OPTISON 0.19 MG / ML DISPERSION FOR INJECTION - summary of medicine characteristics

2   QUALITATIVE AND QUANTITATIVE COMPOSITION

Dispersion for injection.

Clear solution with white microsphere layer on top.

4.1 Therapeutic indications

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 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.

4.2 Posology and method of administration

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 is obtained immediately after administration.

Posology

The recommended dose is 0.5 ml – 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 repeatedlyadmi­nistered, however, the clinical experience is limited.

Paediatric population

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 be made.

4.3 Contraindications

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.

4.4 Special warnings and 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 ofpatients only after careful consideration and monitored closely during and after administration. Other routes of administration not specified in section 4.2 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 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 and batch 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 these biological side effects have not been reported in humans, the use of a low mechanical index and end-diastolic triggering is recommended.

Paediatric population

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

4.5 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

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 ofthis finding is unknown. Therefore, OPTISON should not be used in pregnancy unless benefit outweighs risk and it is considered necessary by the physician.

Breast-feeding

It is not known whether OPTISON is excreted in human milk. Therefore, caution should be

exercisedwhen OPTISON is administered to breast-feeding women.

4.7 Effects on ability to drive and use machines

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

4.8 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 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.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at https://yellowcard.mhra.gov.uk/.

4.9 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 nosignificant adverse events.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

When used in conjunction with diagnostic ultrasound, OPTISON provides opacification of cardiac chambers, 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 generate strong echoes.

OPTISON consists of perflutren -containing microspheres. The microspheres have a mean diameter of

2.5 – 4.5 microns and concentrations of 5–8 × 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 the ultrasound signal, data processing within the ultrasound equipment and the fact that each individual responds differently due to variability in cardiac and pulmonary function, a strict dose/response relationship 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 be recommended for left heart opacification. Higher doses produce greater contrast effect of longer duration. Duration of useful contrast effect at the recommended dose is adequate to perform a complete 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 19 years, the safety profile appeared to be similar to that seen in adults. Doses administered in one study were 0.2 ml above 25 kg body weight and 0.1ml under 25 kg, and in a second study 0.5ml above 20 kg body 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, openlabel studyof 30 patients scheduled for pulmonary artery catheterisation, including 19 with an elevated baseline pulmonary arterial systolic pressure (PASP) (>35 mmHg; mean 70.1±33.0 mmHg; range 36.0–176.0 mmHg) 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 important pulmonary haemodynamic, systemic haemodynamic, or ECG changes were observed. This study didnot assess the effect of OPTISON on visualisation of cardiac or pulmonary structures.

5.2 Pharmacokinetic properties

Following intravenous injection of 0.21 to 0.33 ml/kg of OPTISON to healthy volunteers, the perflutren component of OPTISON was rapidly and nearly completely eliminated in less than 10 minutes 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 determine pharmacokinetic 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, albumin shells and 125I were taken up primarily in the liver. The primary route of elimination of radioactivity was 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).

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Human albuminSodium chloride

N-acetyltryptop­hanCaprylic acid

Sodium hydroxide (pH adjustment)Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

Unopened vial in the outer packaging: 2 years.

Finished product after rubber stopper perforation: 30 minutes.

6.4 Special precautions for storage

Store upright in a refrigerator (2oC – 8°C).

Storage at room temperature (up to 25°C) for 1 day is acceptable.Do not freeze.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal

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 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 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 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 otherwiseOPTISON 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 9 mg/ml (0.9%) solution for injection 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 the three-way stopcock and intravenous infusion started at a “to keep open” (TKO) rate. Immediatelyafter 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.

GE Healthcare Limited Pollards Wood Nightingales Lane Chalfont St Giles Buckinghamshire HP8 4SP United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 00637/0068

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2021