Argatroban

508.63

508.63

1308068-626-2

DTXSID7046467

Crystals from ethanol

B - Blood and blood forming organs

2935009090

189

1.3

white to off-white crystalline solid

1.47±0.1 g/cm3(Predicted)

188-191 °C

801.3ºC at 760 mmHg

438.4ºC

1.674

In water, 51.35 mg/L at 25 °C (est)

Store at +4°C

1.37X10-17 mm Hg at 25 °C (est)

pH 8.8 (Argatroban solution)

pKa1 = 3.06; pKa2 = 11.8 (est)

Crystals from aqueous ethanol; MP: 276-280 °C. Specific optical rotation: +76.1 deg at 27 °C/D (c = 1 in 0.2N HCl) /Argatroban monohydrate/

III

6.1

UN 2020 6.1/PG 3

2

R20/21/22; R51/53

S28; S61

SK2450000

Xn; N

Stable under recommended storage conditions. /Argatroban monohydrate/

P273, P501

H412

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/

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.

H412 (99.38%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]|P273, and P501|Aggregated GHS information provided by 160 companies from 2 notifications to the ECHA C&L Inventory.

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/

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/

Hazardous decomposition products formed under fire conditions -- Carbon oxides, Nitrogen oxides (NOx), Sufur oxides. /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. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /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.

Excessive bleeding|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.

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).

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.

54%

Argatroban's production and administration as an antithrombotic(1) may result in its release to the environment through various waste streams(SRC).

Argatroban is indicated for prevention and treatment of thrombosis caused by heparin-induced thrombocytopenia (HIT). It is also indicated for use in patients with, or at risk for, HIT who are undergoing percutaneous coronary intervention.|FDA Label

Antithrombins; Platelet Aggregation Inhibitors|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Argatroban is included in the database.|Argatroban injection is indicated as an anticoagulant in adult patients with or at risk for heparin-induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention (PCI). /Included in US product label/|Argatroban injection is indicated for prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT). /Included in US product label/|For more Therapeutic Uses (Complete) data for Argatroban (10 total), please visit the HSDB record page.

Other nonhemorrhagic adverse effects occurring in at least 2% of argatroban-treated patients with HIT/HITTS undergoing PCI include chest pain, back pain, headache, bradycardia, and myocardial infarction.|Adverse hemorrhagic effects reported in 2% or more of nonsurgical patients with HIT/HITSS receiving argatroban include major or minor GI bleeding, minor genitourinary bleeding or hematuria, minor decrease in hemoglobin/hematocrit, minor groin or brachial bleeding (e.g., catheter insertion site), and hemoptysis;9 nonhemorrhagic effects include dyspnea, hypotension, fever, diarrhea, sepsis, cardiac arrest, nausea, ventricular tachycardia, pain, urinary tract infection, vomiting, infection, pneumonia, atrial fibrillation, coughing, abnormal renal function, abdominal pain, and cerebrovascular disorder.|Safety and efficacy of argatroban not fully established in pediatric patients; however, the drug has been evaluated in a limited number of seriously ill pediatric patients younger than 16 years of age with HIT or HITTS. In a small, multicenter open-label study, 18 seriously ill pediatric patients with a clinical condition requiring alternative nonheparin anticoagulation received argatroban at an initial dosage of 1 ug/kg per minute titrated to maintain a target aPTT of 1.5-3 times the baseline value. During the 30-day study period, thrombotic events occurred in 5 patients and major bleeding (intracranial hemorrhage) was reported in 2 patients. All of the patients had serious comorbid conditions and were receiving multiple concomitant medications; most were diagnosed with documented or suspected HIT. Pharmacokinetic analysis of the data indicated that argatroban clearance was reduced by 50% in seriously ill pediatric patients compared with healthy adults and by approximately 80% in pediatric patients with elevated bilirubin concentrations compared to pediatric patients with normal bilirubin concentrations. Based on these results, reduced dosages of argatroban are recommended in pediatric patients.|There are no data on the presence of argatroban in human milk, or its effects on milk production. Argatroban is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Argatroban and any potential adverse effects on the breastfed infant from Argatroban or from the underlying maternal condition.|For more Drug Warnings (Complete) data for Argatroban (16 total), please visit the HSDB record page.

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.

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. (See all compounds classified as Platelet Aggregation Inhibitors.)|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. (See all compounds classified as 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.|Argatroban distributes mainly in the extra cellular 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 a1 - acid glycoprotein being 20% and 34%, respectively.|/MILK/ Argatroban is detected in rat milk.

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.

39 and 51 minutes|The terminal elimination half life is 39-51 minutes.

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.

/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.

/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]).

(21R)-argatroban

Parenteral: For injection concentrate, for IV infusion only: 100 mg/mL (250 mg), Argatroban Injection (GlaxoSmithKline).

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients