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Argatroban (Argatroban) - Warnings and Precautions

 
 



WARNINGS

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

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

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. Also, upon cessation of Argatroban infusion in the hepatically impaired patient, 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).

Use of high doses of Argatroban in PCI patients with clinically significant hepatic disease or AST/ALT levels >/=3 times the upper limit of normal should be avoided. Such patients were not studied in PCI trials.

Laboratory Tests: Anticoagulation effects associated with Argatroban infusion at doses up to 40 mcg/kg/min correlate with increases of the activated partial thromboplastin time (aPTT).

Although other global clot-based tests including prothrombin time (PT), the International Normalized Ratio (INR), and thrombin time (TT) are affected by Argatroban, the therapeutic ranges for these tests have not been identified for Argatroban therapy. Plasma Argatroban concentrations also correlate well with anticoagulant effects (see CLINICAL PHARMACOLOGY).

In clinical trials in PCI, the activated clotting time (ACT) was used for monitoring Argatroban anticoagulant activity during the procedure.

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).

Drug Interactions: Heparin: Since heparin is contraindicated in patients with heparin-induced thrombocytopenia, the co-administration of Argatroban and heparin is unlikely for this indication. However, if Argatroban is to be initiated after cessation of heparin therapy, allow sufficient time for heparin's effect on the aPTT to decrease prior to initiation of Argatroban therapy.

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 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 over 18 hours).

Oral Anticoagulant Agents: Pharmacokinetic drug-drug interactions between Argatroban and warfarin (7.5 mg single oral dose) have not been demonstrated. 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 prothrombin time (PT) and International Normalized Ratio (INR) (see CLINICAL 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).

Glycoprotein IIb/IIIa Antagonists: The safety and effectiveness of Argatroban with glycoprotein IIb/IIIa antagonists have not been established.

Co-Administration: Concomitant use of Argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding (see WARNINGS). Drug-drug interactions have not been observed between Argatroban and digoxin or erythromycin (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions).

Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Argatroban.

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.

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.

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. 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.

Nursing Mothers: Experiments in rats show that Argatroban is detected in milk. It is not known whether this drug 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 years have not been established.

Page last updated: 2006-10-22

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