Definity (perflutren lipid microsphere)

Definity (perflutren lipid microsphere) Injectable Suspension is a contrast agent used to brighten and clarify images of the heart during echocardiograms.

Common side effects of Definity include:

• injection site reactions,
• back and chest pain,
• headache,
• dizziness,
• nausea,
• flushing,
• fatigue,
• fever,
• hot flashes,
• fainting,
• fast or slow heart rate,
• palpitations,
• high or low blood pressure,
• indigestion,
• dry mouth,
• toothache,
• abdominal pain,
• diarrhea,
• vomiting,
• joint pain,
• leg cramps,
• spinning sensation (vertigo),
• numbness and tingling,
• cough,
• sore throat,
• runny or stuffy nose,
• shortness of breath,
• itching,
• rash,
• hives,
• increased sweating, and
• dry skin.

Important Administration Instructions

• 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. Do not administer Definity by intra-arterial injection.
• 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.

Dosage

Bolus

• The recommended bolus dose for activated Definity is 10 microliters (microL)/kg of the activated product by intravenous bolus injection within 30 to 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 mL/minute, but titrated as necessary to achieve optimal image enhancement, not to exceed 10 mL/minute.

Imaging Guidelines

• After baseline non-contrast echocardiography is completed, set the mechanical index for the ultrasound device at 0.8 or below.
• 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

Follow directions for activation of Definity carefully and adhere to strict aseptic procedures during preparation.

Note: illustrations of this procedure are contained in the Vialmix or Vialmix RFID User's Guide.

Do not use this drug unless it has completed a full 45 second activation cycle in the Vialmix or Vialmix RFID. Definity will not be properly activated unless the full 45 second activation cycle is completed. Error messages will display if the vial is not properly activated. Do not reactivate the vial if Vialmix or Vialmix RFID did not properly activate the vial.

Never reactivate a successfully activated Definity vial (see step 3). A Vialmix or Vialmix RFID that is not functioning properly must never be used. Only use a vial activated from a properly functioning Vialmix or Vialmix RFID. Refer to the Vialmix or Vialmix RFID User's Guide to ensure that a properly functioning Vialmix or Vialmix RFID is used.

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 device or Vialmix RFID device.
3. Immediately after activation in the Vialmix or Vialmix RFID, 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 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 activation, but only after the microspheres are resuspended by hand agitation. Store the activated Definity at room temperature in the original product vial.
4. 4. Invert the vial and withdraw the activated milky white suspension using the Intellipin (Dispensing Pin), the PINSYNC (Vented Vial Adapter 13mm), 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. 5. Use the product immediately after its withdrawal from the vial; do not allow the product to stand in the syringe.

Special Instructions For The Definity Radio Frequency Identification (RFID)-Tagged Vial

This information is for vials containing Definity that have been labeled with a Radio Frequency Identification (RFID) tag. Full instructions for use of Vialmix RFID are provided on the Vialmix RFID screen and User's Guide.

• The RFID tag allows for the exchange of product information such as activation time and activation rate.
• Vialmix RFID will only activate Definity RFID-tagged vials. Function of the RFID technology is not dependent on vial orientation as it is placed in the Vialmix RFID. If the RFID tag is damaged or otherwise non-functional, the Vialmix RFID will notify the user and the vial with the nonfunctional RFID tag cannot be used to activate Definity with Vialmix RFID. Discard the nonfunctional RFID-tagged Definity vial.
• Follow all manufacturer's guidelines and do not operate any part of the Vialmix RFID and Definity RFID-tagged vials within 6 inches (15 cm) of a pacemaker and/or defibrillator.

• Available data from case reports with Definity use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
• Definity has a very short half-life; therefore, administration of Definity to a pregnant woman is not expected to result in clinically relevant fetal exposure.
• No adverse developmental outcomes were observed in animal reproduction studies with administration of activated Definity in pregnant rats and rabbits during organogenesis at doses up to 8 and 16 times, respectively, the maximum human dose based on body surface area. There are no data on the presence of
• Definity in human milk, the effects on the breastfed infant, or the effects on milk production.
• The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Definity and any potential adverse effects on the breastfed infant from Definity or from the underlying maternal condition.