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Adverse Events
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| Major Hemorrhagic Events* | ||
(n=568) % |
Historical Control (n=193) % |
|
| Overall bleeding | 5.3 | 6.7 |
| Gastrointestinal | 2.3 | 1.6 |
| Genitourinary and hematuria | 0.9 | 0.5 |
| Decrease in hemoglobin and hematocrit | 0.7 | 0 |
| Multisystem hemorrhage and DIC | 0.5 | 1 |
| Limb and BKA stump | 0.5 | 0 |
| Intracranial hemorrhage | 0† | 0.5 |
| Minor Hemorrhagic Events* | ||
(ARG-911 and ARG-915) (n=568) % |
Historical Control (n=193) % |
|
| Gastrointestinal | 14.4 | 18.1 |
| Genitourinary and hematuria | 11.6 | 0.8 |
| Decrease in hemoglobin and hematocrit | 10.4 | 0 |
| Groin | 5.4 | 3.1 |
| Hemoptysis | 2.9 | 0.8 |
| Brachial | 2.4 | 0.8 |
(n=568) % |
Historical Control (n=193) % |
|
| Dyspnea | 8.1 | 8.8 |
| Hypotension | 7.2 | 2.6 |
| Fever | 6.9 | 2.1 |
| Diarrhea | 6.2 | 1.6 |
| Sepsis | 6.0 | 12.4 |
| Cardiac arrest | 5.8 | 3.1 |
| Nausea | 4.8 | 0.5 |
| Ventricular tachycardia | 4.8 | 3.1 |
| Pain | 4.6 | 3.1 |
| Urinary tract infection | 4.6 | 5.2 |
| Vomiting | 4.2 | 0 |
| Infection | 3.7 | 3.6 |
| Pneumonia | 3.3 | 9.3 |
| Artial fibrillation | 3.0 | 11.4 |
| Coughing | 2.8 | 1.6 |
| Abnormal renal function | 2.8 | 4.7 |
| Abdominal pain | 2.6 | 1.6 |
| Cerebrovascular disorder | 2.3 | 4.1 |
5 g/dL, that led to a
transfusion of 2 units, or that was intracranial,
retroperitoneal, or into a major prosthetic joint.| Major Hemorrhagic Events* | |
| Argatroban-Treated
Patients (n=112)† % |
|
| Retroperitoneal | 0.9 |
| Gastrointestinal | 0.9 |
| Intercranial | 0 |
| Minor Hemorrhagic Events* | |
| Argatroban-Treated
Patients (n=112)† % |
|
| Groin (bleeding or hematoma) | 3.6 |
| Gastrointestinal (includes hematemesis) | 2.6 |
| Genitourinary (includes hematuria) | 1.8 |
| Decrease in hemoglobin and/or hematrocrit | 1.8 |
| CABG (coronary arteries) | 1.8 |
| Access site | 0.9 |
| Hemoptysis | 0.9 |
| Other | 0.9 |
| Procedures With
Argatroban* (n=112)† % |
Controls (n=2226)‡ % |
|
| Chest pain | 15.2 | 9.3 |
| Hypotension | 10.7 | 10.3 |
| Back pain | 8.0 | 13.7 |
| Nausea | 7.1 | 11.5 |
| Vomiting | 6.3 | 6.8 |
| Headache | 5.4 | 5.5 |
| Bradycardia | 4.5 | 3.5 |
| Abdominal pain | 3.6 | 2.2 |
| Fever | 3.6 | <0.5 |
| Myocardial infarction | 3.6 | NR§ |
| Coded Term | Procedures
With Argatroban† (n=112) |
| Chest pain | 1 (0.9%) |
| Fever | 1 (0.9%) |
| Retroperitoneal hemorrhage | 1 (0.9%) |
| Angina pectoris | 2 (1.8%) |
| Aortic stenosis | 1 (0.9%) |
| Coronary thrombosis | 2 (1.8%) |
| Arterial thrombosis | 1 (0.9%) |
| Myocardial infarction | 4 (3.5%) |
| Myocardial ischemia | 2 (1.8%) |
| Occlusion coronary | 2 (1.8%) |
| Gastrointestinal hemorrhage | 1 (0.9%) |
| Gastrointestinal disorder (GERD) | 1 (0.9%) |
| Cerebrovascular disorder | 1 (0.9%) |
| Lung edema | 1 (0.9%) |
| Vascular disorder | 1 (0.9%) |
The following adverse reactions occurred in the 1,127
individuals who were treated with Argatroban in clinical pharmacology studies
(n=211) or for other clinical indications (n=916).[2]
Intracranial bleeding: Among patients with
acute myocardial infarction receiving both Argatroban and thrombolytic
therapy (streptokinase or tissue plasminogen activator), the
overall frequency of intracranial bleeding was 1% (8 out of 810 patients).
Intracranial bleeding was not observed in 317 subjects or patients who
did not receive concomitant thrombolysis (see Precautions,
Drug Interactions).[2]
Allergic reactions: 156 allergic reactions or
suspected allergic reactions were observed in 1,127 individuals who were
treated with Argatroban in clinical pharmacology studies or for various
clinical indications. About 95% (148/156) of these reactions occurred in
patients who concomitantly received thrombolytic therapy (e.g., streptokinase)
for acute myocardial infarction and/or contrast media for coronary angiography.[2]
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Contraindications
Argatroban is contraindicated in patients with overt major bleeding, or
in patients hypersensitive to Argatroban or any of its components (see Warnings).[2]
Warnings
Argatroban is intended for intravenous administration.[2]
All parenteral anticoagulants should be discontinued before administration
of Argatroban.
Hemorrhage
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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Precautions
Hepatic impairment
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.[2]
Also, upon cessation of infusion of Argatroban in the hepatically impaired
patient, full reversal of anticoagulant effects may require longer than
4 hours due to the decreased clearance and increased elimination half-life
of Argatroban (see Use of Argatroban).
In patients undergoing PCI who also have clinically significant hepatic
disease or AST/ALT levels 3 times the upper
limit of normal, use of Argatroban should be avoided. Such patients requiring
high doses of Argatroban were not studied in PCI trials.
Laboratory tests
Anticoagulation effects associated with infusion of Argatroban at doses
up to 40 mcg/kg/min are well correlated with the aPTT.[2]
Other global clot-based tests, including the PT, INR, and TT, are affected
by Argatroban, although the therapeutic ranges for these tests have not
been identified for therapy with Argatroban in HIT patients.[2]
Concentrations of plasma argatroban also correlate well with anticoagulant
effects (see Pharmacology).
In clinical trials in PCI, the ACT was used for monitoring anticoagulant
activity of Argatroban during the procedure. The concomitant use of Argatroban
and warfarin results in prolongation of the PT and INR beyond that produced
by warfarin alone.[2] Alternative
approaches for monitoring concurrent therapy with Argatroban and warfarin
are described in a subsequent section (see Use
of Argatroban).
Drug interactions
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]
Carcinogenesis, mutagenesis, and impairment of fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of Argatroban.[2] Argatroban was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the Chinese hamster lung fibroblast chromosome aberration test, the rat hepatocyte and WI-38 human fetal lung cell unscheduled DNA synthesis (UDS) tests, or the mouse micronucleus test.[2] Argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.[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.
Geriatric use
In the clinical studies of adult patients with HIT or HITTS, the effectiveness of Argatroban was not affected by age.
Pediatric use
The safety and effectiveness of Argatroban in patients below the age of 18 have
not been established.[2]
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Overdosage
Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing
Argatroban or by decreasing the infusion dosage of Argatroban (see Warnings).[2]
At therapeutic levels in clinical studies, anticoagulation parameters generally
returned to baseline within 2 to 4 hours after discontinuation of Argatroban.
Reversal of anticoagulant effect may take longer in patients with hepatic
impairment.[2]
No specific antidote to Argatroban is available; if life-threatening bleeding
occurs and excessive plasma levels of Argatroban are suspected, Argatroban
should be discontinued immediately and aPTT and a full coagulation profile
should be determined.[2] Symptomatic
and supportive therapy should be provided to the patient (see Warnings).
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Special populations
Renal impairment
No dosage adjustment is necessary in patients with renal dysfunction.[2] The effect of renal disease on the pharmacokinetics of Argatroban was studied in 6 subjects with normal renal function (mean Clcr [creatinine clearance] = 95 ± 16 mL/min) and in 18 subjects with mild (n=6, mean Clcr = 64 ± 10 mL/min), moderate (n=6, mean Clcr = 41 ± 5.8 mL/min), or severe (n=6, mean Clcr = 5 ± 7 mL/min) renal impairment. The pharmacokinetics and pharmacodynamics of Argatroban at dosages up to 5 mcg/kg/min were not significantly affected by renal dysfunction.[2,6]
Use of Argatroban was evaluated in a study of 12 patients with stable, end-stage renal disease undergoing chronic intermittent hemodialysis. Argatroban was administered at a rate of 2 to 3 mcg/kg/min (begun at least 4 hours prior to dialysis) or as a bolus dose of 250 mcg/kg at the start of dialysis followed by continuous infusion of 2 mcg/kg/min. Although these regimens did not achieve the goal of maintaining ACT values at 1.8 times the baseline value throughout most of the hemodialysis period, the hemodialysis sessions were successfully completed with both of these regimens.
The mean ACTs produced in this study ranged from 1.39 to 1.82 times baseline, and the mean aPTTs ranged from 1.96 to 3.4 times baseline. When Argatroban was administered as a continuous infusion of 2 mcg/kg/min prior to and during a 4-hour hemodialysis session, approximately 20% was cleared through dialysis.
Hepatic impairment
The dosage of Argatroban should be decreased in patients with hepatic impairment
(see Use of Argatroban).[2,6] Hepatic
impairment is associated with a decrease in clearance and increased elimination
half-life of Argatroban (to 1.9 mL/kg/min and 181 minutes, respectively,
for patients with a Child-Pugh score >6).
Patients with hepatic impairment were not studied in PCI trials.
Age, gender
There are no clinically significant effects of age or gender on the pharmacokinetics
or pharmacodynamics (e.g., aPTT) of Argatroban.[2,6]
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Drug-drug interactions
Digoxin
In 12 healthy subjects, intravenous infusion of Argatroban (2 mcg/kg/min over 5 hours) daily for 5 days did not affect the steady-state pharmacokinetics of oral digoxin (0.375 mg daily for 15 days).[2]
Erythromycin
In 10 healthy subjects, orally administered erythromycin (a potent inhibitor of
CYP3A4/5) at 500 mg 4 times daily for 7 days had no effect on the pharmacokinetics
of Argatroban 1 mcg/kg/min (over 5 hours).[2,31]
These data suggest oxidative metabolism by CYP3A4/5 is not an important
elimination pathway in vivo for Argatroban.
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