GE Healthcare Submits Application to European Medicines Agency (EMA) for Its Own Manufacturing of Optison™ 0.19 mg/ml dispersion for injection (Human albumin microspheres containing perflutren)

GE Healthcare today announced that it has submitted an application to amend its European Marketing Authorisation that will allow the company to manufacture Optison™ 0.19 mg/ml dispersion for injection within its own facility. Upon approval, GE Healthcare will provide supply of Optison to the EU market from its manufacturing facility in Oslo, Norway.

Optison is a transpulmonary echocardiographic contrast agent for use in patients with suspected or established cardiovascular disease to provide opacification of cardiac chambers, enhance left ventricular endocardial border delineation with resulting improvement in wall motion visualisation. Optison should only be used in patients where the study without contrast enhancement is inconclusive.

"GE Healthcare is committed to providing safe, reliable, innovative, and effective diagnostic products that aid in the detection of cardiovascular diseases, and today’s filing is further evidence of our commitment,” said Ben Newton, Global Product Leader, Ultrasound, GE Healthcare Medical Diagnostics. "Adding our own manufacturing site for Optison has multiple benefits, including an ability to increase capacity to meet market demands and ensuring robust and secure stock. We look forward to serving the EU contrast media market.”

Optison remains an important diagnostic option for patients with suboptimal echocardiograms. Additionally, Optison offers a unique, convenient value to clinicians and patients: It is stable at room temperature for up to 24 hours and takes less than 60 seconds to prepare, allowing for quick access to contrast in hospital settings like the cardiac lab or emergency room.

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PRESCRIBING INFORMATION OPTISON™ 0.19 mg/ml dispersion for injection (Human albumin microspheres containing perflutren)

Please refer to full Summary of Product Characteristics before prescribing.

PRESENTATION Dispersion for injection supplied as 1 vial of 3 ml and 5 vials of 3 ml. OPTISON consists of perflutren-containing microspheres of heat treated human albumin, suspended in human albumin solution, 1%.

CONCENTRATION Perflutren-containing microspheres, 5-8 x 10 ⁸/ml with a mean diameter range of 2.5-4.5 µm. The approximate amount of perflutren gas in each ml of OPTISON is 0.19 mg.

INDICATIONS This medicinal product is for diagnostic use only. OPTISON is a transpulmonary echocardiographic contrast agent for use in patients with suspected or established cardiovascular disease to provide opacification of cardiac chambers, enhance left ventricular endocardial border delineation with resulting improvement in wall motion visualisation. OPTISON should only be used in patients where the study without contrast enhancement is inconclusive.

DOSAGE AND METHOD OF ADMINISTRATION OPTISON should only be administered by physicians experienced in the field of diagnostic ultrasound imaging. Before administering OPTISON, please see Instructions for use. The product is intended for left ventricular opacification after intravenous administration. Ultrasound imaging must be performed during injection of OPTISON as optimal contrast effect is obtained immediately after administration. Dosage: The recommended dose is 0.5-3.0 ml per patient. A dose of 3.0 ml is usually sufficient, but some patients may need higher doses. The total dose should not exceed 8.7 ml per patient. The duration of the useful imaging time is 2.5-4.5 minutes for a dose of 0.5-3.0 ml. OPTISON could be repeatedly administered, however, clinical experience is limited. Safety and efficacy of OPTISON in children and adolescents below 18 years has not been established; no recommendation on a posology can be made.

CONTRAINDICATIONS Hypersensitivity to the active substance or to any of the excipients. Pulmonary hypertension with a systolic pulmonary artery pressure > 90 mm Hg.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE Hypersensitivity has been reported. Care should therefore be exercised. A course of action should be planned in advance with necessary drugs and equipment available for immediate treatment, in case a serious reaction should occur. The experience of OPTISON in severely ill patients is limited. There is limited clinical experience with 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 with positive end-expiratory pressure, severe heart failure (NYHA IV), endocarditis, acute myocardial infarction with on-going angina or unstable angina, hearts with prosthetic valves, acute states of systemic inflammation or sepsis, known states of hyperactive coagulation system and/or recurrent thromboembolism, renal or hepatic end-stage disease. OPTISON should be used in these categories of patients only after careful consideration, and monitored closely during and after administration. Other routes of administration not specified in section "Dosage and method of administration” above (e.g. intracoronary injection) are not recommended. Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma 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 Pharmacopoeia specifications by established processes. It is strongly recommended that every time that OPTISON is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of 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 these biological 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.

INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION No interaction studies have been performed. Use during anaesthesia with halothane and oxygen has not been studied.

PREGNANCY AND LACTATION The safety of OPTISON for use during human pregnancy has not been established. In pregnant rabbits exposed 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 extreme dilation of ventricles in the brain of developing rabbit embryos was observed. The clinical relevance of this finding is unknown. Therefore, OPTISON should not be used in pregnancy unless benefit outweighs risk and it is considered necessary by the physician. It is not known whether OPTISON is excreted in human milk. Therefore, caution should be exercised when OPTISON is administered to breast-feeding women.

EFFECTS ON THE ABILITY TO DRIVE AND USE MACHINES No studies on the effects on the ability to drive and use machines have been performed.

UNDESIRABLE EFFECTS Adverse reactions to OPTISON are rare and usually of a non-serious nature. In general, the administration of human albumin has been associated with transient altered taste, nausea, flushing, rash, headache, vomiting, chills and fever. Anaphylactic reactions have been associated with the administration 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 full recovery. In clinical trials with OPTISON, undesirable effects were reported as adverse events 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). Undesirable effects: Common: Dysgeusia (altered taste), headache, flushing, nausea, warm sensation. : Uncommon: Eosinophilia, dyspnoea, chest pain. Rare: Dizziness, paraesthesia, tinnitus, ventricular tachycardia. Not Known: Visual disturbances, allergic type symptoms (e.g. anaphylactoid reaction or -shock, facial oedema, urticaria).

OVERDOSE 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 no significant adverse effects.

INSTRUCTIONS FOR USE AND HANDLING Like all parenteral products, the vials of OPTISON should be inspected visually for integrity of the container. Vials are intended for single use only. Homogenous white suspension after resuspension. Once the rubber stopper has been penetrated, the contents should 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 phase that requires resuspension before use. 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 or precipitates before resuspension. • Insert a 20 G plastic cannula in a large antecubital vein, preferably of the right arm. Attach a three-way stopcock to the cannula. • The OPTISON vial must be inverted and gently rotated for approximately three minutes to completely resuspend the microspheres. • Complete resuspension is indicated by a uniformly opaque white suspension and absence of any material 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 of microspheres and loss of contrast effect. Thus, vent the vial with a sterile spike or with a sterile 18 G needle before withdrawing the suspension into the injection syringe. Do not inject air into the 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 syringe horizontally between the palms of the hands and rolling it quickly back and forth for no less than 10 seconds. • Inject the suspension through the plastic cannula, no smaller than 20 G at a maximum injection rate 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 to ensure complete suspension of the microspheres. • Immediately after injection of OPTISON, 10 ml of sodium chloride 9mg/ml (0.9%) solution for injection or glucose 50mg/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 the three-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 from the left ventricle. The infusion should then be returned to a TKO rate.

PHARMACEUTICAL PRECAUTIONS OPTISON must not be mixed with other medicinal products. A separate syringe should be used. OPTISON should be stored upright between 2ºC and 8ºC. Storage at room temperature (up to 25ºC) for 1 day is acceptable. Do not freeze. The shelf life of the product in the outer packaging is 2 years and of finished product after rubber stopper perforation: 30 minutes.

MARKETING AUTHORISATION HOLDER GE Healthcare AS, Nycoveien 1-2, P.O BOX 4220 Nydalen, N-0401 OSLO, Norway.

CLASSIFICATION FOR SUPPLY Subject to medical prescription.

MARKETING AUTHORISATION NUMBERS 1 x 3 ml: EU/1/98/065/001. 5 x 3 ml: EU/1/98/065/002.

PRICE £286.30 for 5 x 3ml vials

Revision of text December 2010.

Adverse events should be reported. Reporting forms and information can be found at

www.mhra.gov.uk/yellowcard. Adverse events should also be reported to GE Healthcare.