Contents of the package leaflet for the medicine LUMINITY 150mcl / ml solution for dispersion for injection / infusion

1. NAME OF THE MEDICINAL PRODUCT

Luminity 150 microlitres/ml gas and solvent for dispersion for injection/infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains a maximum of 6.4 x 109 perflutren-containing lipid microspheres, with a meandiameter range of 1.1-2.5 micrometres (μm). The approximate amount of perflutren gas in each ml is150 microlitres (μl).

Excipient(s) with known effect

Each ml contains 2.679 mg sodium

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Gas and solvent for dispersion for injection/infusion

Colourless, uniformly clear to translucent liquid.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

Luminity is an ultrasound contrast-enhancing agent for use in adult patients in whom non-contrastechocardiography was suboptimal (suboptimal is considered to indicate that at least two of sixsegments in the 4- or 2-chamber view of the ventricular border were not evaluable) and who havesuspected or established coronary artery disease, to provide opacification of cardiac chambers andimprovement of left ventricular endocardial border delineation at both rest and stress.

4.2 Posology and method of administration

Luminity should only be administered by trained physicians with technical expertise in performingand interpreting contrast echocardiograms, and appropriate resuscitation equipment should beavailable in case of cardiopulmonary or hypersensitivity reactions (see section 4.4).

Posology

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 dispersion, followed by a 3 to 5 mlbolus of sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) solution for injection to maintainoptimal contrast enhancement. The total dose of perflutren should not exceed 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, followedby a 10 ml bolus of sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) solution for injection.

If necessary, a second 10 microlitre dispersion/kg dose followed by a second 10 ml bolus of sodiumchloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) solution for injection may be administered5 minutes after the first injection to prolong contrast enhancement.

Intravenous infusion using non-linear contrast imaging technique (rest and stress) or fundamentalimaging technique at rest:

The recommended dose via an intravenous infusion is 1.3 ml dispersion added to 50 ml of sodiumchloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) solution for injection. The rate of infusion shouldbe initiated at 4 ml/minute, but titrated as necessary to achieve optimal image enhancement, not toexceed 10 ml/minute.

Paediatric population

The safety and efficacy of Luminity in children and adolescents below 18 years have not beenestablished. No data are available.

Patients with hepatic impairment

Luminity has not been specifically studied in patients with hepatic impairment. Use in this patientgroup should be on the basis of a benefit risk assessment by the physician.

Patients with renal impairment

Luminity has not been specifically studied in patients with renal impairment. Use in this patient groupshould be on the basis of a benefit risk assessment by the physician.

Elderly patients

Luminity has not been specifically studied in elderly patients. Use in this patient group should be onthe basis of a benefit risk assessment by the physician.

Method of administration
Intravenous use.

Before administering Luminity, the medicinal product must be activated by using a mechanicalshaking device, the Vialmix, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

This product must only be administered intravenously.

Luminity should not be used with fundamental imaging technique for stress echocardiography sinceefficacy and safety have not been established.

Patients with unstable cardiopulmonary status

During contrast-enhanced echocardiography, serious cardiopulmonary reactions, including fatalities,have occurred during or within 30 minutes of Luminity administration in patients including those withsevere cardiac and pulmonary diseases (see section 4.8). Extreme caution should be used whenconsidering the administration of Luminity to patients with unstable cardiopulmonary status, forexample: unstable angina, acute myocardial infarction, severe ventricular arrhythmias, severe heartfailure (NYHA IV) or respiratory failure. Luminity should only be administered to such patients aftercareful risk/benefit assessment.

Contrast-enhanced echocardiography should only be considered in such patients if the results arelikely to produce a change in individual patient management.

Patients with unstable cardiopulmonary status should be monitored during and for at least 30 minutesfollowing Luminity administration. For such patients monitoring should include vital signmeasurements, electrocardiography, and, if clinically appropriate, cutaneous oxygen saturation.

Resuscitation equipment and trained personnel must always be readily available.

Patients with adult respiratory distress syndrome, endocarditis, prosthetic heart valves, systemicinflammation, sepsis, hyperactive coagulation and/or recurrent thromboembolism

Luminity should be used only after careful consideration and such use should be monitored closelyduring administration in patients with adult respiratory distress syndrome, endocarditis, a heart withprosthetic valves, acute states of systemic inflammation or sepsis, known states of hyperactivecoagulation and/or recurrent thromboembolism.

Hypersensitivity reactions

Serious immediate hypersensitivity reactions (eg: anaphylaxis, anaphylactic shock and anaphylactoidreactions, hypotension and angioedema) have been reported following the administration of Luminity,including in patients with prior allergic reaction(s) to polyethylene glycol (see Section 6.1). Patientsshould be closely monitored and administration should be under the direction of a physicianexperienced in the management of hypersensitivity reactions including severe allergic reactions, whichmight require resuscitation. Emergency equipment and personnel trained in its use must be readilyavailable.

Pulmonary disease

Caution should be exercised in patients with clinically significant pulmonary disease, including diffuseinterstitial pulmonary fibrosis and severe chronic obstructive pulmonary disease, as no studies havebeen performed in these patients.

Sickle Cell Disease

In postmarketing use, patients with sickle cell disease reported episodes of severe acute pain (vaso-occlusive pain) shortly following perflutren-containing microsphere administration. Luminity shouldbe used with caution in patients with sickle cell disease following a benefit risk assessment by thephysician.

Patients with Cardiac Shunts

The safety of Luminity in patients with right-to-left, bi-directional or transient right-to-left cardiacshunts has not been studied. In these patients, phospholipid encapsulated microspheres can bypass thelung and directly enter the arterial circulation. Caution must be exercised when considering theadministration of Luminity to these patients.

Patients on mechanical ventilation

The safety of microspheres in patients on mechanical ventilation has not been established. Cautionshould be exercised when considering the administration of Luminity to these patients.

Administration and mechanical activation procedure

Luminity should not be administered by methods not specified in section 4.2 (e.g. intra-arterialinjection).

If Luminity is administered directly to the patient without undergoing the mechanical activationprocedure using the Vialmix (see section 6.6), the product will not produce its intended effect.

Sodium Content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’ .

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed and no other forms of interaction have been identified.

4.6 Fertility, pregnancy and lactation

Pregnancy

For perflutren, no clinical data on exposed pregnancies are available. Animal studies do not indicatedirect or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturitionor postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnantwomen.

Breast-feeding

It is not known whether Luminity is excreted in human breast milk. Therefore, caution should beexercised when Luminity is administered to breast-feeding women.

Fertility

Animal studies do not indicate direct or indirect harmful effects on fertility.

4.7 Effects on ability to drive and use machines

As Luminity has no pharmacologic effect, and on the basis of its pharmacokinetic andpharmacodynamic profiles, no or negligible influence is expected with the use of this product on theability to drive or use machines.

4.8 Undesirable effects

Summary of the safety profile

The reported adverse reactions following the use of Luminity in pivotal and supportive trials (total of2,526 patients) occur within minutes after administration and usually resolve without therapeuticintervention within 15 minutes. The most frequently reported adverse reactions are: headache (2.0%),flushing (1.0%) and back pain (0.9%).

Tabulated list of adverse reactions

Adverse reactions were reported with the following frequencies (Very common ≥ 1/10; Common≥ 1/100 to < 1/10; Uncommon ≥ 1/1,000 to < 1/100; Rare ≥ 1/10,000 to < 1/1,000; Very rare< 1/10,000), not known (cannot be estimated from the available data). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Blood and lymphatic Not known: Sickle cell anaemia vaso-occlusive crisissystem disorders

Immune system disorders Not known: Allergic type reactions, anaphylaxis, anaphylacticshock and anaphylactoid type reactions, hypotension, angioedema,lip swelling, bronchospasm, rhinitis, upper airway swelling, throattightness, facial swelling, eye swelling

Nervous system disorders Common: Headache

Uncommon: Dizziness, dysgeusia

Rare: Paraesthesia

Not known: seizures, facial hypoaesthesia, loss of consciousness

Eye disorders Not known: Abnormal vision

Cardiac disorders Rare: Bradycardia, Tachycardia, Palpitations

Not known: Cardiac arrest, Kounis Syndrome, ventriculararrhythmias (ventricular fibrillation, ventricular tachycardia,premature ventricular contactions), asystole, atrial fibrillation,cardiac ischaemia, supraventricular tachycardia, supraventriculararrhythmia

Vascular disorders Common: Flushing

Uncommon: Hypotension

Rare: Syncope, hypertension, peripheral coldness

Respiratory, thoracic and Uncommon: Dyspnoea, Throat Irritationmediastinal disorders

Rare: Respiratory Distress, Cough, Dry Throat

Not known: Respiratory arrest, decreased oxygenation, hypoxia

Gastrointestinal disorders Uncommon: Abdominal Pain, diarrhoea, nausea, vomiting,

Rare: Dyspepsia

Not known: Tongue disorder

Skin and subcutaneous Uncommon: Pruritus, increased sweatingtissue disorders

Rare: Rash, urticaria, erythema, erythematous rash

Musculoskeletal and Uncommon: Back painconnective tissue disorders

Rare: Arthralgia, flank pain, neck pain, muscle cramp

Not known: Muscle spasm, musculoskeletal pain,musculoskeletal discomfort, myalgia, hypertonia

General disorders and Uncommon: Chest Pain, fatigue, feeling hot, injection site painadministration siteconditions Rare: Pyrexia, rigors

Investigations Rare: Abnormal electrocardiogram

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

4.9 Overdose

The clinical consequences of overdose with Luminity are not known. Single doses of up to100 microlitres dispersion/kg and multiple doses up to 150 microlitres dispersion/kg were toleratedwell in Phase I clinical trials. Treatment of an overdose should be directed towards the support of allvital functions and prompt institution of symptomatic therapy.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ultrasound contrast media, microspheres of phospholipids,

ATC Code: V08DA04

The product consists of lipid encapsulated perflutren microspheres. Microspheres in the 1 to < 10 µmdiameter size range contribute to the contrast effect by generating strongly enhanced echoes.

The ultrasound echoes from blood and biological soft tissues such as fat and muscles are generated atinterfaces due to small differences in the ultrasonic properties of the tissues. The ultrasonic propertiesof the product are very different from those of soft tissue and will generate strong echoes.

As Luminity consists of microspheres that are stable and small enough for transpulmonary passage,enhanced echo signals in the left heart and systemic circulation are obtained.

A strict dose/response relationship cannot be defined, although higher doses have been shown toproduce a contrast effect of longer duration.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of Luminity were evaluated in normal healthy subjects and subjectswith chronic obstructive pulmonary disease (COPD) following intravenous administration of a50 µl/kg dose of the product.

The perflutren component of Luminity was rapidly cleared from the systemic circulation via the lungs.

The percentage of the perflutren dose excreted in expired air was approximately 50% of theadministered dose due to the small quantities of perflutren given and the inability to quantify lowlevels of perflutren by gas chromatography. In most subjects after 4-5 minutes, perflutren wasundetectable in blood and expired air. Perflutren concentrations in blood were shown to decline in amono-exponential 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. Totallung clearance (CLlung) of perflutren was shown to be no different in healthy subjects compared to

COPD subjects. CLlung was found to be significantly reduced (51%) in females compared to males (allsubjects). These results suggest that overall perflutren systemic elimination is rapid and is notsignificantly reduced in COPD patients compared to healthy subjects. Doppler ultrasoundmeasurements were performed with Luminity in conjunction with the pharmacokinetic evaluation ofperflutren. Doppler signal intensity corresponded well with measured and extrapolated perflutrenconcentrations in blood. The time to maximum Doppler signal intensity tmax was shown to be similar tothe perflutren blood tmax (1.13 versus 1.77 minutes). The observed 99% drop in Doppler signalintensity within 10 minutes (t1/2 approximately 2 minutes) was in agreement with the decline inmeasurable blood levels of perflutren.

Fundamental and non-linear imaging techniques (second harmonic, multipulse phase and/or amplitudemodulation) using both continuous and triggered acquisition were utilised in clinical studies with

Luminity.

The naturally occurring phospholipids in Luminity (see section 6.1) are distributed in the endogenouslipid pools in the body (for example, liver) whereas the synthetic component (MPEG5000) has beenshown to be excreted in the urine in preclinical studies. All lipids are metabolised to free fatty acids.

The pharmacokinetics and metabolism of MPEG5000 DPPE have not been evaluated in humans.

Pharmacokinetics in special population groups

Elderly

Pharmacokinetics has not been specifically studied in the elderly.

Renal impairment

Pharmacokinetics has not been specifically studied in the renal disease patients.

Hepatic impairment

Pharmacokinetics has not been specifically studied in the hepatic disease patients.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of genotoxicity,fertility, embryo/foetal development, parturition or post-natal development, and local tolerance.

Abnormal respiration, heart rate changes and decreased activity were observed soon after intravenousinjection of Luminity at doses ≥ 0.3 ml/kg in single and repeat-dose toxicity studies in rats andmonkeys. Higher doses of the product, typically ≥ 1 ml/kg, resulted in more severe signs includingunresponsiveness and occasionally death. These levels are substantially above the recommendedmaximal clinical dose. Rats treated with Luminity for 1 month exhibited dose-related, reversibleperivascular and peribronchiolar eosinophil infiltration, alveolar macrophage accumulation andincreased goblet cell size and number in the lungs. These effects were observed at exposure levels inexcess of the maximum human exposure indicating little relevance to clinical use.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC)1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid, monosodium salt (DPPA)

N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, monosodium salt (MPEG5000 DPPE)

Sodium dihydrogen phosphate monohydrate

Disodium hydrogen phosphate heptahydrate

Sodium chloride

Propylene glycol

Glycerol

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

6.3 Shelf life

2 years.

The product should be used within 12 hours of activation. The product can be re-activated up to 48hours after initial activation and used up to 12 hours after the second activation.

After activation: Do not store above 30°C.

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C)

For storage conditions after activation of the medicinal product, see section 6.3.

6.5 Nature and contents of container

1.5 ml liquid in clear borosilicate Type I glass vial, closed with a chlorobutyl elastomeric stopper, andsealed with an aluminium crimp seal having a plastic flip-off button.

Pack sizes of 1 or 4 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

It is essential to follow instructions for use and handling of Luminity and to adhere to strict asepticprocedures during preparation. Like all parenteral products, the vials must be inspected visually forparticulates and vial integrity. Before administering the product, it must be activated by using the

Vialmix, a mechanical shaking device. The Vialmix is not included in the Luminity pack but will beprovided to healthcare professionals upon ordering the pack.

Luminity is activated by using the Vialmix which has a programmed shaking time of 45 seconds. The

Vialmix will alert the operator if the shaking frequency varies by 5% or more below the targetfrequency. It also has been programmed to shut down and will provide visual and audio warnings ifthe shaking frequency exceeds the target frequency by 5%, or falls below the target frequency by 10%.

Activation process and administration

- The vial should be activated using the Vialmix. Immediately after activation, Luminity appears as amilky white dispersion.

Note: if the product is allowed to stand for more than 5 minutes after activation, it should beresuspended with 10 seconds of hand agitation prior to syringe withdrawal from the vial. Luminityshould be used within 12 hours following activation. The product can be re-activated up to 48 hoursafter initial activation and used up to 12 hours after the second activation, whether stored underrefrigeration or at room temperature. Do not store the vial above 30°C following activation.

- The vial should be vented with a sterile syringe needle or a sterile non-siliconised mini-spike beforewithdrawing the dispersion.

- The dispersion should be withdrawn from the vial using a syringe with a 18 to 20 gauge sterileneedle or attached to a sterile non-siliconised mini-spike. When using a needle, it should be positionedto withdraw the material from the middle of the liquid in the inverted vial. No air should be injectedinto the vial. The product should be used immediately after its withdrawal from the vial.

- Luminity may be diluted with sodium chloride 9 mg/ml (0.9%) solution for injection or glucose50 mg/ml (5%) solution for injection.

The contents of the vial are intended for single use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Lantheus EU Limited

Rocktwist House,

Block 1, Western Business Park

Shannon, Co. Clare V14 FW97

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/361/001 - 002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 September 2006

Date of latest renewal: 15 July 2016

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.

Leaflet LUMINITY 150mcl / ml solution for dispersion for injection / infusion

General data about LUMINITY 150mcl / ml

Marketing authorisation

Pharmaceutical forms available for perflutren