Argatroban

Breast Feeding; Lactation; Milk, Human; Anticoagulants; Antithrombins

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Warning

H302 (25%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P273, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P321, P330, P337+P317, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 4 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including argatroban, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Argatroban monohydrate/

Advice for firefighters: Wear self-contained breathing apparatus for fire fighting if necessary. /Argatroban monohydrate/

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature 2-8 °C. Store with desiccant. /Argatroban monohydrate/

Store the vials in original cartons at 20 deg to 25 °C (68 deg to 77 °F): excursion permitted between 15 deg to 30 °C (59 deg to 86 °F). Do not refrigerate or freeze. Protect from light and store in carton.

ACCIDENT RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /Argatroban monohydrate/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. /Argatroban monohydrate/

ACCIDENT RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. /Argatroban monohydrate/

Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Argatroban monohydrate/

Appropriate engineering controls: General industrial hygiene practice. /Argatroban monohydrate/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Argatroban monohydrate/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Argatroban monohydrate/

Skin protection: Handle with gloves. /Argatroban monohydrate/

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. /Argatroban monohydrate/

Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Argatroban monohydrate/

A combined effect on the INR occurs with coadministration of argatroban and warfarin, and the relationship between INR and bleeding risk is altered. Daily INR determinations are recommended during concomitant use of argatroban and warfarin. Continue to monitor the effects of argatroban using aPTT during conversion to warfarin. Argatroban therapy can be discontinued when the INR exceeds 4 with combined therapy. Repeat INR determinations 4-6 hours after discontinuance of the argatroban infusion should be within the desired therapeutic range for warfarin monotherapy.

Potential pharmacologic interaction (increased risk of hemorrhage) with concomitant use of thrombolytics, antiplatelet agents, or other anticoagulants. No pharmacokinetic or pharmacodynamic interaction demonstrated with low-dose oral aspirin (162.5 mg given 26 and 2 hours prior to argatroban infusion) or oral acetaminophen (1 g given every 6 hours for 5 doses beginning 12 hours prior to argatroban infusion). The manufacturer states that the safety and efficacy of concomitant therapy with argatroban and platelet glycoprotein (GP) IIb/IIIa-receptor antagonists has not been established.

Heparin is contraindicated in patients with heparin-induced thrombocytopenia (HIT). Prior to initiation of argatroban therapy, allow sufficient time for effect of heparin on activated partial thromboplastin time (aPTT) to decrease.

Pharmacodynamic interaction (increased prothrombin time (PT) and international normalized ratio (INR) relative to warfarin alone).

The most common adverse effect of argatroban, as with other anticoagulants, is bleeding, which can manifest as gastrointestinal, genitourinary, intracranial, retroperitoneal bleeding, hemoptysis, and other minor bleedings. Non-hemorrhagic complications include hypotension, dyspnea, fever, sepsis, and cardiac arrest. When used in PCI, chest pain, back pain, nausea, vomiting, hypotension, and headache can occur.

IDENTIFICATION AND USE: Argatroban is antithrombin, platelet aggregation inhibitor. Direct thrombin inhibitors including argatroban are commonly used anticoagulants in patients with known or suspected heparin-induced thrombocytopenia. HUMAN STUDIES: There are two case reports documenting safe use of argatroban during human pregnancy. Argatroban was not genotoxic in the WI-38 human fetal lung cell unscheduled DNA synthesis (UDS) test. ANIMAL STUDIES: 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. Developmental studies performed in rats (during gestation Days 7 to 17) with argatroban at intravenous doses up to 27 mg/kg/day and in rabbits (during gestation Days 6 to 18) at intravenous doses up to 10.8 mg/kg/day have revealed no evidence of harm to the fetus. 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 or the mouse micronucleus test.

The toxicity of argatroban from supratherapeutic dosage is related to its anticoagulant effect. There is no antidote to reverse its actions. In case of overdose, stop the drug and initiate appropriate transfusion therapy, eg, fresh frozen plasma. Patients with hepatic dysfunction are particularly susceptible to the excessive anticoagulant effect of argatroban due to reduced clearance. In such patients, the reversal of its effect takes a longer time.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of February 4, 2019: http://actor.epa.gov/dashboard/]

/CASE REPORTS/ A 6-year-old child developed heparin-induced thrombocytopenia while on extracorporeal life support. Hours after a difficult transition from heparin to argatroban for anticoagulation therapy, the child underwent heart transplantation. Intraoperative management was plagued with circuit thrombus formation while on cardiopulmonary bypass and subsequent massive hemorrhage after bypass. We review the child's anticoagulation management, clinical challenges encountered, and review current literature related to the use of argatroban in pediatric cardiac surgery.

/CASE REPORTS/ Direct thrombin inhibitors are commonly used anticoagulants in patients with known or suspected heparin-induced thrombocytopenia (HIT). All three direct thrombin inhibitors available in the United States-argatroban, bivalirudin, and lepirudin-are pregnancy category B drugs based on animal studies, but little data are available on the safety of these agents during human pregnancy. Whereas several case reports support the safe use of lepirudin, only one case report has been published with argatroban and none with bivalirudin. We describe a 26-year-old pregnant woman with portal vein thrombosis and thrombocytopenia treated with argatroban for possible HIT during her last trimester. An argatroban infusion was started at 2 ug/kg/minute during her 33rd week of pregnancy, with the dosage titrated based on the activated partial thromboplastin time; infusion rates ranged from 2-8 ug/kg/minute. Treatment continued until her 39th week of pregnancy, when labor was induced. Argatroban therapy was discontinued 7 hours before epidural anesthesia. The patient successfully delivered a healthy male newborn, devoid of any known adverse effects from argatroban. The infant was found to have a small ventricular septal defect and patent foramen ovale at birth, but it is unlikely that these were caused by argatroban since organogenesis occurs in the first trimester. Even though the cause of this patient's thrombocytopenia was later determined to be idiopathic thrombocytopenic purpura, this is an important case that adds to the literature on use of argatroban during pregnancy.

/GENOTOXICITY/ Argatroban was not genotoxic in the ... WI-38 human fetal lung cell unscheduled DNA synthesis (UDS) tests ... .

/OTHER TOXICITY INFORMATION/ Argatroban is a highly selective and reversible, small-molecule direct thrombin inhibitor that binds rapidly to the catalytic site/apolar region of both circulating (free) and clot-bound thrombin. Inhibition of thrombin prevents various steps in the coagulation process (e.g., activation of factors V, VIII, and XIII and of protein C; conversion of fibrinogen to fibrin; platelet activation and aggregation). At infusion rates up to 40 ug/kg per minute, argatroban produces dose-dependent increases in activated partial thromboplastin time (aPTT) and several other coagulation assays (activated clotting time [ACT], prothrombin time [PT], and thrombin time [TT]).

Drug Induced Liver Injury Rank (DILIrank 2.0)

Argatroban

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ 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.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Developmental studies performed in rats (during gestation Days 7 to 17) 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 (during gestation Days 6 to 18) 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 harm to the fetus.

/GENOTOXICITY/ 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 ... or the mouse micronucleus test.

Caution is advised in patients with hepatic dysfunction. Achievement of steady-state anticoagulation and reversal of the anticoagulant effect may require longer than 1-3 hours and 4 hours, respectively, because of the decreased clearance and increased elimination half-life of argatroban in such patients.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

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 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 ug/kg/min) prior to and during a 4-hour hemodialysis session, approximately 20% of Argatroban was cleared through dialysis.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including argatroban, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

B - Blood and blood forming organs

QB - Blood and blood forming organs

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 (K_i) of 0.04 µM. At therapeutic concentrations, Argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein). Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.

39 and 51 minutes

The terminal elimination half life is 39-51 minutes.

Liver via hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring. Age and gender do not substantially affect the pharmacodynamic or pharmacokinetic profile of argatroban.

The main route of argatroban metabolism is hydroxylation and aromatization of the 3-methyltetrahydroquinoline 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. The primary metabolite (M1) exerts 3- to 5-fold weaker anticoagulant effects than argatroban. Unchanged argatroban is the major component in plasma. The plasma concentrations of M1 range between 0% and 20% of that of the parent drug. The other metabolites (M2 to M4) are found only in very low quantities in the urine and have not been detected in plasma or feces. These data, together with the lack of effect of erythromycin (a potent CYP3A4/5 inhibitor) on argatroban pharmacokinetics, suggest that CYP3A4/5-mediated metabolism is not an important elimination pathway in vivo.

Argatroban is metabolized principally by the liver via hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring.

IY90U61Z3S

ARGATROBAN

Established Pharmacologic Class [EPC] - Anti-coagulant

Established Pharmacologic Class [EPC] - Direct Thrombin Inhibitor

Mechanisms of Action [MoA] - Thrombin Inhibitors

Argatroban is an Anti-coagulant and Direct Thrombin Inhibitor. The mechanism of action of argatroban is as a Thrombin Inhibitor.

Drugs or agents which antagonize or impair any mechanism leading to blood platelet aggregation, whether during the phases of activation and shape change or following the dense-granule release reaction and stimulation of the prostaglandin-thromboxane system.

Endogenous factors and drugs that directly inhibit the action of THROMBIN, usually by blocking its enzymatic activity. They are distinguished from INDIRECT THROMBIN INHIBITORS, such as HEPARIN, which act by enhancing the inhibitory effects of antithrombins.

Bioavailability is 100% (intravenous).

Argatroban is excreted primarily in the feces (65%), presumably through biliary secretion; 22% is eliminated via urine.

174 mL/kg

5.1 L/kg/hr [infusion doses up to 40 mcg/kg/min]

Argatroban is excreted primarily in the feces, presumably through biliary secretion. In a study in which (14)C-argatroban (5 ug/kg/min) was infused for 4 hours into healthy subjects, approximately 65% of the radioactivity was recovered in the feces within 6 days of the start of infusion with little or no radioactivity subsequently detected. Approximately 22% of the radioactivity appeared in the urine within 12 hours of the start of infusion. Little or no additional urinary radioactivity was subsequently detected. Average percent recovery of unchanged drug, relative to total dose, was 16% in urine and at least 14% in feces.

It is not known if argatroban crosses the human placenta. the molecular weight (about 527 for the hydrated from), low metabolism, and moderate serum protein binding suggest that exposure of the embryo-fetus should be expected, especially sine the drug is given as a continuous infusion.

Antithrombins; Platelet Aggregation Inhibitors

MEDICATION

Use (kg; approx.) in Germany (2009): >10