"SILVER SPRING, MD â€” The US Food and Drug Administration (FDA) is warning of several treatment-related serious adverse events in association with implantable left ventricular assist devices (LVADs) in heart-failure patients.
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- Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal,genitourinary, or respiratory tracts.
- Superficial or surface bleeding,observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or sites of recent surgical intervention.
Should serious bleeding (not controlled by local pressure) occur, any concomitant heparin or antiplatelet agents should be discontinued immediately.
In clinical studies of TNKase (tenecteplase) , patients were treated with both aspirin and heparin. Heparin may contribute to the bleeding risks associated with TNKase (tenecteplase) . The safety of the use of TNKase (tenecteplase) with other antiplatelet agents has not been adequately studied (see PRECAUTIONS: DRUG INTERACTIONS). Intramuscular injections and nonessential handling of the patient should be avoided for the first few hours following treatment with TNKase (tenecteplase) . Venipunctures should be performed and monitored carefully.
Should an arterial puncture be necessary during the first few hours following TNKase (tenecteplase) therapy, it is preferable to use an upper extremity vessel that is accessible to manual compression. Pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.
Each patient being considered for therapy with TNKase (tenecteplase) should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy. In the following conditions, the risk of TNKase (tenecteplase) therapy may be increased and should be weighed against the anticipated benefits:
- Recent major surgery,e.g.,coronary artery bypass graft,obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels
- Cerebrovascular disease
- Recent gastrointestinal or genitourinary bleeding
- Recent trauma
- Hypertension: systolic BP ≥ 180 mm Hg and/or diastolic BP ≥ 110 mm Hg
- High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
- Acute pericarditis
- Subacute bacterial endocarditis
- Hemostatic defects, including those secondary to severe hepatic or renal disease
- Severe hepatic dysfunction
- Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions
- Septic thrombophlebitis or occluded AV cannula at seriously infected site
- Advanced age (see PRECAUTIONS: Geriatric Use)
- Patients currently receiving oral anticoagulants,e.g., warfarin sodium
- Recent administration of GP IIb/IIIa inhibitors
- Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location
Cholesterol embolism has been reported rarely in patients treated with all types of thrombolytic agents; the true incidence is unknown. This serious condition, which can be lethal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. Clinical features of cholesterol embolism may include livedo reticularis, "purple toe" syndrome, acute renal failure,gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.
Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) are not different from those often seen in the ordinary course of acute myocardial infarction and may be managed with standard anti-arrhythmic measures.It is recommended that anti-arrhythmic therapy for bradycardia and/or ventricular irritability be available when TNKase (tenecteplase) is administered.
Use with Percutaneous Coronary Intervention (PCI)
In patients with large ST segment elevation myocardial infarction, physicians should choose either thrombolysis or PCI as the primary treatment strategy for reperfusion.Rescue PCI or subsequent elective PCI may be performed after administration of thrombolytic therapies if medically appropriate; however,the optimal use of adjunctive antithrombotic and antiplatelet therapies in this setting is unknown.
Standard management of myocardial infarction should be implemented concomitantly with TNKase (tenecteplase) treatment.Arterial and venous punctures should be minimized. Noncompressible arterial puncture must be avoided and internal jugular and subclavian venous punctures should be avoided to minimize bleeding from the noncompressible sites. In the event of serious bleeding, heparin and antiplatelet agents should be discontinued immediately. Heparin effects can be reversed by protamine.
Readministration of plasminogen activators, including TNKase (tenecteplase) , to patients who have received prior plasminogen activator therapy has not been systematically studied.Three of 487 patients tested for antibody formation to TNKase (tenecteplase) had a positive antibody titer at 30 days. The data reflect the percentage of patients whose test results were considered positive for antibodies to TNKase (tenecteplase) in a radioimmunoprecipitation assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TNKase (tenecteplase) with the incidence of antibodies to other products may be misleading. Although sustained antibody formation in patients receiving one dose of TNKase (tenecteplase) has not been documented, readministration should be undertaken with caution. If an anaphylactic reaction occurs, appropriate therapy should be administered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies in animals have not been performed to evaluate the carcinogenic potential, mutagenicity, or the effect on fertility.
Pregnancy (Category C)
TNKase (tenecteplase) has been shown to elicit maternal and embryo toxicity in rabbits given multiple IV administrations. In rabbits administered 0.5, 1.5, and 5.0 mg/kg/day, vaginal hemorrhage resulted in maternal deaths. Subsequent embryonic deaths were secondary to maternal hemorrhage and no fetal anomalies were observed. TNKase (tenecteplase) does not elicit maternal and embryo toxicity in rabbits following a single IV administration.Thus,in developmental toxicity studies conducted in rabbits, the no observable effect level (NOEL) of a single IV administration of TNKase (tenecteplase) on maternal or developmental toxicity was 5 mg/kg (approximately 8–10 times the human dose). There are no adequate and well-controlled studies in pregnant women.TNKase (tenecteplase) should be given to pregnant women only if the potential benefits justify the potential risk to the fetus.
It is not known if TNKase (tenecteplase) is excreted in human milk.Because many drugs are excreted in human milk, caution should be exercised when TNKase (tenecteplase) is administered to a nursing woman.
The safety and effectiveness of TNKase (tenecteplase) in pediatric patients have not been established.
Of the patients in ASSENT-2 who received TNKase (tenecteplase) , 4,958 (59%) were under the age of 65; 2,256 (27%) were between the ages of 65 and 74; and 1,244 (15%) were 75 and over. The 30-day mortality rates by age were 2.5% in patients under the age of 65, 8.5% in patients between the ages of 65 and 74, and 16.2% in patients age 75 and over. The ICH rates were 0.4% in patients under the age of 65, 1.6% in patients between the ages of 65 and 74,and 1.7% in patients age 75 and over.The rates of any stroke were 1.0% in patients under the age of 65,2.9% in patients between the ages of 65 and 74,and 3.0% in patients age 75 and over.Major bleeding rates,defined as bleeding requiring blood transfusion or leading to hemodynamic compromise, were 3.1% in patients under the age of 65,6.4% in patients between the ages of 65 and 74,and 7.7% in patients age 75 and over.In elderly patients,the benefits of TNKase (tenecteplase) on mortality should be carefully weighed against the risk of increased adverse events,including bleeding.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 11/6/2008
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