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warnings
WARNINGS Hemorrhagic Events As with other anticoagulants, hemorrhage can occur at any site in patients receiving REFLUDAN. An unexpected fall in hemoglobin, fall in blood pressure or any unexplained symptom should lead to consideration of a hemorrhagic event. While patients are being anticoagulated with REFLUDAN, the anticoagulation status should be monitored closely using an appropriate measure such as the aPTT (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION : Monitoring section.) Intracranial bleeding following concomitant thrombolytic therapy with rt-PA or streptokinase may be life-threatening. There have been reports of intracranial bleeding with REFLUDAN in the absence of concomitant thrombolytic therapy (see ADVERSE REACTIONS .) For patients with increased risk of bleeding, a careful assessment weighing the risk of REFLUDAN administration vs its anticipated benefit has to be made by the treating physician: In particular, this includes the following conditions: • Recent puncture of large vessels or organ biopsy • Anomaly of vessels or organs • Recent cerebrovascular accident, stroke, intracerebral surgery, or other neuraxail procedures • Severe uncontrolled hypertension • Bacterial endocarditis • Advanced renal impairment (see also WARNINGS : Renal Impairment ) • Hemorrhagic diathesis • Recent major surgery • Recent major bleeding (eg, intracranial, gastrointestinal, intraocular, or pulmonary bleeding) • Recent active peptic ulcer Renal Impairment With renal impairment, relative overdose might occur even with standard dosage regimen. Therefore, the bolus dose and the rate of infusion must be reduced in patients with known or suspected renal insufficiency CAUTION: Preparation of a Refludan bolus injection requires dilution following reconstitution in order to obtain the final concentration of 5 mg/mL . (see CLINICAL PHARMACOLOGY : Pharmacokinetic Properties and DOSAGE AND ADMINISTRATION : Monitoring and Adjusting Therapy ; Use in Renal Impairment ).
ADVERSE REACTIONS Adverse Events Reported in Clinical Trials in HIT Patients The following safety information is based on all 198 patients treated with REFLUDAN in the HAT-1 and HAT-2 studies. The safety profile of 113 REFLUDAN patients from these studies who presented with TECs at baseline is compared to 91 such patients in the historical control. Hemorrhagic Events Bleeding was the most frequent adverse event observed in patients treated with REFLUDAN. Table 4 gives an overview of all hemorrhagic events which occurred in at least two patients. Table 4: Hemorrhagic Events Patients may have suffered more than one event HAT-1 HAT-2 (All patients) (n = 198) Patients with TECs REFLUDAN (n = 113) Historical control (n = 91) Bleeding from puncture sites and wounds 14.1% 10.6% 4.4% Anemia or isolated drop in hemoglobin 13.1% 12.4% 1.1% Other hematoma and unclassified bleeding 11.1% 10.6% 4.4% Hematuria 6.6% 4.4% 0 Gastrointestinal and rectal bleeding 5.1% 5.3% 6.6% Epistaxis 3.0% 4.4% 1.1% Hemothorax 3.0% 0 1.1% Vaginal bleeding 1.5% 1.8% 0 Intracranial bleeding 0 0 2.2% Other hemorrhagic events (hemoperitoneum, hemoptysis, liver bleeding, lung bleeding, mouth bleeding, retroperitoneal bleeding) each occurred in one individual among all 198 patients treated with REFLUDAN. Nonhemorrhagic events Table 5 gives an overview of the most frequently observed nonhemorrhagic events. Table 5: Nonhemorrhagic adverse events Patients may have suffered more than one event HAT-1 HAT-2 (All patients) (n = 198) Patients with TECs REFLUDAN (n = 113) Historical control (n = 91) Fever 6.1% 4.4% 8.8% Abnormal liver function 6.1% 5.3% 0 Pneumonia 4.0% 4.4% 5.5% Sepsis 4.0% 3.5% 5.5% Allergic skin reactions 3.0% 3.5% 1.1% Heart failure 3.0% 1.8% 2.2% Abnormal kidney function 2.5% 1.8% 4.4% Unspecified infections 2.5% 1.8% 1.1% Multiorgan failure 2.0% 3.5% 0 Pericardial effusion 1.0% 0 1.1% Ventricular fibrillation 1.0% 0 0 Adverse Events Reported in Clinical Trials in Other Populations The following safety information is based on a total of 2302 individuals who were treated with REFLUDAN in clinical pharmacology studies (n = 323) or for clinical indications other than HIT (n = 1979). Intracranial Bleeding Intracranial bleeding was the most serious adverse reaction found in populations other than HIT patients. It occurred in patients with acute myocardial infarction who were started on both REFLUDAN and thrombolytic therapy with rt-PA or streptokinase. The overall frequency of this potentially life-threatening complication among patients receiving both REFLUDAN and thrombolytic therapy was 0.6% (7 out of 1134 patients). Although no intracranial bleeding was observed in 1168 subjects or patients who did not receive concomitant thrombolysis, there have been post marketing reports of intracranial bleeding with REFLUDAN in the absence of concomitant thrombolytic therapy (see ADVERSE REACTIONS — Adverse Events from Post Marketing Reports and WARNINGS .) Allergic Reactions (See PRECAUTIONS . ) Allergic reactions or suspected allergic reactions in populations other than HIT patients include (in descending order of frequency*): Airway reactions (cough, bronchospasm, stridor, dyspnea): common Unspecified allergic reactions: uncommon Skin reactions (pruritus, urticaria, rash, flushes, chills): uncommon General reactions (anaphylactoid or anaphylactic reactions): uncommon Edema (facial edema, tongue edema, larynx edema, angioedema): rare * The CIOMS (Council for International Organization of Medical Sciences) III standard categories are used for classification of frequencies: very common 10% or more common (frequent) 1 to <10% uncommon (infrequent) 0.1 to<1% rare 0.01 to <0.1% very rare 0.01% or less About 53% (n = 46) of all allergic reactions or suspected allergic reactions occurred in patients who concomitantly received thrombolytic therapy (eg, streptokinase) for acute myocardial infarction and/or contrast media for coronary angiography. Adverse Events from Post Marketing Reports Serious anaphylactic reactions that have resulted in shock or death have been reported. (See PRECAUTIONS .) Intracranial bleeding has been reported in patients treated with REFLUDAN with or without concomitant thrombolytic therapy. (See WARNINGS .) Although no intracranial bleeding was observed in Clinical Trials in those patients who did not receive concomitant thrombolytic therapy (see Adverse Events Reported in Clinical Trials in HIT Patients and Adverse Events Reported in Clinical Trials in Other Populations below), there have been post marketing reports of intracranial bleeding in patients who received REFLUDAN without concomitant thrombolytic therapy.