OPTISON injection suspension medication leaflet

OPTISON 0.19 mg/ml dispersion for injection

OPTISON consists of perflutren-containing microspheres of heat treated human albumin, suspended inhuman albumin solution, 1%.

Concentration: Perflutren-containing microspheres, 5-8 x 108/ml with a mean diameter range of2.5 - 4.5 µm.

The approximate amount of perflutren gas in each ml of OPTISON is 0.19 mg.

Each ml contains 0.15 mmol (3.45 mg) of sodium.

For the full list of excipients, see section 6.1.

Dispersion for injection.

Clear solution with white microsphere layer on top.

This medicinal product is for diagnostic use only.

OPTISON is a transpulmonary echocardiographic contrast agent for use in patients with suspected orestablished cardiovascular disease to provide opacification of cardiac chambers, enhance leftventricular endocardial border delineation with resulting improvement in wall motion visualisation.

OPTISON should only be used in patients where the study without contrast enhancement isinconclusive.

OPTISON should only be administered by physicians experienced in the field of diagnostic ultrasoundimaging.

Before administering OPTISON, please see section 6.6 for instructions for use/handling.

This medicinal product is intended for left ventricular opacification after intravenous administration.

Ultrasound imaging must be performed during injection of OPTISON as optimal contrast effect isobtained immediately after administration.

The recommended dose is 0.5 ml - 3.0 ml per patient. A dose of 3.0 ml is usually sufficient, but somepatients may need higher doses. The total dose should not exceed 8.7 ml per patient. The duration ofthe useful imaging time is 2.5 - 4.5 minutes for a dose of 0.5 - 3.0 ml. OPTISON could be repeatedlyadministered, however, the clinical experience is limited.

The safety and efficacy of OPTISON in children and adolescents below 18 years has not beenestablished.

Currently available data are described in section 5.1 but no recommendation on a posology can bemade.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Pulmonaryhypertension with a systolic pulmonary artery pressure > 90 mm Hg.

Hypersensitivity has been reported. Care should therefore be exercised. A course of action should beplanned in advance with necessary drugs and equipment available for immediate treatment, in case aserious reaction should occur.

The experience of OPTISON in severely ill patients is limited. There is limited clinical experiencewith OPTISON in patients with certain severe states of cardiac, pulmonary, renal and hepatic disease.

Such clinical states include adult respiratory distress syndrome, the use of artificial respiration withpositive end-expiratory pressure, severe heart failure (NYHA IV), endocarditis, acute myocardialinfarction with on-going angina or unstable angina, hearts with prosthetic valves, acute states ofsystemic inflammation or sepsis, known states of hyperactive coagulation system and/or recurrentthromboembolism, renal or hepatic end-stage disease. OPTISON should be used in these categories ofpatients only after careful consideration and monitored closely during and after administration. Otherroutes of administration not specified in section 4.2 above (e.g. intracoronary injection) are notrecommended.

Standard measures to prevent infections resulting from the use of medicinal products prepared fromhuman blood or plasma include selection of donors, screening of individual donations and plasmapools for specific markers of infection and the inclusion of effective manufacturing steps for theinactivation/removal of viruses. Despite this, when medicinal products prepared from human blood orplasma are administered, the possibility of transmitting infective agents cannot be totally excluded.

This also applies to unknown or emerging viruses and other pathogens.

There are no reports of virus transmissions with albumin manufactured to European Pharmacopoeiaspecifications by established processes.

It is strongly recommended that every time that OPTISON is administered to a patient, the name andbatch number of the product are recorded in order to maintain a link between the patient and the batchof the product.

OPTISON contrast echocardiography should be accompanied by ECG monitoring.

In animal studies, the application of echo-contrast agents revealed biological side effects (e.g.endothelial cell injury, capillary rupture) by interaction with the ultrasound beam. Although thesebiological side effects have not been reported in humans, the use of a low mechanical index and end-diastolic triggering is recommended.

Efficacy and safety in patients below 18 years has not been studied.

No interaction studies have been performed.

Use during anaesthesia with halothane and oxygen has not been studied.

The safety of OPTISON for use during human pregnancy has not been established. In pregnant rabbitsexposed to daily doses of 2.5 ml/kg (approximately 15 x the maximum recommended clinical dose)during organogenesis, maternal toxicity and embryo-foetal toxicity including a slight to extremedilation of ventricles in the brain of developing rabbit embryos was observed. The clinical relevance ofthis finding is unknown. Therefore OPTISON should not be used in pregnancy unless benefitoutweighs risk and it is considered necessary by the physician.

It is not known whether OPTISON is excreted in human milk. Therefore, caution should be exercisedwhen OPTISON is administered to breast-feeding women.

No studies on the effects on the ability to drive and use machines have been performed.

Adverse reactions to OPTISON are rare and usually of a non-serious nature. In general, theadministration of human albumin has been associated with transient altered taste, nausea, flushing,rash, headache, vomiting, chills and fever. Anaphylactic reactions have been associated with theadministration of human albumin products. The reported adverse events following the use of

OPTISON in Phase III human clinical studies have been mild to moderate with subsequent fullrecovery.

In clinical trials with OPTISON, undesirable effects were reported as adverse events with thefollowing frequencies given in the table below: 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 frequency grouping, undesirable effects arepresented in order of decreasing seriousness.

System Organ Class Undesirable Effects Frequency

Blood and lymphatic system Eosinophilia Uncommondisorders

Nervous system disorders Dysgeusia (altered taste), headache Common

Tinnitus, dizziness, paraesthesia Rare

Eye disorders Visual disturbances Not known*

Cardiac disorders Ventricular tachycardia Rare

Respiratory, thoracic and Dyspnoea Uncommonmediastinal disorders

Vascular disorders Flushing Common

Gastrointestinal disorders Nausea Common

General disorders and Warm sensation Commonadministration site conditions

Chest pain Uncommon

Immune system disorders Allergic type symptoms (e.g. Not known*anaphylactoid reaction or -shock, faceoedema, urticaria)

* Reactions for which no frequency rate can be provided due to lack of clinical trial data havebeen classified as “Not known”

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.

No case of overdose has been reported.

In the Phase I trial, healthy volunteers have received up to 44.0 ml of OPTISON and experienced nosignificant adverse events.

Pharmacotherapeutic group: Ultrasound contrast medium, ATC Code: V08D A01

When used in conjunction with diagnostic ultrasound, OPTISON provides opacification of cardiacchambers, improvement in delineation of endocardial borders, enhancement of the Doppler signal, andvisualisation of wall motion and blood flow within the heart.

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 microspheres containing perflutren are very different from that of soft tissue and will generatestrong echoes.

OPTISON consists of perflutren-containing microspheres. The microspheres have a mean diameter of2.5 - 4.5 microns and concentrations of 5-8 x 108 microspheres/ml. Microspheres in this size rangecontribute to the contrast effect by generating strongly enhanced echoes.

As OPTISON consists of microspheres that are stable and small enough for transpulmonary passage, itwill also give enhanced echo signals in the left heart cavities.

As a consequence of the complex relationship between the concentration of the microspheres and theultrasound signal, data processing within the ultrasound equipment and the fact that each individualresponds differently due to variability in cardiac and pulmonary function, a strict dose/responserelationship cannot be defined. The dose of OPTISON will therefore have to be adjusted individually,although clinical studies have shown that an initial dose of 0.5 - 3.0 ml per patient can berecommended for left heart opacification. Higher doses produce greater contrast effect of longerduration. Duration of useful contrast effect at the recommended dose is adequate to perform acomplete echocardiographic examination including Doppler assessment.

Use the smallest dose for adequate opacification of cavities since larger doses produce image blockingeffects with the possibility of obscuring important information.

In two uncontrolled studies including a total of 42 children and adolescents, aged 8 months to 19years, the safety profile appeared to be similar to that seen in adults. Doses administered in one studywere 0.2 ml above 25 kg body weight and 0.1ml under 25 kg, and in a second study 0.5ml above 20 kgbody weight and 0.3 ml under 20 kg, by bolus peripheral intravenous injection followed by a salineflush. Low mechanical index was used for ultrasound imaging.

The effect of OPTISON on pulmonary haemodynamics was studied in a prospective, open-label studyof 30 patients scheduled for pulmonary artery catheterisation, including 19 with an elevated baselinepulmonary arterial systolic pressure (PASP) (>35 mmHg; mean 70.1±33.0 mmHg; range 36.0-176.0mmHg) and 11 with a normal PASP (≤35 mmHg; mean 29.3±4.6 mmHg; range 22.0-35.0 mmHg).

Systemic haemodynamic parameters and ECGs were also evaluated. No clinically importantpulmonary haemodynamic, systemic haemodynamic, or ECG changes were observed. This study didnot assess the effect of OPTISON on visualisation of cardiac or pulmonary structures.

Following intravenous injection of 0.21 to 0.33 ml/kg of OPTISON to healthy volunteers, theperflutren component of OPTISON was rapidly and nearly completely eliminated in less than 10minutes with a dominating pulmonary elimination half-life of 1.3±0.7 minutes. The perflutren levelsdetected in blood following this dosage were too low and transient to accurately determinepharmacokinetic parameters.

The disposition and elimination of the albumin microspheres have not been studied in humans.

Information obtained from a preclinical study in rats with 125I-labelled albumin microspheres indicatedthat microspheres were rapidly cleared from the circulation, and radio-labelled microspheres, albuminshells and 125I were taken up primarily in the liver. The primary route of elimination of radioactivitywas the urine. High levels of radioactivity were also retained in lungs for a considerable time, approx.10% of the total dose 40 minutes after dose administration (cf. 35% in liver).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, acute and repeated dose toxicity and genotoxicity. In the rabbit embryotoxicity study, asignificant increase in the number of foetuses with dilated ventricles in the brain was observed (seesection 4.6). No such finding was observed in the rat embryotoxicity study.

Human albumin

Sodium chloride

N-acetyltryptophan

Caprylic acid

Sodium hydroxide (pH adjustment)

Water for injections

OPTISON must not be mixed with other medicinal products. A separate syringe should be used.

Unopened vial in the outer packaging: 2 years.

Finished product after rubber stopper perforation: 30 minutes.

Store upright in a refrigerator (2oC - 8ºC).

Storage at room temperature (up to 25ºC) for 1 day is acceptable.

Do not freeze.

3 ml type I glass vial, closed with bromobutyl rubber stopper, and sealed with aluminium cap withcoloured plastic flip-off top.

OPTISON is supplied as: 1 vial of 3 ml or 5 vials of 3 ml.

Not all pack sizes may be marketed.

Like all parenteral products, the vials of OPTISON should be inspected visually for integrity of thecontainer.

Vials are intended for single use only. Once the rubber stopper has been penetrated, the contentsshould be used within 30 minutes and any unused product discarded.

OPTISON in the non-resuspended form has a white layer of microspheres on top of the liquid phasethat requires resuspension before use. Homogenous white suspension after resuspension.

The following instructions should be followed:

- Cold solutions taken directly from the refrigerator should not be injected.

- Allow the vial to reach room temperature and inspect the liquid phase for particulate matter orprecipitates before resuspension.

- Insert a 20 G plastic cannula in a large antecubital vein, preferably of the right arm. Attach athree-way stopcock to the cannula.

- The OPTISON vial must be inverted and gently rotated for approximately three minutes tocompletely resuspend the microspheres.

- Complete resuspension is indicated by a uniformly opaque white suspension and absence of anymaterial on stopper and vial surfaces.

- OPTISON should be withdrawn with care into a syringe within 1 minute after resuspension.

- Any pressure instability within the vial should be avoided since it may cause disruption ofmicrospheres and loss of contrast effect. Thus, vent the vial with a sterile spike or with a sterile18 G needle before withdrawing the suspension into the injection syringe. Do not inject air intothe vial as this will damage the product.

- Use the suspension within 30 minutes after withdrawal.

- OPTISON will segregate in an undisturbed syringe and must be resuspended before use.

- Resuspend the microspheres in the syringe immediately before injection by holding the syringehorizontally between the palms of the hands and rolling it quickly back and forth for no lessthan 10 seconds.

- Inject the suspension through the plastic cannula, no smaller than 20 G at a maximum injectionrate of 1.0 ml/s.

Warning: Never use any other type of route but the open flow connection. If injected otherwise

OPTISON bubbles will be destroyed.

- Immediately before injection a careful visual inspection of the syringe is mandatory in order toensure complete suspension of the microspheres.

Immediately after injection of OPTISON, 10 ml of sodium chloride 9 mg/ml (0.9%) solution forinjection or glucose 50 mg/ml (5%) solution for injection should be injected at a rate of 1 ml/s.

Alternately, the flushing may be performed by infusion. The infusion set should then be attached to thethree-way stopcock and intravenous infusion started at a “to keep open” (TKO) rate. Immediately after

OPTISON injection, the intravenous infusion should be wide open until contrast begins to fade fromthe left ventricle. The infusion should then be returned to a TKO rate.

GE Healthcare AS

Nycoveien 1

NO-0485 Oslo

Norway

1 x 3 ml presentation: EU/1/98/065/0015 x 3 ml presentation: EU/1/98/065/002

Date of first authorisation: 18 May 1998

Date of latest renewal: 12 June 2008