ARGATROBAN Drug Interactions: What You Need to Know

INTERACTIONS

• Heparin: Allow sufficient time for heparin’s effect on aPTT to decrease before initiating argatroban injection therapy ( 7.1 ).
• Warfarin: Concomitant use results in increased prolongation of PT and INR ( 7.2 ).
• Thrombolytic agents or glycoprotein IIb/IIIa antagonists: Safety and effectiveness of concomitant use with argatroban have not been established ( 7.4 , 7.5 ).

7.1 Heparin 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.

7.2 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) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.2 )]</span> .

7.3 Aspirin/Acetaminophen No drug-drug interactions have been demonstrated between argatroban and concomitantly administered aspirin or acetaminophen <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.4 Thrombolytic Agents The safety and effectiveness of argatroban with thrombolytic agents have not been established <span class="opacity-50 text-xs">[see Adverse Reactions (6.3) ]</span>.

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

7.1 Heparin 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.

7.2 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) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.2 )]</span> .

7.3 Aspirin/Acetaminophen No drug-drug interactions have been demonstrated between argatroban and concomitantly administered aspirin or acetaminophen <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.4 Thrombolytic Agents The safety and effectiveness of argatroban with thrombolytic agents have not been established <span class="opacity-50 text-xs">[see Adverse Reactions (6.3) ]</span>.

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

Argatroban in sodium chloride injection is contraindicated in: Patients with major bleeding, [ see Warnings and Precautions (5.1) ] Patients with a history of hypersensitivity to argatroban products. Airway, skin, and generalized hypersensitivity reactions have been reported [ see Adverse Reactions (6.1) ] . Major bleeding (4) History of hypersensitivity to this product (4)

AND PRECAUTIONS

• Risk of hemorrhage: Hemorrhage at any site can occur (unexplained fall in hematocrit or blood pressure or other unexplained symptom may indicate hemorrhage.) Use with caution in patients at risk, including those receiving antiplatelet agents, thrombolytics, or other anticoagulants. ( 5.1 ).
• Use in hepatic impairment: Adjust starting dose and titrate carefully in patients with HIT who have moderate or severe hepatic impairment. Avoid use in PCI in patients with clinically significant hepatic impairment ( 5.2 ).

5.1 Risk of Hemorrhage Hemorrhage can occur at any site in the body in patients receiving argatroban. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. Intracranial and retroperitoneal hemorrhage have been reported <span class="opacity-50 text-xs">[see Adverse Reactions (6.1, 6.2 , and 6.3 )]</span> . The risk of hemorrhage with argatroban may be increased in 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. Concomitant use of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding.

5.2 Use in Hepatic Impairment When administering argatroban to patients with hepatic impairment, start with a lower dose and carefully titrate until the desired level of anticoagulation is achieved. Achievement of steady-state aPTT levels may take longer and require more argatroban dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]</span> . Avoid the use of high doses of argatroban in patients undergoing PCI who have clinically significant hepatic disease or AST/ALT levels greater than or equal to 3 times the upper limit of normal.

5.3 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. 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.2 )]</span> .

5.1 Risk of Hemorrhage Hemorrhage can occur at any site in the body in patients receiving argatroban. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. Intracranial and retroperitoneal hemorrhage have been reported <span class="opacity-50 text-xs">[see Adverse Reactions (6.1, 6.2 , and 6.3 )]</span> . The risk of hemorrhage with argatroban may be increased in 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. Concomitant use of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding.

5.2 Use in Hepatic Impairment When administering argatroban to patients with hepatic impairment, start with a lower dose and carefully titrate until the desired level of anticoagulation is achieved. Achievement of steady-state aPTT levels may take longer and require more argatroban dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]</span> . Avoid the use of high doses of argatroban in patients undergoing PCI who have clinically significant hepatic disease or AST/ALT levels greater than or equal to 3 times the upper limit of normal.

5.3 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. 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.2 )]</span> .