LUMINITY - LUMINITY - CT 4539 - English version

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Introduction LUMINITY 150 microlitres/ml, solution for dispersion for injection or infusion Box of 1 vial – CIP 379 253-3 Box of 4 vials – CIP 377 450-6 Posted on Jun 17 2009 Active substance (DCI) perflutren ATC Code V08DA04 Laboratory / Manufacturer BRISTOL-MYERS SQUIBB PHARMACEUTICALS LUMINITY 150 microlitres/ml, solution for dispersion for injection or infusion Box of 1 vial – CIP 379 253-3 Box of 4 vials – CIP 377 450-6 Posted on Jun 17 2009

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• Publié par: haute-autorite-sante-traitement-medicamenteux
• Publié le: 20 juin 2007
• Nombre de lectures: 25
• Licence : En savoir +
  Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
• Langue: English

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The legally binding text is the original French version


TRANSPARENCY COMMITTEE

OPINION

20 June 2007


LUMINITY 150 microlitres/ml, solution for dispersion for injection or infusion
Box of 1 vial – CIP 379 253-3
Box of 4 vials – CIP 377 450-6


Applicant : BRISTOL-MYERS SQUIBB PHARMACEUTICALS

Perflutren

List I
Medicine to be prescribed by some specialists only.
Medicine requiring specific monitoring during treatment.

Date of Marketing Authorisation: September 20, 2006 (centralised procedure)

Reason for request: Inclusion on the list of medicines reimbursed by National Insurance
and approved for use by hospitals: Box of 1 - CIP 379 253-3
Inclusion on the list of medicines approved for use by hospitals:
Box of 4 - CIP 377 450-6




















Health Technology Assessment Division
1 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT

1.1. Active ingredient
9
Each ml contains a maximum of 6.4 x 10 perflutren-containing lipid microshperes, with a
mean diameter range of 1.1 and 2.5 μm.
The approximate amount of perflutren gas in each ml is 150 μl.
®The product must be activated using a mechanical agitator: Vialmix .
1.2. Indication
This medicinal product is for diagnostic use only.

Luminity™ is an ultrasound contrast-enhancing agent for use in patients in whom non-
contrast echocardiography was suboptimal (suboptimal is considered to indicate that at least
2 of 6 segments in the 4- or 2-chamber view of the ventricular border were not evaluable)
and who have suspected or established coronary artery disease, to provide opacification of
cardiac chambers and improvement of left ventricular endocardial border delineation at both
rest and stress.
1.3. Dosage
Luminity™ may only be administered by trained physicians specialising in performing and
interpreting contrast echocardiograms.
Before administering Luminity™, the product must be activated by using a mechanical
agitator, Vialmix®.

This product should only be administered intravenously.

Bolus intravenous injection using non-linear contrast imaging technique at rest and stress:
The recommended dose is multiple injections of 0.1 to 0.4 ml of Luminity™, followed by a 3
to 5 ml bolus of sodium chloride 9 mg/ml (0.9 %) or glucose 50mg/ml (5%) to maintain
optimal contrast enhancement. The maximum dose is 1.6 ml.

Bolus intravenous injection using fundamental imaging technique at rest.
The recommended dose is 10 microlitre dispersion/kg by slow bolus intravenous injection,
followed by a 10 ml bolus of sodium chloride 9 mg/ml (0.9%) or glucose 50mg/ml (5%). If
necessary, a second 10 microlitre dispersion/kg dose followed by a second 10 ml bolus of
sodium chloride 9 mg/ml (0.9%) or glucose 50mg/ml (5%) solution for injection may be
administered 5 minutes after the first injection to prolong contrast enhancement.

Intravenous infusion using non-linear contrast imaging technique (rest and stress) or
fundamental imaging technique at rest.
The recommended dose via intravenous infusion is 1.3 ml of Luminity™ diluted in 50 ml of
sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) 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.
Luminity™ should not be used with fundamental imaging technique for stress
echocardiography as efficacy and safety have not been established.

Children and adolescents
Luminity™ should not be used in patients under 18 years as clinical studies have not been
conducted on this patient group.

2 1.4. Pharmacodynamics
The product consists of lipid encapsulated perflutren microshperes. Microspheres in the 1 to
10 μm diameter size range contribute to the contrast effect by generating strongly enhanced
echoes.
Ultrasound echoes from blood and 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 the product are very different from those of soft tissues and will generate strong
echoes.
As the Luminity™ microspheres are stable and small enough to pass through the pulmonary
barrier, enhanced echo signals in the left heart and systemic circulation are obtained.
A strict effect/dose response relationship cannot be defined; however, higher doses have
been shown to produce a contrast effect of longer duration.

2 SIMILAR MEDICINAL PRODUCTS
2.1. ATC Classification
V: Various
08: Contrast agents
D: Ultrasound contrast agent
A: Ultrasound contrast agent
04: Phospholipid microspheres

2.2. Medicines in the same therapeutic category
Ultrasound contrast products, qualified as second generation products, are directly
comparable to Luminity™:
®
- Optison (perflutren-containing albumin microspheres), a medicinal product included on
the list of medicines reimbursed by National Insurance and approved for use by hospitals
and various public services but not marketed to this day,
®
- SonoVue (phospholipid coated sulphur hexafluoride microspheres).

Two other ultrasound contrast products belonging to the same therapeutic category are
considered as first generation products:
®
- Levovist (gas microspheres with galactose/palmitic acid surfactant). Marketing
terminated on 1/01/2007.
®
- Echovist (galactose granules and solution for injection): approved for use by hospitals
and various public services only.

2.3. Medicines with a similar therapeutic aim
Diagnostic alternatives exist, such as MRI, isotopic ventriculography, angiography scan, or
coronary angiography.







3 3 ANALYSIS OF AVAILABLE DATA
Six studies were provided by the laboratory:
- 2 phase III, placebo-controlled, randomised, double-blind, parallel group studies
- 2 phase III, open-label, non-randomised studies
- 2 phase IV, open-label studies

3.1. Diagnostic efficacy
Studies DMP 115-004 and DMP 115-005
The 2 phase III, placebo-controlled, randomised, double-blind, parallel group studies were
conducted on 211 subjects (87 for DMP115-004 and 124 for DMP115-005) referred for
evaluation of ventricular function and having suboptimal echocardiography images.

Methodology
Subjects were randomly assigned to 3 groups (placebo, 5 μL/kg Luminity™ or 10 μL/kg
Luminity™) in a 1:2:2 ratio. Each subject was administered two bolus IV (one per imaging
session) doses at a minimum of 30 minutes interval. Investigators (reading investigator) and
three independent cardiologists analysed the images under blind to protect the identity of
the subjects and the dosage group (blind reading).

Inclusion criteria
Adult patients with known or suspected heart disease and in whom non-contrast
echocardiography was suboptimal (suboptimal is considered to indicate that at least 2 of 6
segments in the 4- or 2-chamber view of the ventricular border were not evaluable).

Exclusion criteria
- Patients with a history of acute heart disease (unstable angina, recent MI, etc.).
- Patients with a recent history (within the last 6 months) of severe psychiatric disturbances.
- Patients with right-left ventricular shunt.

Primary endpoint:
Enhancement of the left ventricular chamber:
- Percentages of subjects with satisfactory or complete enhancement of the left ventricular
apical chamber view (4 chambers, 69 subjects; 2 chambers, 54 subjects).
- Mean duration of ventricular chamber enhancement.
- Mean duration of clinically useful chamber enhancement (defined as satisfactory or
complete enhancement by the investigators).

Secondary endpoints:
Delineation of the endocardial border
- Percentage of segments with changes in evaluability (using the 12 segment heart model)
before and after administration of Luminity™.
- Recovery of non-diagnostic tests.

4 Results:
Only the LUMINITY 10μL/mL arm results, at the dosage indicated in the Marketing
Authorisation, are presented.

Patient characteristics
Study DMP 115-004 Study DMP 115-005
Total number of subjects 87 124
Distribution by gender
Male 69 (79.3%) 70 (56.5%)
Female 18 (20.7%) 54 (43.5%)
Distribution by age: mean (range-type) 62.5 (12.3) 52.1 (16.3)
Distribution by dose group
Placebo 18 24
5 μL/kg Luminity™ 35 50
10 μL/kg Luminity™ 34 50


Primary endpoint results: enhancement of the left ventricular chamber
- Percentages of subjects achieving satisfactory or complete enhancement of the left
ventricular chamber
The percentage of subjects in whom satisfactory or complete enhancement of the left
ventricular chamber was high