Clinical Trials Experience
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 adverse reaction (Table 6.1). 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 appeared 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 noncardiac disease. However, a role for DEFINITY® in the initiation or course of these adverse events cannot be ruled out.
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. These adverse reactions 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 reactions, the overall incidence of adverse experiences was similar for the < 65 year age group and 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. Table 6.1 summarizes the most common adverse reactions.
Table 6.1: New-Onset Adverse Reactions Occurring in ≥ 0.5% of All Activated DEFINITY®-Treated Subjects
|All activated DEFINITY ®
|Total Number of Adverse Reactions||269|
|Total Number of Subjects with an Adverse Reaction||144||(8.4%)|
|Body system Preferred term||n||(%)|
|Application Site Disorders||11||(0.6)|
|Injection Site Reactions||11||(0.6)|
|Body as a Whole||41||(2.4)|
|Central and peripheral nervous system disorder||54||(3.1)|
|Vascular (extracardiac) disorders||19||(1.1)|
|N=Sample size 1716 subjects who received activated DEFINITY®
n=Number of subjects reporting at least one Adverse Reaction
Other adverse reactions that occurred in ≤ 0.5% of the activated DEFINITY®-dosed subjects were:
Body as a Whole: Fatigue, fever, hot flushes, pain, rigors, and syncope
Cardiovascular: Abnormal ECGs, bradycardia, tachycardia, palpitation, hypertension and hypotension
Digestive: Dyspepsia, dry mouth, tongue disorder, toothache, abdominal pain, diarrhea and vomiting
Hematology: Granulocytosis, leukocytosis, leukopenia, and eosinophilia
Nervous System: Leg cramps, hypertonia, vertigo and paresthesia
Platelet, Bleeding, and Clotting: Hematoma
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
In a prospective, multicenter, open-label registry of 1053 patients receiving DEFINITY® in routine clinical practice, heart rate, respiratory rate, and pulse oximetry were monitored for 30 minutes after DEFINITY® administration. No deaths or serious adverse reactions were reported, suggesting that these reactions are unlikely to occur at a rate of more than 0.3% when DEFINITY® is used according to recommendations.
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 cardiopulmonary and anaphylactoid events and other serious but non-fatal adverse reactions were uncommonly reported. These events typically occurred within 30 minutes of DEFINITY® administration. These serious events may be increased among patients with unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, or serious ventricular arrhythmias [see WARNINGS AND PRECAUTIONS].
Reported reactions included:
Fatal cardiac or respiratory arrest, shock, syncope, symptomatic arrhythmias (atrial fibrillation, tachycardia, bradycardia, supraventricular tachycardia, ventricular fibrillation, ventricular tachycardia), hypertension, hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing.
Anaphylactic/anaphylactoid reaction, anaphylactic shock, hypersensitivity, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, erythema.
Coma, loss of consciousness, convulsion, seizure, transient ischemic attack, agitation, tremor, vision blurred, dizziness, headache, fatigue.