Consumer medicine information

DEFINITY

Perflutren

BRAND INFORMATION

Brand name

Definity

Active ingredient

Perflutren

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DEFINITY.

SUMMARY CMI

DEFINITY®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using DEFINITY®?

DEFINITY® contains the active ingredient perflutren. DEFINITY® is used in patients on contrast-enhanced diagnostic ultrasound imaging to improve characterisation of focal lesions of the liver and kidney. It is also used in patients with suboptimal echocardiograms to provide opacification of cardiac chambers, improvement of left ventricular endocardial border delineation and assessment of regional wall motion at both rest and stress.

For more information, see Section 1. Why am I using DEFINITY®? in the full CMI.

2. What should I know before I use DEFINITY®?

Do not use if you have ever had an allergic reaction to DEFINITY®, Polyethylene glycol or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions especially if you are diagnosed with Sickle Cell Disease, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use DEFINITY®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DEFINITY® and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use DEFINITY®?

  • Your doctor will decide how much you will be given DEFINITY®. This depends on which organ (liver, kidney or heart) is being examined and other factors such as weight.
  • DEFINITY® is given as an injection or infusion (drip) into a vein.

More instructions can be found in Section 4. How do I use DEFINITY®? in the full CMI.

5. What should I know while using DEFINITY®?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are allergic or hypersensitive to perflutren, polyethylene glycol (PEG) or any of the ingredients listed at the end of this leaflet.
  • Remind your doctor if you have been diagnosed with Sickle Cell Disease.
  • Tell your doctor if you experience any side effects, especially acute pain episodes such as moderate to severe back pain, during or after the DEFINITY® administration.
Things you should not do
  • Not notifying your doctor that you are pregnant, intend to be pregnant, breast feeding, intend to breastfeed, taking other medications and current medical conditions.
Driving or using machines
  • Do not drive or operate machinery until you know how DEFINITY® affects you.

For more information, see Section 5. What should I know while using DEFINITY®? in the full CMI.

6. Are there any side effects?

Common side effects are headache, flushing, dizziness, altered taste, back pain, pain at the injection site.

Serious side effects could be swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing; changes in your heart rate; feeling faint; nausea, vomiting; rash, itchin, hives; allergic reaction/anaphylactic (shortness of breath or difficulty breathing, slow heart rate, dizziness or light-headedness, feeling unusually tired or weak); moderate to severe back pain and vaso occlusive crisis for patients with Sickle Cell Disease. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

DEFINITY® perflutren lipid microsphere injection vial

Active ingredient(s): perflutren


Consumer Medicine Information (CMI)

This leaflet provides important information about using Definity®. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Definity®.

Where to find information in this leaflet:

1. Why am I using DEFINITY®?
2. What should I know before I use DEFINITY®?
3. What if I am taking other medicines?
4. How do I use DEFINITY®?
5. What should I know while using DEFINITY®?
6. Are there any side effects?
7. Product details

1. Why am I using DEFINITY®?

Definity® contains the active ingredient perflutren. Definity® is a prescription medicine which is only available to the Healthcare Practitioners for diagnostic use only. It is administered to you via intravenous injection.

Definity® is indicated for use in patients:

  • In contrast-enhanced diagnostic ultrasound imaging to improve characterisation of focal lesions of the liver and kidney.
  • With suboptimal echocardiograms to provide opacification of cardiac chambers, improvement of left ventricular endocardial border delineation and assessment of regional wall motion at both rest and stress.

2. What should I know before I use DEFINITY®?

Warnings

Do not use Definity® if:

  • You are allergic or hypersensitive to perflutren, polyethylene glycol (PEG) or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • You have or suspected of having cardiac shunts.
  • You are below 18 years old.

Check with your doctor if you:

  • Have any other medical conditions, especially if you have been told that you have a heart shunt or have any mechanical device to aid your breathing and if you have been diagnosed with Sickle Cell Disease.
  • Have allergies, anaphylactic or hypersensitive to perflutren, polyethylene glycol or other ingredients listed at the end of this leaflet. Symptoms of allergic reactions are:
    - rash, itching or hives on the skin
    - shortness of breath, wheezing or difficulty breathing
    - swelling of the face, lips, tongue, throat or any other parts of the body
  • Take any medicines for any other condition, including medicines that you buy without prescription from pharmacy, supermarket or health food shop.
  • You have chronic pulmonary vascular disorders.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect DEFINITY®.

4. How do I use DEFINITY®?

How much to take / use

  • Your doctor will decide how much you will be given DEFINITY®. This depends on which organ (liver, kidney or heart) is being examined and other factors such as weight.
  • DEFINITY® is given as an injection or infusion (drip) into a vein. You may be given more than one injection of Definity, followed by an injection of sodium chloride solution. Definity will only be given to you by a doctor or a nurse.

When to take / use DEFINITY®

  • DEFINITY® may cause dizziness in some people. Make sure you know how you react to Definity before you drive a car, operate machinery or do anything else that could be dangerous if you are dizzy.
    Do not drive or operate machinery until you know how Definity affects you.

If you take too much DEFINITY®

If you think that you have been injected with too much DEFINITY® or experience immediate side effects, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using DEFINITY®?

Things you should do

Tell your doctor if you have been diagnosed with Sickle Cell Disease and/or do not feel well during the injection or after being given Definity. All medicines have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some side effects.

Tell your doctor or nurse if you experience any of the following and they worry you

  • headache
  • flushing
  • dizziness
  • altered taste
  • back pain
  • pain at the injection site

These are usually mild and resolve within 15 minutes

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • headache
  • flushing
  • dizziness
  • altered taste
  • back pain
  • pain at the injection site
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • changes in your heart rate
  • feeling faint
  • nausea, vomiting
  • rash, itching or hives (itchy swellings on the skin)
  • allergic reaction – shortness of breath or difficulty breathing, slow heart rate, dizziness or light-headedness, feeling unusually tired or weak
  • acute pain episodes such as moderate to severe back pain and vaso occlusive crisis (VOC)
Call your doctor or nurse straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

7. Product details

This medicine is only with a doctor's prescription and only made available to your doctor only.

What DEFINITY® contains

Active ingredient
(main ingredient)
Perflutren
Other ingredients
(inactive ingredients)
  • (R)-hexadecanoic acid, 1–[(phosphonoxy)methyl]-1,2-ethanediyl ester, monosodium salt (abbreviated DPPA)
  • (R)-4-hydroxy-N,N,N-trimethyl-l0-oxo-7-[(l-oxohexadecyl)oxy]-3,4,9-trioxa-4-phosphapentacosan-l-aminium, 4-oxide, inner salt (abbreviated DPPC);
  • (R)ά-[6-hydroxy-6-oxido-9-[(1-oxohexadecyl)oxy]5,7,11-trioxa-2-aza-6-phosphahexacos-1-yl]-ω-methoxypoly(ox-l,2-ethanediyl), commonly called N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, monosodium salt (abbreviated MPEG5000 DPPE)
  • Propylene Glycol
  • Glycerine
  • Monobasic sodium phosphate monohydrate
  • Dibasic sodium phosphate heptahydrate
  • Sodium chloride
  • Water for injection
Potential allergensPolyethylene Glycol

Do not take this medicine if you are allergic to any of these ingredients.

What DEFINITY® looks like

DEFINITY® is supplied in vials. An injection is prepared by shaking the vial immediately before it is injected. It is a milky white liquid. (Aust R 124808).

Who distributes DEFINITY®

Global Medical Solutions Australia Pty Limited T/A Radpharm Scientific
53-57 Oatley Court, BELCONNEN, ACT 2617 Australia

This leaflet was prepared on 23/1/2024.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Definity

Active ingredient

Perflutren

Schedule

Unscheduled

 

1 Name of Medicine

Perflutren.

2 Qualitative and Quantitative Composition

The perflutren lipid microspheres are composed of perflutren encapsulated in an outer lipid shell consisting of (R)-hexadecanoic acid, 1-[(phosphonoxy)methyl]-1,2-ethanediyl ester, monosodium salt (abbreviated DPPA); (R)-4-hydroxy-N,N,N-trimethyl-10-oxo-7-[(l-oxohexadecyl)oxy]-3,4,9-trioxa-4-phosphapentacosan-l-aminium, 4-oxide, inner salt (abbreviated DPPC); and (R) á-[6-hydroxy-6-oxido-9-[(1-oxohexadecyl)oxy] 5,7,11-trioxa-2-aza-6-phosphahexacos-1-yl]- ω-methoxypoly(ox-1,2-ethanediyl), commonly called N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3- phosphatidylethanolamine, monosodium salt (abbreviated MPEG5000 DPPE).
Prior to Vialmix activation, the Definity vial contains 6.52 mg/mL perflutren in the headspace. Each mL of the clear liquid contains 0.75 mg lipid blend (consisting of 0.045 mg DPPA, 0.401 mg DPPC, and 0.304 mg MPEG5000 DPPE), 103.5 mg propylene glycol, 126.2 mg glycerin, 2.34 mg monobasic sodium phosphate monohydrate, 2.16 mg dibasic sodium phosphate heptahydrate, and 4.87 mg sodium chloride in Water for Injection. The pH is 6.2-6.8.
After activating the contents of the vial in a Vialmix, each mL of the milky white suspension contains a maximum of 1.2 x 1010 perflutren lipid microspheres, and about 1.1 mg/mL perflutren. The microsphere particle size parameters are listed in Table 1:
Octafluoropropane and perfluoropropane are synonyms for perflutren.

3 Pharmaceutical Form

Definity contains a clear, colourless, sterile, nonpyrogenic, hypertonic liquid, which upon activation with the aid of a Vialmix, provides a homogeneous, opaque, milky white injectable suspension of perflutren lipid microspheres.

4 Clinical Particulars

4.1 Therapeutic Indications

This medicinal product is for diagnostic use only.
Definity is indicated for use in patients in contrast enhanced diagnostic ultrasound imaging to improve characterisation of focal lesions of the liver and kidney.
Definity is indicated for use in patients with suboptimal echocardiograms to provide opacification of cardiac chambers, improvement of left ventricular endocardial border delineation and assessment of regional wall motion at both rest and stress.

4.2 Dose and Method of Administration

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.
Definity may be injected by either an intravenous bolus or infusion.

Abdominal ultrasound of the liver and kidney.

Bolus intravenous injection using nonlinear contrast imaging technique.

The recommended dose for Definity is multiple injections of 0.1-0.4 mL, followed by a 3-5 mL 0.9% sodium chloride solution for injection. The total dose of Definity should not exceed 1.6 mL.

Bolus intravenous injection using fundamental imaging technique.

The recommended dose for Definity is 10 microL/kg of the product by slow bolus intravenous injection, followed by a 10 mL 0.9% sodium chloride solution for injection.

Echocardiography.

Bolus intravenous injection using nonlinear contrast imaging technique.

The recommended dose for Definity is multiple injections of 0.1-0.4 mL, followed by a 3-5 mL 0.9% sodium chloride solution for injection to maintain optimal contrast enhancement. The total dose of Definity should not exceed 1.6 mL.

Bolus intravenous injection using fundamental imaging technique.

The recommended dose for Definity is 10 microL/kg of the product by slow bolus intravenous injection, followed by a 10 mL 0.9% sodium chloride solution for injections. If necessary, a second 10 microL/kg dose followed by a second 10 mL 0.9% sodium chloride solution for injection may be administered 5 minutes after the first injection to prolong contrast enhancement.

Intravenous infusion using nonlinear contrast of fundamental imaging technique.

The recommended dose for Definity is via an intravenous infusion of 1.3 mL added to 50 mL of 0.9% sodium chloride solution for injection. 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.
Definity should not be used in patients below 18 years until efficacy and safety in these groups have been established.

Instructions for use.

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 User's 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 functioning Vialmix is used.
3. Immediately after activation in the Vialmix, activated Definity appears as a milky white suspension and may be used immediately after activation. If the product is not used within 5 minutes of Vialmix activation, the microspheres should be resuspended by 10 seconds of hand agitation by inverting the vial before the product is withdrawn in a syringe. The activated Definity may be used for up to 12 hours from the time of Vialmix activation, but only after the microspheres are resuspended by hand agitation. Store the activated Definity at room temperature in the original product vial.
4. Invert the vial and withdraw the activated milky white suspension using an 18 to 20 gauge syringe needle. Position the needle to withdraw the material from the middle of the liquid in the inverted vial. Do not inject air into the Definity vial*.
5. Use the product immediately after its withdrawal from the vial; do not allow the product to stand in the syringe.

Use in one patient on one occasion only.

Definity does not contain antimicrobial preservative. Bacterial contamination with the risk of postadministration septicemia can occur following the puncture of the elastomeric septum. It is essential to follow directions for activation of Definity carefully and to adhere to strict aseptic procedures during preparation.

*Note.

When using an 18 to 20 gauge needle, the entire contents of the vial should be removed, then small injections from the syringe should be given to a single patient.

4.3 Contraindications

Activated Definity should not be administered to patients with known hypersensitivity to perflutren lipid microsphere or any other components of Definity (see Section 2 Qualitative and Quantitative Composition; Section 4.4 Special Warnings and Precautions for Use).
Do not administer Definity to patients with known or suspected right to left, bidirectional, or transient right to left cardiac shunts.
Activated Definity should not be administered by direct intra-arterial injection (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

General.

Diagnostic procedures that involve the use of contrast agents should be carried out under the direction of a physician with a thorough knowledge of the procedure to be performed.
The safety of microspheres in patients on mechanical ventilation has not been studied.

Serious cardiopulmonary reactions.

Serious cardiopulmonary reactions, including fatalities, have occurred during or following perflutren-containing microsphere administration, typically within 30 minutes of administration. The risk for these reactions may be increased among patients with unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failures, or serious ventricular arrhythmias). Always have cardiopulmonary resuscitation personnel and equipment readily available prior to Definity administration and monitor all patients for acute reactions.

Anaphylactoid/ anaphylactic/ hypersensitivity reactions.

Post-marketing reports of acute anaphylactoid reactions including, shock, bronchospasm, dyspnea, angioedema, throat tightness, swelling of the lips, tongue, eyes, face and upper airway, urticaria, and pruritus have occurred in patients with no prior exposure to Definity, including patients with prior allergic reaction(s) to polyethylene glycol (see Section 2 Qualitative and Quantitative Composition). Monitor all patients for signs and symptoms of anaphylactoid reactions (see Section 4.8 Adverse Effects (Undesirable Effects)).

Cardiac shunts.

The safety of activated Definity in patients with right to left, bidirectional, or transient right to left cardiac shunts has not been studied. In these patients, phospholipid encapsulated microspheres can bypass the pulmonary particle filtering mechanisms and directly enter the arterial circulation with potential for microsphere trapping in small arterioles (< 15 micrometre) and in capillaries. Extreme caution should be exercised when considering the administration of activated Definity in patients that may have cardiac shunts.

Pulmonary vascular compromise.

The safety of activated Definity in humans with compromised pulmonary vascular beds or with small cross sectional vascular area has not been studied. Therefore, activated Definity should be administered with caution to patients with chronic pulmonary vascular disorders (e.g. severe emphysema, pulmonary vasculitis or other causes of reduced pulmonary vascular cross sectional area).

High ultra mechanical index.

High ultrasound mechanical index values may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. Additionally, end systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias. The safety of activated Definity at mechanical indices greater than 0.8 has not been established. The safety of activated Definity with the use of end systolic triggering has not been established.

QTc prolongation.

ECG parameters for doses up to 10 microL/kg were monitored in 221 subjects at multiple time points from 1 hour to 72 hours after the first bolus injection. In the 221 subjects, QTc prolongations of > 30 msec were noted in 64 (29%) subjects. Forty six out of 64 subjects with QTc prolongations were further evaluated and 39% (18/46) showed associated cardiac rhythm changes. No malignant cardiac symptomatology or events of syncope were reported as a result of these ECG changes. However, predisposing conditions may increase the risk of ventricular arrhythmias associated with QTc prolongation. Definity should be used only after careful consideration in patients with ongoing proarrhythmic conditions, previous history of symptomatic arrhythmias, family history of congenital long QT syndrome and on drugs known to cause QTc prolongation.

Pain episodes in patients with sickle cell disease.

In postmarketing reports, acute pain episodes shortly following Definity administration have been reported in patients with sickle cell disease (SCD). The pain episodes included moderate to severe back pain and vaso-occlusive crisis. If a patient with sickle cell disease experiences new or worsening pain, discontinue Definity.

Use in the elderly.

The pharmacokinetics of activated Definity in the elderly has not been studied.

Paediatric use.

The safety and effectiveness of activated Definity have not been established in the paediatric population (see Section 4.4 Special Warnings and Precautions for Use).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drug-drug interactions for activated Definity have not been studied.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effect on male or female fertility was found when rats were treated with Definity at up to 5 mL/kg/day IV (35 x the maximal human dose based on body surface area).
(Category B)
There was no evidence for a direct fetotoxic or teratogenic effect of Definity in rats or rabbits given 1 mL/kg/day IV (7 x and 18 x the maximal human dose based on body surface area, respectively). 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.
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.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The reported adverse effects following the use of Definity in pivotal and supportive trials (total of 2,526 patients) have generally been mild to moderate in intensity, occur within minutes after administration and usually resolve without therapeutic intervention within 15 minutes. The most frequently reported adverse reactions are: headache (2.0%), flushing (1.0%) and back pain (0.9%). See Table 2.
In addition, the following adverse events were reported with the following frequencies (see Table 3):

Postmarketing experience.

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 postmarketing 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 nonfatal 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 Section 4.4 Special Warnings and Precautions for Use].
Reported reactions included:

Cardiopulmonary.

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.

Anaphylactoid.

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.

Neurologic.

Coma, loss of consciousness, convulsion, seizure, transient ischemic attack, agitation, tremor, vision blurred, dizziness, headache, fatigue.

Blood and lymphatic system.

Acute pain episodes including vaso-occlusive crisis in patients with sickle cell disease.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

The clinical consequences of overdosing with activated Definity are not known. Single doses of up to 100 microL/kg and multiple doses up to 150 microL/kg were tolerated well in phase I clinical trials.
Treatment of an overdose should be directed toward the support of all vital functions and prompt institution of symptomatic therapy (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

When used in conjunction with diagnostic ultrasound, Definity provides opacification of cardiac chambers, improvement in delineation of endocardial borders and assessment of regional myocardial wall motion. Definity provides contrast enhancement in ultrasound studies of the liver and kidney and enhancement of Doppler ultrasound assessment of the vasculature of the liver and kidney.
The ultrasound echoes from blood and biological soft tissues such as fat and muscles are generated at interfaces due to small differences in the ultrasonic properties of the tissues. The ultrasonic properties of Definity are very different from those of soft tissue and will generate strong echoes.
Upon activation, Definity consists of lipid encapsulated perflutren microspheres. Microspheres in the 1 to < 10 micrometre diameter size range contribute to the contrast effect by generating strongly enhanced echoes.
As Definity consists of microspheres that are stable and small enough for transpulmonary passage, enhanced echo signals in the left heart, systemic circulation and abdominal organs are obtained.
A strict dose/ response relationship cannot be defined, although higher doses have been shown to produce a contrast effect of longer duration. In a crossover study, the duration of clinically useful contrast enhancement for fundamental imaging was approximately 3.4 minutes after a 10 microL/kg bolus and approximately 7.1 minutes after a continuous infusion of 1.3 mL activated Definity in 50 mL saline at a rate of 4 mL/min.

Clinical trials.

A total of 2827 subjects were evaluated in clinical trials (2538 received activated Definity and 169 received placebo: there were an additional 60 healthy controls in clinical pharmacology studies). Of those patients that received Definity, 1545 (61.2%) were male and 980 (38.8%) were female; 1881 (74.6%) were White, 386 (15.3%) were Black and 256 (10.1%) were classified as other racial or ethnic groups. The mean age was 56.3 (range 18 to 93).
Key features of 5 echocardiography studies and 3 ultrasound imaging of liver and kidney studies evaluating activated Definity are summarised in Tables 4 and 5.
Echocardiography. Outcome measures in the echocardiology studies included blinded assessment of improvement in ventricular chamber enhancement, endocardial border length (EBL) measured by direct measurement and qualitative assessment of wall motion.

Ventricular chamber enhancement.

Left ventricular chamber enhancement after activated Definity was significantly enhanced from baseline compared to placebo. Mean changes from baseline with 10 microL/kg of activated Definity were significantly better than those with placebo in both regions (apex and midchamber) and both apical views (4- and 2-chamber views) at each of the three points of the cardiac cycle evaluated.

Endocardial border delineation.

Activated Definity significantly improved endocardial border delineation over baseline (noncontrast enhanced) echocardiography examinations (p < 0.05) at both rest and stress. In those subjects with nondiagnostic examinations at baseline (defined as four or more nonevaluable segments at baseline in either the apical 4 or 2 chamber view) the use of activated Definity converted 76% of nondiagnostic examinations to diagnostic examinations.

Wall motion.

A significant improvement in the number of segments demonstrating exact wall motion concordance with MRI was demonstrated for five out of six blind reads following administration of activated Definity. When examined on a segment by segment basis, the administration of activated Definity had a significant impact on improving segmental wall motion concordance (normal versus abnormal) with MRI in the apical, lateral and anterior segments which had the poorest correlation at baseline.
Ejection fraction was assessed in several echocardiography studies but Definity did not reliably improve accuracy of assessment of ejection fraction. See Figure 1.
Ultrasound imaging of liver and kidney. A total of 309 subjects were enrolled and treated with activated Definity in the three pivotal studies: 230 (74%) had suspected liver pathology and 79 (26%) had suspected kidney pathology. Administration of activated Definity was clinically effective in providing additional diagnostic information when comparing the unenhanced ultrasound assessment to the postactivated Definity assessment. The percentages of all subjects having additional diagnostic information ranged from 33% to 76% for the blinded readers and 83% for the institutional read.
Additional diagnostic information included increased lesion conspicuity, improved delineation (extent) of pathology, detection of additional lesions, improved gray scale vascular assessment, improved lesion characterisation and better visualisation of the length and/or extent of microvasculature.
Diagnostic accuracy was assessed by a prospectively defined diagnostic algorithm and to assess enhancement pattern concordance with CT/MRI.
There was a 93% sensitivity and 92% specificity in differentiating benign and malignant focal lesions. The algorithm correctly characterized lesion subtypes as follows: focal nodular hyperplasia (95%), haemangioma (92%), hepatocellular carcinoma (85%) and metastatic disease (71%). Analyses of the blinded read demonstrated that the contrast enhancement patterns observed with activated Definity were highly concordant with the contrast enhancement patterns observed on CT and MRI.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of perflutren gas were evaluated in normal healthy subjects and subjects with chronic obstructive pulmonary disease (COPD) following intravenous administration of a 50 microL/kg dose of Definity. Perflutren is a stable gas that is not metabolized.
The perflutren component of Definity was rapidly cleared from the systemic circulation via the lungs. In most subjects after 4-5 minutes, Perflutren was undetectable in blood and in expired air. Perflutren concentration in blood were shown to decline in a monoexponential fashion with a mean half-life of 1.3 minutes in healthy subjects and 1.9 minutes in COPD subjects. The systemic clearance of perflutren was similar in healthy and COPD subjects. Total lung clearance (CLlung) of perflutren was shown to be no different in healthy subjects compared to COPD subjects. CLlung was found to be statistically significantly reduced (51%) in females compared to males (all subjects). These results suggest that overall perflutren systemic elimination is rapid and is not statistically significantly reduced in COPD patients compared to healthy subjects.
Doppler ultrasound measurements were performed with Definity in conjunction with the pharmacokinetic evaluation of perflutren. Doppler signal intensity corresponded well with measured and extrapolated perflutren concentrations in blood. The time to maximum Doppler signal intensity tmax was shown to be similar to the perflutren blood tmax (1.13 versus 1.77 minutes). The observed 99% drop in Doppler signal intensity within 10 minutes (t1/2 approximately 2 minutes) was in agreement with the decline in measurable blood levels of perflutren.
Human pharmacokinetic information is not available for lipid microspheres. The naturally occurring phospholipids in Definity are distributed in the endogenous lipid pools in the body (for example, liver) whereas the synthetic component (MPEG5000) has been shown to be excreted in the urine in nonclinical studies. All lipids are metabolized to free fatty acids.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of genotoxicity was 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.

Carcinogenicity.

Studies with activated Definity have not been performed to evaluate carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2-8°C (Refrigerate. Do not freeze.).

6.5 Nature and Contents of Container

Definity is supplied as a single use, clear glass vial containing clear liquid. Each package (clear plastic clamshell) contains four (4) single-use vials.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Perflutren is chemically characterized as 1,1,1,2,2,3,3,3-octafluoropropane. It has a molecular weight of 188, empirical formula of C3F8 and has the following structural formula:

CAS number.

The CAS number of perflutren is [76-19-7].
The physical and chemical characteristics of perflutren gas are provided in Table 6.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

Summary Table of Changes