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OverviewMechanism of ActionHow To UseUsesBenfitsIndicationsMethod of AdministrationDosage StrengthsDosage FormsDietary RestrictionsContraindicationsWarnings and Precautions for usingAdverse ReactionsSide EffectsUse of Argatroban in Specific PopulationsOverdosage Clinical Pharmacology Clinical StudiesAuthored by Reviewed by References
Argatroban

Argatroban

Indications, Uses, Dosage, Drugs Interactions, Side effects
Argatroban
Medicine Type :
Allopathy
Prescription Type:
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Pharmacological Class:
Direct Thrombin Inhibitor,
Therapy Class:
Anticoagulant,

Argatroban is an anticoagulant agent belonging to Direct thrombin Inhibitors.

Argatroban is a synthetic direct thrombin inhibitor used for the prevention and treatment of thrombosis related to heparin use.

The onset of action is immediate, with 100% bioavailability. Time taken to reach peak plasma concentration is found to be 1-3 hours. Argatroban distributes mainly in the extracellular fluid as evidenced by an apparent steady-state volume of distribution of 174 mL/kg (12.18 L in a 70 kg adult). Argatroban is 54% bound to human serum proteins, with binding to albumin and α1-acid glycoprotein being 20% and 34%, respectively. The main route of Argatroban metabolism is hydroxylation and aromatization of the 3­methyltetrahydroquinoline ring in the liver. Primarily in the feces via the bile, as metabolites and at least 14% as unchanged drug; via urine (approximately 16% as unchanged drug). Terminal elimination half-life is about 39-51 min.

Argatroban shows common side effects like Abdominal pain or swelling, arm, back, or jaw pain, black, tarry stools, blood in the eyes, blood in the urine, blurred vision, bruising or purple areas on the skin, chest pain or discomfort, chest tightness or heaviness, confusion, coughing up blood, decreased alertness, dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly, headache, joint pain or swelling, nausea, nervousness, nosebleeds, pounding in the ears, shortness of breath, slow, fast, or irregular heartbeat, sweating, unusual tiredness or weakness.

Argatroban is available in the form of an Intravenous solution.

Argatroban is available in India, the US, the UK, South Korea, Canada, China, Japan, and Australia.

Argatroban belonging to the Direct thrombin Inhibitor, acts as an anticoagulant agent.

Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation.

The Immediate onset of action is achieved while taking Argatroban.

The Tmax of Argatroban is found to be 1-3 hours.

The Data on the duration of Action of Argatroban is not available.

Argatroban is available in the form of an Intravenous solution.

Argatroban is given Intravenously only.

Argatroban is a synthetic direct thrombin inhibitor used for the prevention and treatment of thrombosis related to heparin use.

Argatroban is an anticoagulant agent belonging to a Direct thrombin inhibitor.

Argatroban is a synthetic direct thrombin inhibitor that reversibly binds to the active thrombin site of free and clot-associated thrombin. It exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, e.g., fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.

Argatroban is approved for use in the following clinical indications

  • Heparin-Induced Thrombocytopenia

For prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia.

  • Percutaneous Coronary Intervention

As an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention.

  • Heparin-induced thrombocytopenia

Adult Dose

Continuous IV infusion

Initial dose: 2 mcg/kg/minute; titrate to maintain aPTT in the desired range.

Maintenance dose: Measure aPTT after 2 hours. In critically ill patients, consider measuring aPTT 2 hours after initiation, then every 4 hours to allow for a steady state to be achieved. Adjust the dose until the steady state aPTT is 1.5 to 3 times the initial baseline value, not exceeding 100 seconds; dosage should not exceed 10 mcg/kg/minute.

Pediatric Dose (off-label)

Continuous IV infusion

Initial dose: 0.75 mcg/kg/minute.

Maintenance dose: Measure aPTT after 2 hours; adjust the dose until the steady state aPTT is 1.5 to 3 times the initial baseline value, not exceeding 100 seconds; adjust in increments of 0.1 to 0.25 mcg/kg/minute for normal hepatic function; reduce dose in hepatic impairment.

  • Percutaneous coronary intervention:

Intravenous:

Initial: Begin infusion of 25 mcg/kg/minute and administer a bolus dose of 350 mcg/kg (over 3 to 5 minutes). ACT should be checked 5 to 10 minutes after bolus infusion; proceed with the procedure if ACT >300 seconds.

Following initial bolus:

ACT <300 seconds: Give an additional 150 mcg/kg bolus and increase infusion rate to 30 mcg/kg/minute (recheck ACT in 5 to 10 minutes).

ACT >450 seconds: Decrease infusion rate to 15 mcg/kg/minute (recheck ACT in 5 to 10 minutes).

Once a therapeutic ACT (300 to 450 seconds) is achieved, the infusion should be continued for the duration of the procedure.

If dissection, impending abrupt closure, thrombus formation during PCI, or inability to achieve ACT >300 seconds: An additional bolus of 150 mcg/kg, followed by an increase in infusion rate to 40 mcg/kg/minute may be administered.

Argatroban is available in various strengths as (250 mg/2.5 mL) 100 mg/mL and 1 mg/mL.

Argatroban is available in the form of an Intravenous solution.

Dosage Adjustment in Kidney Patient

Mild to severe impairment: No dosage adjustment necessary.

Dosage Adjustment in Hepatic impairment Patient

Heparin-induced thrombocytopenia:

  • Mild impairment (Child-Pugh class A): There are no specific dosage adjustments provided. Use with caution; dosage reduction is necessary.
  • Moderate impairment (Child-Pugh class B): Continuous IV infusion: Initial: 0.5 mcg/kg/minute; measure aPTT after 2 hours and adjust the dose as needed. In critically ill patients, consider measuring aPTT 2 hours after initiation, then every 4 hours to allow for a steady state to be achieved. Adjust the dose until the steady state aPTT is 1.5 to 3 times the initial baseline value, not exceeding 100 seconds.
  • Severe impairment (Child-Pugh class C): Continuous IV infusion: Initial: 0.25 mcg/kg/minute; measure aPTT after 2 hours and adjust the dose as needed; in critically ill patients, consider measuring aPTT 2 hours after initiation, then every 4 hours to allow for steady state to be achieved. Adjust the dose until the steady state aPTT is 1.5 to 3 times the initial baseline value, not exceeding 100 seconds.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba. Caution should be taken with grapefruit products as it inhibits CYP3A4 metabolism, which may increase the serum concentration of Argatroban. Exercise caution with St. John's Wort.

Argatroban is contraindicated in patients with

  • Patients with major bleeding
  • Patients with a history of hypersensitivity to Argatroban. Airway, skin, and generalized hypersensitivity reactions have been reported
  • Risk of Hemorrhage

Hemorrhage can occur at any site in the body in patients receiving Argatroban. An unexplained fall in hematocrit or blood pressure may indicate hemorrhage. Intracranial and retroperitoneal hemorrhage have been reported. 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.

  • 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. 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, Clinical Pharmacology. Avoid the use of high doses of Argatroban in patients undergoing PCI who have a clinically significant hepatic disease or AST/ALT levels ≥3 times the upper limit of normal.

Breast Feeding Warning

It is not known if Argatroban is present in breast milk. The decision to continue or discontinue breastfeeding during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Pregnancy Warning

Argatroban has been assigned to pregnancy category B by the FDA. Animal studies have failed to reveal evidence of fetal harm. There are no controlled data on human pregnancy. Argatroban should only be given during pregnancy when the need has been clearly established.

Food Warning

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba. Caution should be taken with grapefruit products as it inhibits CYP3A4 metabolism, which may increase the serum concentration of Argatroban. Exercise caution with St. John's Wort.

  • Common Adverse effects

Chest pain, hypotension, Gastrointestinal hemorrhage, Genitourinary tract hemorrhage, Acute myocardial infarction, angina pectoris, brachial artery hemorrhage, bradycardia, coronary occlusion, coronary thrombosis, ischemic heart disease, ventricular tachycardia, Abdominal pain, diarrhea, nausea, vomiting, decreased hematocrit, decreased hemoglobin, groin bleeding, headache, Back pain, cough, hemoptysis, fever.

  • Rare Adverse effects

Aortic valve stenosis, atrial thrombosis, vascular disease, gastroesophageal reflux disease, disseminated intravascular coagulation, retroperitoneal bleeding, bleeding at the injection site, local hemorrhage, cerebrovascular disease, pulmonary edema, hypersensitivity reaction.

  • 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.

  • 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).

  • Aspirin/Acetaminophen

No drug-drug interactions have been demonstrated between Argatroban and concomitantly administered aspirin or acetaminophen.

  • Thrombolytic Agents

The safety and effectiveness of Argatroban with thrombolytic agents have not been established.

  • Glycoprotein IIb/IIIa Antagonists

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

The common side effect of Argatroban include the following

  • Common

Bleeding from the bladder, blood in the urine, blurred vision, chest pain, confusion, dizziness, faintness, or light-headedness when getting up from a lying or sitting position suddenly, fever, no blood pressure or pulse, stopping of heart, sweating, unconsciousness, unusual tiredness, or weakness.

  • Rare

Abdominal pain or swelling, back pain or backaches, blue lips and fingernails, changes in skin color, cold hands and feet, coughing that sometimes produces pink frothy sputum, diarrhea, difficult, fast, noisy breathing, sometimes with wheezing, increased sweating, indigestion, loss of appetite, pain, redness, or swelling in the arm or leg, pains in the chest, groin, or legs, especially calves of the legs, pale skin, passing of gas, severe headaches of sudden onset, stomach pain, fullness, or discomfort, sudden loss of coordination, sudden onset of shortness of breath for no apparent reason, sudden onset of slurred speech, sudden vision changes, swelling in the legs and ankles.

  • Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Argatroban use in pregnant women. Developmental studies performed in rats with Argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the maximum recommended human dose, based on body surface area) and in rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the maximum recommended human dose, based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

  • Nursing Mothers

It is not known whether Argatroban is excreted in human milk. Argatroban is detected in rat 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.

  • Pediatric Use

As per FDA, safety and effectiveness have not been established in pediatric patients.

  • Geriatric Use

Of the total number of subjects (1340) in clinical studies of Argatroban, 35% were 65 and over. In the clinical studies of adult patients with HIT (with or without thrombosis), the effectiveness of Argatroban was not affected by age. No trends were observed across age groups for both aPTT and the ACT. The safety analysis did suggest that older patients had increased underlying conditions, which may predispose them to adverse reactions. The studies were not sized appropriately to detect differences in safety between age groups.

  • Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing Argatroban or by decreasing the Argatroban dose. In clinical studies, anticoagulation parameters generally returned from therapeutic levels to baseline within 2 to 4 hours after discontinuation of the drug. Reversal of the anticoagulant effect may take longer in patients with hepatic impairment.
  • No specific antidote to Argatroban is available; if life-threatening bleeding occurs and excessive plasma levels of Argatroban are suspected, discontinue Argatroban immediately and measure aPTT and other coagulation parameters. When Argatroban was administered as a continuous infusion (2 mcg/kg/min) prior to and during a 4-hour hemodialysis session, approximately 20% of Argatroban was cleared through dialysis.
  • Single intravenous doses of Argatroban at 200, 124, 150, and 200 mg/kg were lethal to mice, rats, rabbits, and dogs, respectively. The symptoms of acute toxicity were loss of righting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma.

Pharmacodynamic

Argatroban is a synthetic direct thrombin inhibitor derived from L-arginine indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia. Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require 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 factors V, VIII, and XIII; protein C; and platelet aggregation. Argatroban is highly selective for thrombin with an inhibitory constant (Ki) of 0.04 µM. At therapeutic concentrations, Argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein). Argatroban can inhibit the action of both free and clot-associated thrombin.

Pharmacokinetics

  • Absorption

The onset of action is immediate, with 100% bioavailability Time taken to reach peak plasma concentration is found to be 1-3 hours.

  • Distribution

Argatroban distributes mainly in the extracellular fluid as evidenced by an apparent steady-state volume of distribution of 174 mL/kg (12.18 L in a 70 kg adult). Argatroban is 54% bound to human serum proteins, with binding to albumin and α1-acid glycoprotein being 20% and 34%, respectively.

  • Metabolism and Excretion

The main route of Argatroban metabolism is hydroxylation and aromatization of the 3­ methyl-tetrahydro quinoline ring in the liver. The formation of each of the 4 known metabolites is catalyzed in vitro by the human liver microsomal cytochrome P450 enzymes CYP3A4/5. Primarily in the feces via the bile, as metabolites and at least 14% as unchanged drug; via urine (approx 16% as unchanged drug). Terminal elimination half-life is about 39-51 min.

There are some clinical studies of the drug Argatroban mentioned below:
  1. Kathiresan S, Shiomura J, Jang IK. Argatroban. Journal of thrombosis and thrombolysis. 2002 Feb;13(1):41-7.
  2. Walenga JM. An overview of the direct thrombin inhibitor argatroban. Pathophysiology of hemostasis and thrombosis. 2002;32(Suppl. 3):9-14.
  3. Miyata S, Yamamoto H, Kamei M, Nakatani T, Kobayashi J, Tsuji T, Minematsu K, Tomoike H. Heparin-induced thrombocytopenia clinical studies and the efficacy of argatroban in Japan. InSeminars in thrombosis and hemostasis 2008 Oct (Vol. 34, No. S 01, pp. 037-047). © Thieme Medical Publishers.

  • https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022485lbl.pdf
  • https://www.rxlist.com/argatroban-drug.htm#interactions
  • https://reference.medscape.com/drug/acova-argatroban-342145
  • https://go.drugbank.com/drugs/DB00278
  • https://www.drugs.com/dosage/argatroban.html
  • https://www.mims.com/india/drug/info/argatroban?type=full&mtype=generic
  • https://www.uptodate.com/contents/argatroban-drug-information#F6273425
  • https://www.mayoclinic.org/drugs-supplements/argatroban-intravenous-route/side-effects/drg-20072368
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Jyoti Suthar
Jyoti is a Post graduate in Pharmaceutics ( M Pharm) She did her graduation ( B Pharm) From SSR COLLEGE OF PHARMACY And thereafter did her M Pharm specialized in Pharmaceutics from SSR COLLEGE OF PHARMACY
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Dr JUHI SINGLA
Dr JUHI SINGLA has completed her MBBS from Era’s Lucknow Medical college and done MD pharmacology from SGT UNIVERSITY Gurgaon. She can be contacted at editorial@medicaldialogues.in. Contact no. 011-43720751
Published on: 27 Oct 2022 7:08 PM GMT
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