DEFINITY

1 Dosing Considerations  For Single Use Only: DEFINITY contains no preservative. Bacterial contamination with the risk of post-administration septicemia can occur following the puncture of the elastomeric septum. It is essential to follow directions for preparation of DEFINITY carefully and to adhere to strict aseptic procedures during preparation.

 No dosage adjustment required in hepatic or renal impairment. 2 Recommended Dose and Dosage Adjustment Bolus Administration The recommended dose for DEFINITY is a single dose of 10 mcL/kg of the activated product by intravenous bolus injection over 30-60 seconds, followed by a 10 mL saline flush.

If necessary, a second 10 mcL/kg dose may be administered 5 minutes after the first injection to prolong contrast enhancement. V. 3 mL added to 50 mL of preservative-free saline. 7 mcL/kg (60 kg person). Health Canada has not authorized an indication for pediatric use.

3 Reconstitution The DEFINITY vial must be activated prior to use with a mechanical shaking device (Vialmix™). Upon activation, DEFINITY appears as a milky white suspension. The activated product has an initial concentration of perflutren of 150±100 mcL/mL.

Instructions for Reconstitution: 1. Allow the vial to warm to room temperature. 2. Activate DEFINITY by shaking the vial using the Vialmix™. Immediately after shaking, DEFINITY appears as a milky white suspension. The contents of the vial are not to be administered to the patient without first undergoing the mechanical activation procedure.

3. Withdraw DEFINITY from the vial using an 18- to 20-gauge syringe needle. The needle should be positioned to withdraw the material from the middle of the liquid in the inverted vial. Do not inject air into the vial. 4. If the product is allowed to sit for more than 5 minutes after Vialmix™ shaking, it should be resuspended with 10 seconds of hand agitation prior to syringe withdrawal.

Following activation (steps 1, 2), DEFINITY can be stored at room temperature and should be used within 12 hours of preparation. See 11 STORAGE, STABILITY AND DISPOSAL. The contents of the vial are intended only for use in the preparation of DEFINITY and are not to be administered directly to the patient without first undergoing the preparative procedure (steps 1-4).

The contents of the vial are intended for use in a single patient. 4 Administration Bolus Administration The product is administered via intravenous bolus injection over 30-60 seconds, followed by a 10 mL saline flush. V. 0 mL/minute and could be titrated as necessary to achieve optimal image enhancement but should not exceed 10 mL/min.

Note:

DEFINITY should be used immediately after dilution with preservative-free saline.

1 Adverse Reaction Overview Serious cardiopulmonary reactions, including fatalities, have occurred during or following DEFINITY administration. The risk for these reactions may be increased among patients with unstable cardiopulmonary conditions.

In these patients, observe closely for at least 30 minutes after DEFINITY administration. DEFINITY should only be administered to such patients after a careful risk/benefit assessment. Serious immediate hypersensitivity reactions which could be life threatening have also been reported following the administration of DEFINITY, including in patients with prior allergic reaction(s) to polyethylene glycol.

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse event rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse event information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. Clinical Trials Experience During Rest A total of 1716 patients were evaluated in clinical trials of activated DEFINITY (perflutren injectable suspension).

3%) were classified as other racial or ethnic groups. 1 (range 18 to 93). 4%) patients had at least one treatment-related adverse reaction (Table 2). 5% and included: abnormal ECGs, bradycardia, tachycardia, palpitation, hypertension, and hypotension.

Two patients had treatment- related cardiac adverse events in addition to QTc changes (1 increase and 1 decrease) of ≥ 30 msec from baseline. In 610 subjects (568 received DEFINITY and 42 received placebo) during rest echocardiography, ECG parameters after doses up to 40 mcL/kg were recorded for up to 72 hours after the first bolus injection.

6%) placebo treated subjects. 8%) placebo treated subjects. ECG parameters for doses up to 10 mcL/kg were monitored in 509 patients in five placebo-controlled efficacy trials using stress echocardiography (exercise treadmill and pharmacologic stress [dobutamine and dipyridamole]).

ECG parameters were assessed at Baseline, 0 to 60 minutes, and 24 hours post- dose. Across all ECG parameters, comparisons of patients in the placebo and DEFINITY groups find only minor differences between the treatment groups except for what would be anticipated by undergoing a treadmill or pharmacologic stress test.

There were no significant DEFINITY - related ECG changes in PR, QRS, and QTc intervals. 55) bpm in RR during the first 60 minutes post-dose is expected during stress testing. 3% in the DEFINITY group.  Deaths and serious adverse events Among the 1716 DEFINITY patients studied, serious adverse events were reported in 30 patients, which DEFINITY (Perflutren Injectable Suspension) Page 11 of 40 included 8 deaths.

None of the serious adverse events were considered related to DEFINITY administration. The 8 deaths occurred several days after DEFINITY administration and were attributed to underlying disorders. The other serious adverse events reported were attributed to progression or treatment of underlying disorders.

5 years. Nine of these patients were discontinued after the first injection. One experienced a hypersensitivity reaction with urticaria and pruritis 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.

Sub-analyses by age, gender and race were performed. The overall incidence of adverse events was similar for the <65 year age group and the ≥65 year age group, similar in males and in females, and similar among all racial or ethnic groups.

8%). 0%). 5% of all patients in DEFINITY studies at rest are summarized in Table 2. 5) Although headache was the most frequently reported adverse event, its incidence was similar to placebo. Data from clinical trials presented in the safety table has shown that DEFINITY, administered intravenously in the […]

, Immune 02/2021 7 WARNINGS AND PRECAUTIONS, Cardiovascular 09/2022 7 WARNINGS AND PRECAUTIONS, Hematologic 09/2022 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed. RECENT MAJOR LABEL CHANGES ..........................................................................................

2 TABLE OF CONTENTS ............................................................................................................ 2 PART I: HEALTH PROFESSIONAL INFORMATION ....................................................................

4 1 INDICATIONS ............................................................................................................. 1 Pediatrics..................................................................................................................

2 Geriatrics .................................................................................................................. 4 2 CONTRAINDICATIONS ................................................................................................

4 3 SERIOUS WARNINGS AND PRECAUTIONS BOX ........................................................... 4 4 DOSAGE AND ADMINISTRATION................................................................................ 1 Dosing Considerations .............................................................................................

2 Recommended Dose and Dosage Adjustment ........................................................ 3 Reconstitution .......................................................................................................... 4 Administration .........................................................................................................

6 5 OVERDOSAGE............................................................................................................ 6 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 6 7 WARNINGS AND PRECAUTIONS .................................................................................

1 Special Populations .................................................................................................. 1 Pregnant Women ...............................................................................................

2 Breast-feeding .................................................................................................... 3 Pediatrics............................................................................................................

9 8 ADVERSE REACTIONS............................................................................................... 1 Adverse Reaction Overview ................................................................................... 2 Clinical Trial Adverse Reactions .............................................................................

3 Less Common Clinical Trial Adverse Reactions ...................................................... 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data.............................................................................................................

5 Post-Market Adverse Reactions............................................................................. 14 9 DRUG INTERACTIONS .............................................................................................. 2 Drug Interactions Overview ...................................................................................

4 Drug-Drug Interactions .......................................................................................... 5 Drug-Food Interactions .......................................................................................... 6 Drug-Herb Interactions ..........................................................................................

7 Drug-Laboratory Test Interactions......................................................................... 15 10 CLINICAL PHARMACOLOGY ...................................................................................... 1 Mechanism of Action .......................................................................................

2 Pharmacodynamics .......................................................................................... 3 Pharmacokinetics ............................................................................................. 15 11 STORAGE, STABILITY AND DISPOSAL ........................................................................

16 PART II: SCIENTIFIC INFORMATION ..................................................................................... 17 13 PHARMACEUTICAL INFORMATION .......................................................................... 17 14 CLINICAL TRIALS ......................................................................................................

1 Clinical Trials by Indication .............................................................................. 17 15 MICROBIOLOGY ......................................................................................................

35 16 NON-CLINICAL TOXICOLOGY .................................................................................... 35 DEFINITY (Perflutren Injectable Suspension) Page 4 of 40 PART I: HEALTH PROFESSIONAL INFORMATION 1 INDICATIONS DEFINITY (perflutren injectable suspension) is indicated for:  Echocardiography: Contrast-enhanced ultrasound imaging of cardiac structures (ventricular chambers and endocardial borders) and function (regional wall motion) in adult patients with suboptimal echocardiograms.

 Abdominal Ultrasound: Contrast-enhanced ultrasound imaging of the liver and kidneys in adult patients to improve the evaluation of pathology. 1 Pediatrics Pediatrics (below […]

Perflutren injectable suspension is contraindicated:  In patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or components of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

 In patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts. See 7 WARNINGS AND PRECAUTIONS - Cardiovascular.  For direct intra-arterial injection. See 7 WARNINGS AND PRECAUTIONS - Cardiovascular.  Within 24 hours prior to extracorporeal shock wave lithotripsy.