Definity

Perflutren is an ultrasound contrast agent that is used to improve the quality of an echocardiogram (ultrasound of the heart). Perflutren works by changing the way ultrasound waves travel within your heart. This helps the ultrasound portray a sharper image of your heart.

Perflutren is used to allow certain segments of the heart to be seen more clearly on an echocardiogram.

Perflutren may also be used for purposes not listed in this medication guide.

You should not be treated with perflutren if you have a genetic heart condition called "cardiac shunt."

In rare cases, serious or fatal reactions may occur during the injection or shortly afterward. Tell your caregiver right away if you feel dizzy, nauseated, light-headed or short of breath, or if you have a severe headache, pounding in your ears, chest pain, fast or slow heartbeats, wheezing, or shallow breathing.

You may be more likely to have a serious reaction if you have severe or uncontrolled heart problems (congestive heart failure, a recent heart attack, serious heart rhythm disorder).

You should not be treated with perflutren if you are allergic to it, or if you have:

• a genetic heart condition called "cardiac shunt"; or
• if you are allergic to blood products or to a medicine that contains albumin.

To make sure perflutren is safe for you, tell your doctor if you have:

• a congenital heart defect;
• a lung condition that has recently become worse; or
• if you have ever had an allergic reaction during a blood transfusion.

FDA pregnancy category B. It is not known whether perflutren can harm an unborn baby. Tell your doctor if you are pregnant.

It is not known whether perflutren passes into breast milk or if it could harm a nursing baby. However, if you are breast-feeding a baby, use a breast pump to empty your milk supply one time after you are treated with perflutren. Throw out the milk you collect during this time and do not feed it to your baby.

Perflutren is made from human plasma (part of the blood) which may contain viruses and other infectious agents. Donated plasma is tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

Since perflutren is given with an echocardiogram, you will not be on a regular dosing schedule.

Get emergency medical help if you have any of these signs of an allergic reaction: hives, skin redness, itching; warmth, redness, numbness, or tingly feeling; wheezing, trouble breathing, tight feeling in your chest or throat; swelling of your face, lips, tongue, or throat.

In rare cases, serious or fatal reactions may occur during the injection or shortly afterward. Tell your caregivers right away if you have:

• a light-headed feeling, like you might pass out;

• severe dizziness, or a cold sweat;

• chest pain, wheezing, trouble breathing;

• fast or slow heartbeats;

• severe headache, blurred vision, pounding in your neck or ears, anxiety, confusion; or

• slow heart rate, weak pulse, fainting, weak or shallow breathing.

You may be more likely to have a serious reaction if you have severe or uncontrolled heart problems (congestive heart failure, a recent heart attack, serious heart rhythm disorder).

Common side effects may include:

• headache, dizziness;

• flushing (warmth, redness, or tingly feeling);

• nausea, vomiting;

• pain in your side or lower back; or

• altered sense of taste.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In the U.S.

• Definity

Available Dosage Forms:

• Suspension

Therapeutic Class: Radiological Non-Ionic Contrast Media

Use Definity as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given into a vein for a period of time.
• This medicine must not be given into an artery. Talk with the doctor.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of high or low blood pressure like very bad headache or dizziness, passing out, change in eyesight.
• Chest pain or pressure.
• A heartbeat that does not feel normal.
• Shortness of breath.
• Fast or slow heartbeat.
• Seizures.
• Numbness or tingling of the face.
• Flushing.

Definity® is intended for administration only after activation in the VIALMIX® apparatus. Before injection, this product must be activated and prepared according to the instructions outlined below. The VIALMIX® apparatus should be ordered from Lantheus Medical Imaging, 331 Treble Cove Road, North Billerica, MA, 01862. For customer orders call 1-800-299-3431.

Definity® may be injected by either an intravenous (IV) bolus or infusion. The maximum dose is either two bolus doses or one single intravenous infusion. The safety of bolus and infusion dosing in combination or in sequence, has not been studied.

Bolus

The recommended bolus dose for activated Definity® is 10 microliters (microL)/kg of the activated product by intravenous bolus injection within 30-60 seconds, followed by a 10 mL saline flush. If necessary, a second 10 microliters (microL)/kg dose followed by a second 10 mL saline flush may be administered 30 minutes after the first injection to prolong contrast enhancement.

Infusion

The recommended infusion dose for activated Definity® is via an IV infusion of 1.3 mL added to 50 mL of preservative-free saline. 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.

Imaging

After baseline non-contrast echocardiography is completed, set the mechanical index for the ultrasound device at 0.8 or below [see WARNINGS AND PRECAUTIONS (5.4)]. Then inject activated Definity® (as described above) and begin ultrasound imaging immediately. Evaluate the activated Definity® echocardiogram images in combination with the non-contrast echocardiogram images.

In a crossover trial of 64 patients randomized to both bolus and infusion, the duration of clinically useful contrast enhancement for fundamental imaging was approximately 3.4 minutes after a 10 microL/kg bolus and was approximately 7.1 minutes during the continuous infusion of 1.3 mL activated Definity® in 50 mL saline at a rate of 4 mL/min.

Definity® Activation, Preparation and Handling Instructions

1. Allow the vial to warm to room temperature before starting the activation procedure.
2. Activate Definity® by shaking the vial for 45 seconds using a VIALMIX®.
   
   Note: illustrations of this procedure are contained in the VIALMIX® Users Guide.
   
   Do not use this drug unless it has completed a full 45 second activation cycle in the VIALMIX®. Definity® will not be properly activated unless the full 45 second activation cycle is completed. Do not reactivate the vial if VIALMIX® did not complete a full 45 second cycle. Do not reactivate a successfully activated Definity® vial (see step 3). Do not use a VIALMIX® that is not functioning properly. Refer to the "VIALMIX® User's Guide" for the "VIALMIX® calibration and replacement procedures" to ensure that a properly functioning VIALMIX® is used.
3. Immediately after activation in the VIALMIX®, activated Definity® appears as a milky white suspension and may be used immediately after activation. If the product is not used within 5 minutes of VIALMIX® activation, the microspheres should be resuspended by 10 seconds of hand agitation by inverting the vial before the product is withdrawn in a syringe. The activated Definity® may be used for up to 12 hours from the time of VIALMIX®, but only after the microspheres are resuspended by hand agitation. Store the activated Definity® at room temperature in the original product vial.
4. Invert the vial and withdraw the activated milky white suspension using the Intellipin™ (Dispensing Pin) or 18 to 20 gauge syringe needle. Withdraw the material from the middle of the liquid in the inverted vial. Do not inject air into the Definity® VIAL.
5. Use the product immediately after its withdrawal from the vial; do not allow the product to stand in the syringe.

For single use only: Definity® does not contain bacterial preservative. Bacterial contamination with the risk of post-administration septicemia can occur following the puncture of the elastomeric septum. It is essential to follow directions for activation of Definity® carefully and to adhere to strict aseptic procedures during preparation.

Definity® is supplied as a single use 2 mL clear glass vial containing a clear liquid. in packages of four (4) and sixteen (16) single-use vials.

Prior to activation, the headspace of each vial contains 6.52 mg/mL octafluoropropane and the clear liquid contains 0.75mg/mL of a lipid blend. After activation, each vial contains a maximum of 1.2 × 1010 perflutren lipid microspheres, and about 150 microL/mL (1.1 mg/mL) octafluoropropane [see DESCRIPTION (11)].

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Definity® in pregnant women. Reproduction studies performed in rats and rabbits at doses up to 24 and 15 times the human dose based on body surface area (in rats and rabbits respectively) revealed no evidence of impaired fertility or harm to the fetus due to Definity®. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether Definity® is excreted in human milk. Based on the rapid clearance of this drug, advise nursing mothers to pump and discard breast milk once after treatment [see CLINICAL PHARMACOLOGY (12)]. Because many drugs are excreted in human milk, caution should be exercised when Definity® is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of activated Definity® have not been established in the pediatric population.

The safety of injecting activated Definity® in neonates and infants with immature pulmonary vasculature has not been studied.

The pharmacokinetics of activated Definity® in pediatric subjects has not been studied.

Geriatric Use

In clinical trials, the overall incidence of adverse reactions was similar for the <65 year age group and the ≥65 year age group. Of the total number of subjects in clinical trials of Definity®, 144 (33%) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Gender

The overall incidence of adverse reactions was similar between males and females.

Race

The overall incidence of adverse reactions was similar among all racial and ethnic groups.

Unlike the perflutren lipid microsphere injectable suspension (Definity(R)), the perflutren protein-type A microsphere injectable suspension has shown evidence of fetotoxicity, embryofetal toxicity, and teratogenicity in rats and rabbits. AU TGA pregnancy category B3 (Definity(R)): Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category B (Definity(R)): Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. US FDA pregnancy category C (Optison(TM)): Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Definity(R): This drug should be used in pregnancy only if clearly needed. Optison(TM): This drug should be used during pregnancy only if the benefit outweighs the risk. AU TGA pregnancy category: Definity(R): B3 US FDA pregnancy category: Definity(R): B; Optison(TM): C