Definity

Overdose

No information provided.

Contraindications

Do not administer DEFINITY to patients with known or suspected:

• Hypersensitivity to perflutren.

Undesirable effects

The following serious adverse reactions are described elsewhere in the labeling:

• Serious Cardiopulmonary Reactions
• Hypersensitivity Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 1716 subjects were evaluated in pre-market clinical trials of activated DEFINITY. In this group, 1063 (61.9%) were male and 653 (38.1%) were female, 1328 (77.4%) were White, 258 (15.0%) were Black, 74 (4.3%) were Hispanic, and 56 (3.3%) were classified as other racial or ethnic groups. The mean age was 56.1 years (range 18 to 93). Of these, 144 (8.4%) had at least one adverse reaction (Table 1). There were 26 serious adverse events and 15 (0.9%) subjects discontinued because of an adverse event.

Among the 1716 study patients, 19 (1.1%) suffered serious cardiopulmonary adverse reactions.

For all adverse reactions, the overall incidence of adverse experiences was similar for the < 65 year age group and the > 65 year age group, similar in males and in females, similar among all racial or ethnic groups, and similar for bolus and infusion dosing. Table 1 summarizes the most common adverse reactions.

Table 1 : New-Onset Adverse Reactions Occurring in ≥ 0.5% of All DEFINITY-Treated Subjects

Other adverse reactions that occurred in ≤ 0.5% of the activated DEFINITY-dosed subjects were:

Body as a Whole: Fatigue, fever, hot flushes, pain, rigors, and syncope

Cardiovascular: Abnormal ECGs, bradycardia, tachycardia, palpitation, hypertension and hypotension

Digestive: Dyspepsia, dry mouth, tongue disorder, toothache, abdominal pain, diarrhea and vomiting

Hematology: Granulocytosis, leukocytosis, leukopenia, and eosinophilia

Musculoskeletal: Arthralgia Nervous System: Leg cramps, hypertonia, vertigo and paresthesia

Platelet, Bleeding, and Clotting: Hematoma

Respiratory: Coughing, hypoxia, pharyngitis, rhinitis and dyspnea

Special Senses: Decreased hearing, conjunctivitis, abnormal vision and taste perversion

Skin: Pruritus, rash, erythematous rash, urticaria, increased sweating, and dry skin

Urinary: Albuminuria

In a prospective, multicenter, open-label registry of 1053 patients receiving DEFINITY in routine clinical practice, heart rate, respiratory rate, and pulse oximetry were monitored for 30 minutes after DEFINITY administration. No deaths or serious adverse reactions were reported, suggesting that these reactions are unlikely to occur at a rate of more than 0.3% when DEFINITY is used according to recommendations.

The following adverse reactions have been identified during the post-marketing use of perflutren-containing microsphere products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Fatal cardiopulmonary and hypersensitivity reactions and other serious but non-fatal adverse reactions were uncommonly reported. These reactions typically occurred within 30 minutes of DEFINITY administration. These serious reactions may be increased among patients with unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, or serious ventricular arrhythmias.

Reported reactions included:

Fatal cardiac or respiratory arrest, shock, syncope, symptomatic arrhythmias (atrial fibrillation, tachycardia, bradycardia, supraventricular tachycardia, ventricular fibrillation, ventricular tachycardia), hypertension, hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing.

Anaphylactic reaction, anaphylactic shock, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, erythema.

Coma, loss of consciousness, convulsion, seizure, transient ischemic attack, agitation, tremor, vision blurred, dizziness, headache, fatigue.

Therapeutic indications

Activated DEFINITY (Perflutren Lipid Microsphere) Injectable Suspension is indicated for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border.

Pharmacokinetic properties

Human pharmacokinetics information is not available for the intact or degassed lipid microspheres. The pharmacokinetics of octafluoropropane gas (OFP) was evaluated in healthy subjects (n=8) after the IV administration of activated DEFINITY at a 50 microL/kg dose.

OFP gas binding to plasma proteins or partitioning into blood cells has not been studied. However, OFP protein binding is expected to be minimal due to its low partition coefficient into whole blood.

OFP is a stable gas that is not metabolized. The phospholipid components of the microspheres are thought to be metabolized to free fatty acids.

OFP was not detectable after 10 minutes in most subjects either in the blood or in expired air. OFP concentrations in blood were shown to decline in a mono-exponential fashion with a mean half-life of 1.3 minutes in healthy subjects.

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

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.

Qualitative and quantitative composition

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 X 1010 perflutren lipid microspheres, and about 150 microL/mL (1.1 mg/mL) octafluoropropane.

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

One (1) 2mL vial -NDC (11994-011-01)
Four (4) 2mL vials per kit - NDC (11994-011-04)
Sixteen (16) 2mL vials per kit - NDC (11994-011-16)

Store between 2-8°C (36°-46°F).

Distributed By Lantheus Medical Imaging 331 Treble Cove Road N. Billerica, Massachusetts 01862 USA. For ordering, tel. toll free: 800-299-3431. All Other Business: 800-362-2668 (For Massachusetts and International, call 978-667-9531). Revised: Jan 2017

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Serious cardiopulmonary reactions including fatalities have occurred uncommonly during or shortly following perflutren-containing microsphere administration, typically within 30 minutes of administration. The risk for these reactions may be increased among patients with unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, or serious ventricular arrhythmias). Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY administration and monitor all patients for acute reactions.

The reported reactions include: fatal cardiac or respiratory arrest, shock, syncope, symptomatic arrhythmias (atrial fibrillation, tachycardia, bradycardia, supraventricular tachycardia, ventricular fibrillation, ventricular tachycardia), hypertension, hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing, loss of consciousness, and convulsions.

In postmarketing use, serious hypersensitivity reactions were observed during or shortly following perflutren-containing microsphere administration including:

Shock, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, and erythema have occurred in patients with no prior exposure to perflutren-containing microsphere products. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY administration and monitor all patients for hypersensitivity reactions.

When administering DEFINITY to patients with a cardiac shunt, the microspheres can bypass filtering by the lung and enter the arterial circulation. Assess patients with shunts for embolic phenomena following DEFINITY administration. DEFINITY is only for intravenous administration; do not administer DEFINITY by intra-arterial injection.

High ultrasound mechanical index values may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. Additionally, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias. DEFINITY is not recommended for use at mechanical indices greater than 0.8.

Studies with activated DEFINITY have not been performed to evaluate carcinogenic potential. Evidence of genotoxicity was not found in the following studies with activated DEFINITY: 1) bacterial mutagenesis assay (Ames assay), 2) in vitro mammalian mutagenesis assay, 3) in vitro human lymphocyte chromosome aberration assay, and 4) in vivo rat micronucleus assay.

Impairment of male or female fertility was not observed in rats and rabbits treated with activated DEFINITY at doses up to 24 and 15 times the human dose based on body surface area (in rats and rabbits respectively).

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.

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. Because many drugs are excreted in human milk, caution should be exercised when DEFINITY is administered to a nursing mother.

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.

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.

Dosage (Posology) and method of administration

• 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.

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.

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.

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.

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 User's 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), 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. 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.

Interaction with other medicinal products and other forms of interaction

The following serious adverse reactions are described elsewhere in the labeling:

• Serious Cardiopulmonary Reactions
• Hypersensitivity Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 1716 subjects were evaluated in pre-market clinical trials of activated DEFINITY. In this group, 1063 (61.9%) were male and 653 (38.1%) were female, 1328 (77.4%) were White, 258 (15.0%) were Black, 74 (4.3%) were Hispanic, and 56 (3.3%) were classified as other racial or ethnic groups. The mean age was 56.1 years (range 18 to 93). Of these, 144 (8.4%) had at least one adverse reaction (Table 1). There were 26 serious adverse events and 15 (0.9%) subjects discontinued because of an adverse event.

Among the 1716 study patients, 19 (1.1%) suffered serious cardiopulmonary adverse reactions.

For all adverse reactions, the overall incidence of adverse experiences was similar for the < 65 year age group and the > 65 year age group, similar in males and in females, similar among all racial or ethnic groups, and similar for bolus and infusion dosing. Table 1 summarizes the most common adverse reactions.

Table 1 : New-Onset Adverse Reactions Occurring in ≥ 0.5% of All DEFINITY-Treated Subjects

Other adverse reactions that occurred in ≤ 0.5% of the activated DEFINITY-dosed subjects were:

Body as a Whole: Fatigue, fever, hot flushes, pain, rigors, and syncope

Cardiovascular: Abnormal ECGs, bradycardia, tachycardia, palpitation, hypertension and hypotension

Digestive: Dyspepsia, dry mouth, tongue disorder, toothache, abdominal pain, diarrhea and vomiting

Hematology: Granulocytosis, leukocytosis, leukopenia, and eosinophilia

Musculoskeletal: Arthralgia Nervous System: Leg cramps, hypertonia, vertigo and paresthesia

Platelet, Bleeding, and Clotting: Hematoma

Respiratory: Coughing, hypoxia, pharyngitis, rhinitis and dyspnea

Special Senses: Decreased hearing, conjunctivitis, abnormal vision and taste perversion

Skin: Pruritus, rash, erythematous rash, urticaria, increased sweating, and dry skin

Urinary: Albuminuria

In a prospective, multicenter, open-label registry of 1053 patients receiving DEFINITY in routine clinical practice, heart rate, respiratory rate, and pulse oximetry were monitored for 30 minutes after DEFINITY administration. No deaths or serious adverse reactions were reported, suggesting that these reactions are unlikely to occur at a rate of more than 0.3% when DEFINITY is used according to recommendations.

The following adverse reactions have been identified during the post-marketing use of perflutren-containing microsphere products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Fatal cardiopulmonary and hypersensitivity reactions and other serious but non-fatal adverse reactions were uncommonly reported. These reactions typically occurred within 30 minutes of DEFINITY administration. These serious reactions may be increased among patients with unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, or serious ventricular arrhythmias.

Reported reactions included:

Fatal cardiac or respiratory arrest, shock, syncope, symptomatic arrhythmias (atrial fibrillation, tachycardia, bradycardia, supraventricular tachycardia, ventricular fibrillation, ventricular tachycardia), hypertension, hypotension, dyspnea, hypoxia, chest pain, respiratory distress, stridor, wheezing.

Anaphylactic reaction, anaphylactic shock, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, erythema.

Coma, loss of consciousness, convulsion, seizure, transient ischemic attack, agitation, tremor, vision blurred, dizziness, headache, fatigue.

No information provided.