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Drug Safety-related Labeling Changes (SrLC)

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Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/29/2019 (SUPPL-4)

Approved Drug Label (PDF)

6 Adverse Reactions

(additions underlined)

The following clinically significant adverse reaction is also discussed in other sections of the labeling:

  • Risk of Hemorrhage

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary


Limited data from published literature and postmarketing reports do not suggest an association between argatroban and adverse fetal outcomes. There are risks to the mother associated with untreated thrombosis in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulants (see Clinical Considerations). In animal reproduction studies, there was no evidence of adverse developmental outcomes with intravenous administration of argatroban during organogenesis in rats and rabbits at doses up to 0.3 and 0.2-times, respectively, the maximum recommended human dose (MHRD) (see Data).


The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.


Clinical Considerations


Disease-Associated Maternal and/or Embryo/Fetal Risk


Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high risk pregnancy conditions. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy.


Fetal/Neonatal Adverse Reactions


Use of anticoagulants, including argatroban, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding .


Labor or Delivery


All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Pregnant women receiving argatroban should be carefully monitored for evidence of excessive bleeding or unexpected changes in coagulation parameters.




Animal Data


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 harm to the fetus.

8.2 Lactation

(PLLR conversion)

There are no data on the presence of argatroban in human milk, or its effects on milk production. Argatroban is detected in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s need for Argatroban and any potential adverse effects on the breastfed child from Argatroban or from the underlying maternal condition.

08/25/2017 (SUPPL-3)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

 (additions underlined)

Safety and effectiveness have not been established in pediatric patients.

Argatroban was studied among 18 seriously ill pediatric patients who required an alternative to heparin anticoagulation. Most patients were diagnosed with HIT or suspected HIT. Age ranges of patients were < 6 months, n = 8; six months to < 8 years, n = 6; 8 to 16 years, n = 4. All patients had serious underlying conditions a continuous infusion (no bolus dose). Dosing was       initiated in the majority of these 13 patients at 1 mcg/kg/min and subsequently titrated as needed to achieve and maintain an aPTT of 1.5 to 3 times the baseline value. Most patients required multiple dose adjustments to maintain anticoagulation parameters within the desired range. During the 30-day study period, thrombotic events occurred during argatroban administration to two patients and following argatroban discontinuation in three other patients. Major bleeding occurred among two patients; one patient experienced an intracranial hemorrhage after 4 days of argatroban therapy in the setting of sepsis and thrombocytopenia and another patient experienced an intracranial hemorrhage afer receiving argatroban     for greater than 14 days. The study findings did not establish the safe and effective use of argatroban in pediatric     patients and the dosing of 1mcg/kg/min was not supported by the pharmacokinetic data described below.

Pediatric Pharmacokinetics (PK) and Pharmacodynamics (PD)

Pharmacokinetic parameters of argatroban were characterized in a population PK/PD analysis model with sparse data from 15 seriously ill pediatric patients. Argatroban clearance in these seriously ill pediatric patients (0.16 L/hr/kg) was 50% lower compared to argatroban clearance in healthy adults (0.31 L/hr/kg). Four pediatric patients with elevated bilirubin (secondary to cardiac complications or hepatic impairment) had, on average, 80% lower clearance (0.03 L/hr/kg) when compared to pediatric patients with normal bilirubin levels.

These PK/PD analysis models based upon a goal of aPTT prolongation of 1.5 to 3 times the baseline value and avoidance of an aPTT > 100 seconds for seriously ill pediatric patients with HIT/HITTS who require an alternative to heparin suggested the following:

  • For patients with normal hepatic function, a starting infusion rate of 0.75 mcg/kg/min may have comparable aPTT responses as a starting dose of 2 mcg/kg/min in healthy adults. Additionally, based on an evaluation of aPTT every two hours, increasing the dosage by 0.1 to 0.25 mcg/kg/min could achieve additional aPTT responses.
  • For patients with hepatic impairment, a starting dose of 0.2 mcg/kg/min with increasing dosing by 0.05 mcg/kg/min may have comparable argatroban exposure as expected with adult doses.

The safety and effectiveness of argatroban with the above dosing have not been adequately assessed in pediatric patients and the safety and effectiveness of argatroban is not established in pediatric patients. In addition, the described dosage did not take into account multiple factors that could affect the dosage such as current aPTT, target aPTT, and the clinical status of the patient.