Cardiovascular Business - November/December 2008 - (Page 12)

515835-0508 May 2008 PRECAUTIONS Information For Patients Patients receiving activated DEFINITY® should be instructed to inform their healthcare provider if they: 1. have a congenital heart defect, or recent worsening of heart or lung conditions, 2. have had prior reactions to DEFINITY® (see CONTRAINDICATIONS and WARNINGS), 3. may be pregnant, are trying to become pregnant, or are nursing. Carcinogenesis, Mutagenesis, Impairment of Fertility Respiratory: Coughing, hypoxia, pharyngitis, rhinitis and dyspnea Special Senses: Decreased hearing, conjunctivitis, abnormal vision and taste perversion Skin: Pruritus, rash, erythematous rash, urticaria, increased sweating, and dry skin Urinary: Albuminuria and abnormal urine Miscellaneous: Lymphadenopathy Post-Marketing Experience For Intravenous Use BRIEF SUMMARY WARNING: Serious Cardiopulmonary Reactions Serious cardiopulmonary reactions, including fatalities, have occurred during or following perﬂutren-containing microsphere administration. • Assess all patients for the presence of any condition that precludes DEFINITY® administration (see CONTRAINDICATIONS). • In patients with pulmonary hypertension or unstable cardiopulmonary conditions, monitor vital sign measurements, electrocardiography and cutaneous oxygen saturation during and for at least 30 minutes after DEFINITY® administration (see WARNINGS). • Always have resuscitation equipment and trained personnel readily available. Studies with activated DEFINITY® have not been performed to evaluate carcinogenic potential. Evidence of genotoxicity was not found in the following studies with activated DEFINITY®: 1) bacterial mutagenesis assay (Ames assay), 2) in vitro mammalian mutagenesis assay, 3) in vitro human lymphocyte chromosome aberration assay, and 4) in vivo rat micronucleus assay. Impairment of male or female fertility was not observed in rats and rabbits treated with activated DEFINITY® at up to 1 mL/kg (24x and 15x maximal human dose based on body surface area, respectively). Pregnancy Category B The following adverse reactions have been identiﬁed during the post-marketing use of perﬂutren-containing microsphere products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Fatal cardiac arrests and other serious but non-fatal adverse reactions were uncommonly reported. Most of these uncommon reactions included cardiopulmonary symptoms and signs such as cardiac or respiratory arrest, hypotension, supraventricular and ventricular arrhythmias, respiratory distress or decreased oxygenation. Reports also identiﬁed neurologic reactions (loss of consciousness or convulsions) as well as anaphylactoid reactions (see WARNINGS). OVERDOSAGE Reproduction toxicity studies have been performed in rats and rabbits at up to 3 mL/kg and, 1 mL/kg (24x and 15x maximal human dose based on body surface area for rats and rabbits, respectively). The studies revealed no evidence of an effect of activated DEFINITY® treatment on the developing fetus. Adequate and well-controlled studies in pregnant women have not been conducted. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers The clinical consequences of overdosing with activated DEFINITY® are not known. Treatment of an overdose should be directed toward the support of all vital functions and prompt institution of symptomatic therapy (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS). DOSAGE AND ADMINISTRATION DESCRIPTION The DEFINITY® vial contains components that upon activation yield perﬂutren lipid microspheres, a diagnostic drug that is intended to be used for contrast enhancement during the indicated echocardiographic procedures. The vial contains a clear, colorless, sterile, non-pyrogenic, hypertonic liquid, which upon activation with the aid of a Vialmix®, provides a homogeneous, opaque, milky white injectable suspension of perﬂutren lipid microspheres. The suspension of activated DEFINITY® is administered by intravenous injection. Studies to detect if activated DEFINITY® is excreted in human milk have not been conducted. Because many drugs are excreted in human milk, caution should be exercised when activated DEFINITY® is administered to a nursing woman. Pediatric Use DEFINITY® IS INTENDED FOR ADMINISTRATION ONLY AFTER ACTIVATION IN THE VIALMIX® APPARATUS. Before injection, this product must be activated and prepared according to the instructions outlined below. The Vialmix® apparatus should be ordered from Lantheus Medical Imaging, Inc., 331 Treble Cove Road, North Billerica, MA 01862. For customer orders call 1-800-299-3431. DEFINITY® may be injected by either an intravenous bolus or infusion. Bolus: The recommended dose for activated DEFINITY® is 10 microliters (μL)/kg of the activated product by intravenous bolus injection within 30-60 seconds, followed by a 10 mL saline ﬂush. If necessary, a second 10 microliters (μL)/kg dose followed by a second 10 mL saline ﬂush may be administered 30 minutes after the ﬁrst injection to prolong contrast enhancement. Infusion: The recommended dose for activated DEFINITY® is via an IV infusion of 1.3 mL added to 50 mL of preservative-free saline. The rate of infusion should be initiated at 4.0 mL/minute, but titrated as necessary to achieve optimal image enhancement, not to exceed 10 mL/minute. The maximum dose is either two bolus doses or one single intravenous infusion. The safety of bolus and infusion dosing in combination or in sequence, has not been studied. Imaging: After baseline non-contrast echocardiography is completed, the mechanical index for the ultrasound device should be set at 0.8 or below (see WARNINGS). Then inject activated DEFINITY® (as described above) and begin ultrasound imaging immediately. The activated DEFINITY® echocardiogram images should be evaluated in combination with the non-contrast echocardiogram images. DEFINITY® ACTIVATION, PREPARATION AND HANDLING INSTRUCTIONS: The safety and effectiveness of activated DEFINITY® have not been established in the pediatric population (see WARNINGS). ADVERSE REACTIONS Clinical Trials Experience INDICATIONS AND USAGE Activated DEFINITY® (Perﬂutren Lipid Microsphere) Injectable Suspension is indicated for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. The safety and efﬁcacy of DEFINITY® with exercise stress or pharmacologic stress testing have not been established. CONTRAINDICATIONS Do not administer DEFINITY® to patients with known or suspected: • Right-to-left, bi-directional, or transient right-to-left cardiac shunts, • Hypersensitivity to perﬂutren (see WARNINGS). Do not administer DEFINITY by intra-arterial injection. ® A total of 1716 subjects were evaluated in pre-market clinical trials of activated DEFINITY®. In this group, 1063 (61.9%) were male and 653 (38.1%) were female, 1328 (77.4%) were White, 258 (15.0%) were Black, 74 (4.3%) were Hispanic, and 56 (3.3%) were classiﬁed as other racial or ethnic groups. The mean age was 56.1 years (range 18 to 93). Of these, 144 (8.4%) had at least one treatment-related adverse reaction (Table 1). There were 26 serious adverse events and 15 (0.9%) subjects discontinued because of an adverse event. Deaths and serious adverse events: Among the 1716 activated DEFINITY® patients, 19 (1.1%) suffered serious cardiopulmonary adverse events including eight deaths. The deaths occurred several days after activated DEFINITY® administration and appear to be related to the course of underlying disease. Of the 11 other serious adverse events, which appeared within days of the drug administration (2-15 days), all appeared to be a progression underlying cardiac and non-cardiac disease. However, a role for DEFINITY® in the initiation or course of these adverse events can not be ruled out. Discontinuations: There were 15 discontinuations reported with a mean age of 41.5 years. Nine of these patients were discontinued after the ﬁrst injection. One patient experienced a hypersensitivity reaction with urticaria and pruritus and all the other patients experienced dizziness, chest pain, dyspnea or back pain. Adverse events appeared within minutes (1 – 15 min) of the drug administration and were of moderate intensity resolving usually without treatment within minutes or hours after onset. For all adverse events, the overall incidence of adverse experiences was similar for the 65 year age group, similar in males and in females, similar among all racial or ethnic groups and similar for bolus and infusion dosing. As shown in Table 1, the most common adverse events were reported in the Central and peripheral nervous system (3.1%), Body as a Whole (2.4%) and Gastrointestinal system (1.8%). The most common events were headache (2.3%), back and renal pain (1.2%), ﬂushing (1.1%) and nausea (1.0%). Table 1 Treatment-Related, New-Onset Adverse Experiences Occurring in ≥0.5% of All Activated DEFINITY®-Treated Subjects 1. Allow the vial to warm to room temperature before starting the activation procedure. 2. Activate DEFINITY® by shaking the vial for 45 seconds using a Vialmix®. Note: illustrations of this procedure are contained in the Vialmix® Users Guide. WARNING: DO NOT USE THIS DRUG UNLESS IT HAS COMPLETED A FULL 45 SECOND ACTIVATION CYCLE IN THE VIALMIX®. DEFINITY® WILL NOT BE PROPERLY ACTIVATED UNLESS THE FULL 45 SECOND ACTIVATION CYCLE IS COMPLETED. DO NOT REACTIVATE the vial if Vialmix® did not complete a full 45 second cycle. DO NOT REACTIVATE a successfully activated DEFINITY® vial (see step 3). DO NOT USE a Vialmix® that is not functioning properly. Refer to the “VIALMIX® User’s Guide” for the “VIALMIX® CALIBRATION AND REPLACEMENT PROCEDURES” to ensure that a properly funct

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Cardiovascular Business - November/December 2008 Contents First Word Cover Story: Practice Management Software Moves Beyond Bean Counting The Death of CME as We Know It? Clinical Study Digets: Triple-Antiplatelet Therapy; Ex-Vioxx Users Beware Shockwaves Subside from the FDA's Echo Contract Warning Burning Question: Does Laser Heart Therapy for Angina Really Work? Advanced Visualization Adds New Practive Dimension Coronary Calcium Scoring Program Reaps Dividends Interventionalists Get Pumped Up About Mechanical Chest Compression Trials Force Physicians to Re-Examine Oral Anti-Diabetic Drug Protocols News & Views Calendar Reader Resources The ACC Corner

Cardiovascular Business - November/December 2008

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