the aPTT, the ACT, the
prothrombin time (PT), the International Normalized Ratio (INR), and the
thrombin time (TT) in healthy volunteers and cardiac patients. Representative
steady-state plasma concentration of plasma argatroban and anticoagulant
effects are shown below for infusion doses of Argatroban up to 10 mcg/kg/min.
Relationship at Steady State Between Dose of Argatroban,
Concentration of Plasma
Argatroban, and Anticoagulant Effect in Healthy Subjects[2,13]
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What clinical studies have been done to show the efficacy of Argatroban?
Two clinical studies, ARG-911 and ARG-915, form the basis of the conclusion
that Argatroban is well tolerated and an effective treatment for heparin-induced
thrombocytopenia (HIT) with or without thrombosis. These studies were comparable
with regard to study design, study objectives, and dosing regimens, as well
as study outline, conduct, and monitoring.
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What are the contraindications and warnings for the use of Argatroban?
Argatroban is contraindicated in patients with overt major bleeding, or
in patients hypersensitive to Argatroban or any of its components.[2]
Argatroban is intended for intravenous administration.[2]
All parenteral anticoagulants should be discontinued before administration
of Argatroban.
Hemorrhage can occur at any site in the body in patients receiving Argatroban.[2]
An unexplained fall in hematocrit, fall in blood pressure, or any other
unexplained symptom should prompt 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 congenital or acquired bleeding disorders, and gastrointestinal
lesions such as ulcerations.[2]
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What adverse reactions have been reported with Argatroban?
Argatroban is generally well tolerated in HIT patients, a patient population
that often has poor medical status. Major bleeding, minor bleeding, and
most frequently observed (2%) nonhemorrhagic adverse events among Argatroban-treated
patients in the pivotal trials, ARG-911 and ARG-915, are presented here.
The adverse events include all events regardless of relationship to treatment.
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What precautions apply to drug interactions with Argatroban?
Heparin: Since heparin is contraindicated in
patients with HIT, the coadministration of Argatroban and heparin is unlikely
for this indication.[2] When Argatroban
is initiated after cessation of heparin therapy, allow sufficient time for
heparin's effect on the aPTT to decrease prior to initiation of therapy
with Argatroban.
Aspirin/acetaminophen: Pharmacokinetic or pharmacodynamic
drug-drug interactions have not been demonstrated between Argatroban and
concomitantly administered aspirin (162.5 mg orally given 26 and 2 hours
prior to initiation of Argatroban 1 mcg/kg/min given over 4 hours) or acetaminophen
(1,000 mg orally given 12, 6, and 0 hours prior to, and 6 and 12 hours subsequent
to, initiation of Argatroban 1.5 mcg/kg/min given over 18 hours).[2]
In clinical trials involving HIT/HITTS patients undergoing PCI, all patients
received oral aspirin (325 mg) 2 to 24 hours prior to the interventional
procedure as per protocol.
Oral anticoagulant agents: Pharmacokinetic drug-drug
interactions between Argatroban and warfarin (7.5 mg single oral dose) have
not been demonstrated.[2] However,
the concomitant use of Argatroban and warfarin (5 to 7.5 mg initial oral
dose, followed by 2.5 to 6 mg/day orally for 6 to
10 days) results in prolongation of the PT and INR (see Pharmacology
and Dosage and Administration).
Thrombolytic agents: The safety and effectiveness
of Argatroban with thrombolytic agents have not been established (see Adverse
reactions: Intracranial bleeding).[2]
Glycoprotein IIb/IIIa antagonists: The safety
and effectiveness of Argatroban with glycoprotein IIb/IIIa antagonists have
not yet been established.
Coadministration: Concomitant use of Argatroban
with antiplatelet agents, thrombolytics, and other anticoagulants may increase
the risk of bleeding (see Warnings).[2]
Drug-drug interactions have not been observed between Argatroban and digoxin
or erythromycin (see Drug-drug
interactions).[2]
Pregnancy
Teratogenic effects: Pregnancy Category B. Teratology
studies have been performed in rats with intravenous doses up to 27 mg/kg/day
(0.3 times the recommended maximum human dose based on body surface area)
and rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the recommended
maximum human dose based on body surface area) and have revealed no evidence
of impaired fertility or harm to the fetus due to Argatroban.[2]
There are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of
human response, this drug should be used during pregnancy only if clearly
needed.[2]
Nursing mothers
Experiments in rats show Argatroban is detected in milk.[2]
It is not known whether Argatroban is excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for serious
adverse reactions in nursing infants from Argatroban, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
What is the recommended dosage for Argatroban in HIT patients?
Before administering Argatroban, discontinue heparin therapy and obtain
a baseline aPTT. The recommended initial dose of Argatroban for adult patients
without hepatic impairment is 2 mcg/kg/min, administered as a continuous
infusion. See below for standard infusion rates,
a dosing checklist, and a summary
of recommended dosing.
Table 1. Recommended Doses and Infusion Rates
for 2 mcg/kg/min Dose of
Argatroban for Patients With HIT/HITTS (Without Hepatic Impairment)
(1 mg/mL Final Concentration)
| Body Weight (kg) |
Dose (mcg/min) |
Infusion Rate (mL/hr) |
| 50 |
100 |
6 |
| 60 |
120 |
7 |
| 70 |
140 |
8 |
| 80 |
160 |
10 |
| 90 |
180 |
11 |
| 100 |
200 |
12 |
| 110 |
220 |
13 |
| 120 |
240 |
14 |
| 130 |
260 |
16 |
| 140 |
280 |
17 |
|
Table 2. Dosing Checklist for Argatroban
| • |
Heparin must be discontinued before
administration of Argatroban |
| • |
A baseline aPTT should be obtained
before initiating therapy with Argatroban |
| • |
Argatroban is administered by
intravenous infusion only |
| • |
Patients with hepatic impairment
require a dosage adjustment |
| • |
The aPTT should be rechecked 2
hours after initiation and the dose should be adjusted until
target aPTT value of 1.5 to 3.0 times baseline is attained (not
to exceed 100 seconds) |
| • |
Doses >10 mcg/kg/min should not
be administered |
|
Figure 1. Recommended Dosing for Argatroban[2]
| HIT Patients |
HIT Patients With
Renal Impairment |
HIT Patients With
Hepatic Impairment
|
Initiate at 2 mcg/kg/min
Titrate until steady-state aPTT
is 1.5 to 3.0 times baseline value* |
No dosage adjustment required
Titrate until steady-state aPTT
is 1.5 to 3.0 times baseline value* |
Initiate at 0.5 mcg/kg/min†
Titrate until steady-state aPTT
is 1.5 to 3.0 times baseline value* |
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How is therapy with Argatroban monitored and adjusted?
In general, therapy with Argatroban is monitored using the aPTT. Steady-state
anticoagulant effects (including the aPTT) typically occur within 1 to 3
hours following initiation of Argatroban. Dose adjustment may be required
to attain the target aPTT. Check the aPTT 2 hours after initiation of therapy
to confirm the patient has attained the desired therapeutic range.[2]
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Are dosage adjustments needed for hepatically impaired and renally-impaired
patients?
Hepatic impairment in HIT/HITTS patients undergoing
PCI: Use of high doses of Argatroban in PCI patients with clinically
significant hepatic disease or AST/ALT levels greater than 3 times the upper
level of normal should be avoided. Such patients were not studied in percutaneous
coronary intervention (PCI) trials.
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Renal impairment: No dosage adjustment is necessary
in patients with renal impairment (see Precautions and Special populations:
renal impairment).
How do you convert Argatroban to oral therapy if oral therapy is required?
Once the decision is made to initiate oral anticoagulant therapy, it is
important to recognize the coadministration of Argatroban and warfarin has
the potential for combined effects on the INR (see Effect
on International Normalized Ratio).[2,9,10]
| • |
A loading dose of warfarin should not be used. |
| • |
Initiate therapy using the expected daily dose of
warfarin |
| • |
To avoid prothrombotic effects and to ensure continuous
anticoagulation when initiating warfarin, it is recommended to overlap
therapy with Argatroban and warfarin |
| • |
There are insufficient data available to recommend
the duration of the overlap |
Conversion to Oral Anticoagulant Therapy[2]
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|
2
mcg/kg/min, the INR on monotherapy may be estimated from the INR on cotherapy
(see full Prescribing
Information).