Israel - English - Ministry of Health
recommended dose and mode of administration and procedures of activation of
(perflutren injectable suspension) should be strictly adhered to.
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
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
, 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
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
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
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
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
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
A total of 1716 patients were evaluated in pre-market clinical trials of activated
(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.
is also indicated for contrast-enhanced ultrasound imaging of the
liver and kidneys in adult patients to improve the evaluation of pathology.
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
Hypersensitivity to DEFINITY
or its components (See WARNINGS -
Hypersensitivity Reactions and ADVERSE REACTIONS - Post Market
Adverse Drug Reactions).
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.
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
administration. In the absence of these underlying conditions, observe
patients closely during and following DEFINITY
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
, 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
injection (see CONTRAINDICATIONS).
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
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
Always have resuscitation equipment and trained personnel readily available.
Contrast Enhancing Imaging Agent for Echocardiography and Diagnostic
Ultrasound of Liver and Kidney.
ACTION AND CLINICAL PHARMACOLOGY
(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.
is a sterile, non-pyrogenic suspension of phospholipid-encapsulated
perfluoropropane microbubbles that is activated by shaking with the aid of the
, and is used for contrast enhancement during cardiac and abdominal
ultrasound imaging procedures.
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.
The pharmacokinetics of the perfluoropropane (PFP) component of activated
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.
PFP is a stable gas that is not metabolized. The three lipid components of
(DPPA, DPPC and DPPE) are naturally occurring in man as blood
lipids. The amount of these lipids in a dose of DEFINITY
(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
INDICATIONS AND CLINICAL USE
(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
The format and contents of this leaflet was determined, checked and approved
by the Israeli Ministry of Health 06/2010
Physicians Prescribing Information
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)
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.
(perflutren injectable suspension) comes in a 2-mL clear vial
containing a 1.5 mL fill volume. Each mL of DEFINITY
Sodium Chloride, USP
Propylene Glycol, USP
Water for Injection, USP
QS to 1.0 mL
Sodium phosphate monobasic, monohydrate, ACS
Sodium phosphate dibasic, heptahydrate, ACS
µL/mL when shaken
* 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
(perflutren injectable suspension) is supplied as a sterile and
non-pyrogenic liquid in a 2-mL glass vial.
will be provided with the initial DEFINITY
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
Albuminuria and abnormal urine
Increased bilirubin, AST/SGOT, SGPT/ALT,
creatine phosphokinase, LDH, creatinine,
glucose and non-protein nitrogen
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.
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
(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.
vial must be activated prior to use with a mechanical shaking device
). Upon activation, DEFINITY
appears as a milky white suspension. The
activated product has an initial concentration of perflutren of 150±100 µl/mL.
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.
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:
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.
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.
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
studied, serious adverse events were reported in 30 patients, which included
8 deaths. None of the serious adverse events were considered related to
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
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.
Treatment-Related, New-Onset Adverse Experiences in Clinical Trials
0.5% of All Subjects
Total Number of Subjects
Total Number of Subjects with an AE
Application Site Disorders
Injection Site Reactions
Body as a Whole - General Disorders
Central and Peripheral Nervous System Disorders
Vascular (extracardiac) disorders
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
-dosed patients were:
Body as a Whole:
Fatigue, fever, hot flushes, pain, rigors and
Abnormal ECGs, bradycardia, tachycardia,
palpitation, hypertension and hypotension
Dyspepsia, dry mouth, tongue disorder,
toothache, abdominal pain, diarrhea and
Granulocytosis, leukocytosis, leukopenia,
monocytosis, and eosinophilia
Leg cramps, hypertonia, vertigo and paresthesia
Platelet, Bleeding, and Clotting:
Coughing, hypoxia, pharyngitis, rhinitis and
Decreased hearing, conjunctivitis, abnormal
vision and taste perversion
Pruritus, rash, erythematous rash, urticaria,
increased sweating and dry skin