DEFINITY

recommended dose and mode of administration and procedures of activation of

DEFINITY

(perflutren injectable suspension) should be strictly adhered to.

DEFINITY

should be administered with caution in patients with a history of

drug allergies, asthma or hay fever, and multiple allergies.

The safety of microbubbles in patients on mechanical ventilation has not been

established.

A specific analysis correlating the mechanical index values (0.3 to 1.9) used

in clinical trials with DEFINITY

with the observed cardiac disturbances is not

available. The safety of DEFINITY

at mechanical indices greater than 0.8 has not

been established. Users of diagnostic ultrasound devices should employ exposures,

in any relevant mode, which are As Low As Reasonably Achievable (ALARA).

High Ultrasound Mechanical Index: High Ultrasound Mechanical Index (MI) values

may cause microspheres cavitation or rupture and in combination with end systolic

triggering may induce premature ventricular contractions (PVC). In addition,

end-systolic triggering with high MI has been reported to cause ventricular

arrhythmias following administration of a microsphere product. In clinical trials

with DEFINITY

, the majority of patients were imaged at or below a mechanical

index of 0.8. The safety of DEFINITY

at MI values greater than 0.8 or with the use

of high mechanical index end-systolic triggering has not been evaluated.

A total of 1716 patients received DEFINITY

in clinical trials. The incidence of

treatment-related cardiovascular events was < 0.5% and included: abnormal

ECGs, bradycardia, tachycardia, palpitation, hypertension, and hypotension.

Two patients had treatment-related cardiac adverse events and associated QTc

changes (1 increase and 1 decrease) of

30 msec from baseline.

QTc Interval Prolongation: In 610 subjects (568 received DEFINITY

and 42

received placebo), ECG parameters after doses up to 40 FL/kg were recorded for

up to 72 hours after the first bolus injection. QTc prolongation of =30 msec was

noted in 70 (12.3%) DEFINITY

treated subjects and in 12 (28.6%) placebo treated

subjects. QTc prolongation of >60 msec was noted in 20 (3.5%) DEFINITY

treated

subjects and 2 (4.8%) placebo treated subjects.

Use in Pregnancy and Lactation: Results of reproduction toxicity studies in

rats and rabbits revealed that DEFINITY

in doses up to 1.0 mL/kg (24x and

15x maximal human dose based on body surface area for rats and rabbits,

respectively) did not adversely affect fetal growth, survival or morphological

development. There are no adequate and well controlled studies in pregnant

women. Because animal reproduction studies are not always predictive of

human response, DEFINITY

should be used in pregnancy only if potential

benefit to the mother justifies the potential risk to the fetus.

It is not known whether DEFINITY

is excreted in human milk; therefore, caution

should be exercised when DEFINITY

is administered to a nursing woman.

Pediatric Use: Safety and effectiveness in the pediatric population below the age

of 16 have not been established.

Drug Interactions: Drug-drug interactions with DEFINITY

have not been studied.

Information For Patients: To assure safe and effective use of DEFINITY

, patients

should be advised of the following information and instructions when appropriate:

to inform their physician if they have a congenital heart defect, or recent

worsening of heart or lung conditions

have had prior reactions to DEFINITY

that DEFINITY

may add to the QTc prolonging effects of other drugs such

as cisapride, erythromycin, some antipsychotics, and tricyclic antidepressants

to inform their physician if they are currently receiving Class IA (e.g. quinidine,

procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic agents

to inform their physician of any family history of QTc prolongation or

proarrhythmic conditions such as recent hypokalemia, significant

bradycardia, acute myocardial ischemia, clinically relevant heart failure with

reduced left-ventricular ejection fraction or previous history of symptomatic

arrhythmias

to inform their physician if they are or may be pregnant or nursing

to inform their physician of any medications they take

to contact their physician if they experience palpitations or fainting spells

after injection of DEFINITY

ADVERSE REACTIONS

A total of 1716 patients were evaluated in pre-market clinical trials of activated

DEFINITY

(perflutren injectable suspension). 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 (range 18 to 93). Of these, 144

(8.4%) patients had at least one treatment-related adverse reaction (Table 1).

The safety and efficacy of DEFINITY

with exercise stress or pharmacologic

stress testing have not been established.

Abdominal Ultrasound

DEFINITY

is also indicated for contrast-enhanced ultrasound imaging of the

liver and kidneys in adult patients to improve the evaluation of pathology.

CONTRAINDICATIONS

Do not administer DEFINITY

(perflutren injectable suspension) to patients with

known or suspected:

Right-to-left, bi-directional, or transient right-to-left cardiac shunts (see

WARNINGS),

Hypersensitivity to DEFINITY

or its components (See WARNINGS -

Hypersensitivity Reactions and ADVERSE REACTIONS - Post Market

Adverse Drug Reactions).

DEFINITY

should not be injected by direct intra-arterial injection (see WARNINGS).

Gas Contrast Agents, for use in diagnostic ultrasound examinations, should not

be administered within 24 hours prior to extracorporeal shock wave lithotripsy.

WARNINGS

Serious Cardiopulmonary Reactions:

Serious cardiopulmonary reactions, including fatalities, have occurred during

or following perflutren-containing microsphere administration. The risk for

these reactions may be increased among patients with pulmonary hypertension

or unstable cardiopulmonary conditions (acute myocardial infarction, acute

coronary artery syndromes, worsening or unstable congestive heart failure,

serious ventricular arrhythmias or respiratory failure, including patients receiving

mechanical ventilation). In these patients, monitor vital signs, electrocardiography,

and cutaneous oxygen saturation during and for at least 30 minutes after

DEFINITY

administration. In the absence of these underlying conditions, observe

patients closely during and following DEFINITY

administration.

In postmarketing use, uncommon but serious reactions observed during or

shortly following perflutren-containing microsphere administration included

fatal cardiac or respiratory arrest, loss of consciousness, convulsions,

symptomatic arrhythmias (atrial fibrillation, supraventricular tachycardia,

ventricular tachycardia or fibrillation), hypotension, respiratory distress or

cardiac ischemia (see ADVERSE REACTIONS).

Always have cardiopulmonary resuscitation personnel and equipment readily available

prior to DEFINITY

administration and monitor all patients for acute reactions.

Serious immediate hypersensitivity reactions which could be life threatening

have been rarely reported within minutes of the administration of DEFINITY

therefore, patients should be closely monitored. These reactions include

anaphylactoid / anaphylactic reactions, shock, bronchospasm, tongue /

throat swelling, decreased O2 saturation, loss of consciousness. Therefore,

emergency supplies and equipment, and personnel experienced with

resuscitative measures should always be available.

In dogs, activated DEFINITY

given at a dose of 1mL/kg (13.5 x maximum

human dose based on body surface area) increased the respiratory rate and

pulmonary pressure (300% and 188% respectively). One dog died displaying

signs consistent with cardiopulmonary collapse. In dogs with artifically induced

acute pulmonary hypertension, DEFINITY

(tested up to 200 µl/kg) did not alter

hemodynamics (includes pulmonary arterial pressure).

Systemic Embolization of DEFINITY

in Patients with Cardiac Shunts:

The safety of DEFINITY

in patients with right-to-left, bi-directional or transient

right-to-left cardiac shunts has not been studied. In these patients, encapsulated

microspheres can bypass the pulmonary particle-filtering mechanisms and

directly enter the arterial circulation resulting in microvascular occlusion and

ischemia. In an animal study utilizing intra-arterial administration of activated

DEFINITY

, microspheres trapping was seen in small arterioles < 15 µm,

especially at branch points and in capillaries at all doses tested (1-6x the

maximal human dose based on body surface area). An animal study utilizing an

intravenous administration did not result in microvascular obstruction because

of presumed filtering by the lungs. Do not administer DEFINITY

by intra-arterial

injection (see CONTRAINDICATIONS).

PRECAUTIONS

General Precaution

Diagnostic procedures that involve the use of intravenous contrast-enhancing

agents containing microbubbles of gas should be carried out under the direction of

a physician with a prerequisite training and a thorough knowledge of the procedure

to be performed in appropriate facilities for conducting diagnostic imaging. The

515686-0819

August 2019

WARNING: serious Cardiopulmonary Reactions

Serious cardiopulmonary reactions, including fatalities, have occurred during or

within 30 minutes 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.

THERAPEUTIC CLASSIFICATION

Contrast Enhancing Imaging Agent for Echocardiography and Diagnostic

Ultrasound of Liver and Kidney.

ACTION AND CLINICAL PHARMACOLOGY

DEFINITY

(perflutren injectable suspension) is an ultrasound contrast imaging

agent that is designed to improve echocardiographic and radiologic ultrasound

image quality by enhancing the echogenicity of the organs/tissues of interest.

DEFINITY

is a sterile, non-pyrogenic suspension of phospholipid-encapsulated

perfluoropropane microbubbles that is activated by shaking with the aid of the

VIALMIX

, and is used for contrast enhancement during cardiac and abdominal

ultrasound imaging procedures.

DEFINITY

microbubbles exhibit lower acoustic impedance than blood.

Ultrasound waves are scattered and reflected at the microbubble-blood interface

and are ultimately visualized in the ultrasound image. At the frequencies used

in diagnostic ultrasound (1-7.5 MHz), the microbubbles resonate, further

increasing the extent of ultrasound scattering and reflection.

Pharmacokinetics

The pharmacokinetics of the perfluoropropane (PFP) component of activated

DEFINITY

was studied in 12 normal and 12 chronic obstructive pulmonary

disease (COPD) patients following a 50 µl/kg dose. PFP was rapidly cleared

from the systemic circulation (via the lungs). PFP was not detectable after

10 minutes in most subjects, either in the blood or expired air. In all subjects,

maximal concentrations of PFP were achieved at approximately 1.0 to

2.0 minutes after the start of injection.

Doppler ultrasound measurements were performed with DEFINITY

conjunction with the pharmacokinetic evaluation of PFP. Doppler signal intensity

corresponded well with measured and extrapolated PFP concentrations in blood.

The time to maximum Doppler signal intensity t

was shown to be similar to the

PFP blood t

(1.13 versus 1.77 minutes). The observed 99% drop in Doppler

signal intensity within 10 minutes (t

approximately 5 minutes) was in agreement

with the decline in measurable blood levels of PFP. Human pharmacokinetic data

on the fate of intact or degassed microbubbles is not available.

Metabolism

PFP is a stable gas that is not metabolized. The three lipid components of

DEFINITY

(DPPA, DPPC and DPPE) are naturally occurring in man as blood

lipids. The amount of these lipids in a dose of DEFINITY

represent ~1%

(DPPE), ~0.02% (DPPC) and ~0.002% (DPPA) of the naturally occurring levels

in plasma and are expected to follow similar metabolic pathways as reported for

endogenous phospholipids.

INDICATIONS AND CLINICAL USE

Echocardiography

DEFINITY

(perflutren injectable suspension) is indicated for contrast-enhanced

ultrasound imaging of cardiac structures (ventricular chambers and endocardial

borders) and function (regional wall motion) in adult patients with suboptimal

echocardiograms.

(Perflutren)

The format and contents of this leaflet was determined, checked and approved

by the Israeli Ministry of Health 06/2010

Physicians Prescribing Information

(Lipid-Encapsulated Perfluoropropane

Microbubbles, Injectable)

Art File 41405 Format: 3 Flat: 9.375” x 8.625” Folded: 3.125” x 2.25” PMS Black & 294 Blue 10/22/19 (Head to Head)

41405

Injectable Suspension

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.

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.

PHARMACEUTICAL INFORMATION

Drug Substance

Common Name:

Perfluoropropane

Chemical Name:

1,1,1,2,2,3,3,3-Octafluoropropane

Molecular Formula:

Molecular Weight:

188.02 g/mol

Structural Formula:

Description:

Colourless gas

Composition

DEFINITY

(perflutren injectable suspension) comes in a 2-mL clear vial

containing a 1.5 mL fill volume. Each mL of DEFINITY

contains:

Sodium Chloride, USP

4.87 mg

Propylene Glycol, USP

103.5 mg

Glycerin, USP

126.2 mg

Water for Injection, USP

QS to 1.0 mL

Lipid Blend*

0.75 mg

Sodium phosphate monobasic, monohydrate, ACS

2.34 mg

Sodium phosphate dibasic, heptahydrate, ACS

2.16 mg

Perfluoropropane Gas

perflutren 150±100

µL/mL when shaken

(activated)

* The Lipid Blend is composed of the following lipids in a mole % ratio

of 10:82:8: 1,2-dipalmitoyl-snglycero-3-phosphatidic acid, monosodium

salt (DPPA); 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC);

N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-snglycero-

3-phosphatidylethanolamine, monosodium salt (MPEG5000 DPPE).

Stability and Storage Recommendations

Store in a refrigerator (2-8°C) prior to activation.

As with all parenteral drug products, intravenous admixtures should be

inspected visually for clarity, particulate matter, precipitate, discolouration

and leakage prior to administration whenever solution and container permit.

Solutions showing haziness, particulate matter, precipitate, discolouration or

leakage should not be used.

Following activation, DEFINITY

can be stored at room temperature and should

be used within 12 hours of preparation.

The activated vials are for single use only and unused portions should be discarded.

When activated, DEFINITY

appears as a milky white suspension. If allowed to

sit for more than 5 minutes after VIALMIX

shaking, it should be resuspended

with 10 seconds of hand agitation prior to administration. (See INSTRUCTIONS

FOR PREPARATION OF DEFINITY

®

AVAILABILITY OF DOSAGE FORMS

DEFINITY

(perflutren injectable suspension) is supplied as a sterile and

non-pyrogenic liquid in a 2-mL glass vial.

The VIALMIX

will be provided with the initial DEFINITY

order. Product

monograph available upon request.

Israeli Drug Registration Numbers: 133.15.31138.00

Manufacturer: Lantheus Medical Imaging Inc., North Billerica, MA, U.S.A.

License Holder: Ami Technologies Ltd.

22 Hanager St., Hod-Hasharon 4501317, Israel

515686-0819

Urinary:

Albuminuria and abnormal urine

Laboratory Abnormalities:

Increased bilirubin, AST/SGOT, SGPT/ALT,

creatine phosphokinase, LDH, creatinine,

glucose and non-protein nitrogen

Miscellaneous:

Lymphadenopathy

Post Market Adverse Drug Reactions: The following adverse reactions

have been identified during the post-approval 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 (see WARNINGS).

Allergic type reactions (e.g. anaphylactoid like reactions) have been reported

rarely as part of ongoing post-marketing surveillance (See Warnings). Central

nervous system reactions, including loss of consciousness, seizures, and / or

seizure like reactions have also been reported rarely which may or may not be

associated with immediate hypersensitivity reactions.

REPORTING OF SUSPECTED ADVERSE REACTIONS

Reporting suspected adverse reactions after authorisation of the medicinal

product is important. It allows continued monitoring of the benefit/risk balance

of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health

according to the National Regulation by using an online form https://sideeffects.

health.gov.il/

SYMPTOMS AND TREATMENT OF OVERDOSAGE

During clinical trials there was no incidence of an overdose with DEFINITY

(perflutren injectable suspension). Should an overdose be suspected,

supportive measures should be taken in response to symptoms.

DOSAGE AND ADMINISTRATION

For Single Use Only

DEFINITY

(perflutren injectable suspension) 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.

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 µl/mL.

Bolus Administration

The recommended dose for DEFINITY

is a single dose of 10 µl/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 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

DEFINITY

may also be administered via an I.V. infusion of 1.3 mL added to 50 mL

of preservative-free saline. The rate of infusion is suggested to be initiated at 4.0 mL/

minute and could be titrated as necessary to achieve optimal image enhancement

but should not exceed 10 mL/min. The total dose administered per kg will range

from approximately 14.4 µl/kg (90 kg person) to 21.7 µl/kg (60 kg person). Note:

DEFINITY

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

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.

Instructions for Preparation of DEFINITY

(Perflutren Injectable Suspension):

Allow the vial to warm to room temperature.

Activate DEFINITY

by shaking the vial for 45 seconds 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.

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.

Deaths and serious adverse events: Among the 1716 DEFINITY

patients

studied, serious adverse events were reported in 30 patients, which 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. However, a role for DEFINITY

in the initiation or course

of these adverse events cannot 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 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.

Subanalyses by age, gender and race were performed. The overall incidence of

AEs 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.

The most frequent adverse events were reported for the Central and Peripheral

Nervous System (3.1%), Body as a Whole (2.4%) and Gastrointestinal

System (1.8%).

The most frequently occurring treatment-related adverse experiences (AEs) were

headache (2.3%), back/renal pain (1.2%), flushing (1.1%), and nausea (1.0%).

The incidence of all treatment-related new-onset adverse experiences occurring

0.5% of all patients in DEFINITY

studies are summarized in Table 1.

Table 1

Treatment-Related, New-Onset Adverse Experiences in Clinical Trials

Occurring in

≥

0.5% of All Subjects

PLACEBO

DEFINITY

®

n

(%)

n

(%)

Total Number of Subjects

Total Number of Subjects with an AE

(7.1)

1716

(8.4)

Application Site Disorders

Injection Site Reactions

(1.1)

(1.1)

(0.6)

(0.6)

Body as a Whole - General Disorders

Back Pain

Chest Pain

(0.5)

(0.0)

(0.0)

(2.4)

(1.2)

(0.8)

Central and Peripheral Nervous System Disorders

Headache

Dizziness

(2.7)

(2.2)

(0.5)

(3.1)

(2.3)

(0.6)

Gastrointestinal System

Nausea

(1.1)

(0.5)

(1.8)

(1.0)

Vascular (extracardiac) disorders

Flushing

(0.5)

(0.5)

(1.1)

(1.1)

AE = Adverse Event

n = number of subjects

Although headache was the most frequently reported adverse experience, its

incidence was similar to placebo.

Data from clinical trials presented in the safety tablehas shown that DEFINITY

administered intravenously in the recommended dose as a bolus injection or as

an infusion, was safe and well tolerated.

Other treatment-related adverse experiences that occurred in < 0.5% of the

DEFINITY

-dosed patients 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,

monocytosis, and eosinophilia

Musculoskeletal:

Arthralgia

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