Drug: Definity

DEFINITY® (Perflutren Lipid Microsphere) Injectable Suspension is an ultrasound contrast agent. The DEFINITY® vial contains components that upon activation yield perflutren lipid microspheres, a diagnostic drug that is intended to be used for contrast enhancement during the indicated echocardiographic procedures. The vial contains a clear, colorless, sterile, non-pyrogenic, hypertonic liquid, which upon activation with the aid of a VIALMIX®, provides a homogeneous, opaque, milky white injectable suspension of perflutren lipid microspheres. The suspension of activated DEFINITY® is administered by intravenous injection. The perflutren lipid microspheres are composed of octafluoropropane encapsulated in an outer lipid shell consisting of (R) – hexadecanoic acid, 1-[(phosphonoxy)methyl]-1,2ethanediyl ester, monosodium salt (abbreviated DPPA); (R) - 4-hydroxy-N,N,N-trimethyl10-oxo-7-[(1-oxohexadecyl)oxy]-3,4,9-trioxa-4-phosphapentacosan-1-aminium, 4-oxide, inner salt (abbreviated DPPC); and (R)-∝-[6-hydroxy-6-oxido-9-[(1-oxohexadecyl)oxy]5,7,11-trioxa-2-aza-6-phosphahexacos-1-yl]-ω-methoxypoly(ox-1,2-ethanediyl), monosodium salt (abbreviated MPEG5000 DPPE). Octafluoropropane is chemically characterized as 1,1,1,2,2,3,3,3-octafluoropropane. It has a molecular weight of 188, empirical formula of C3F8 and has the following structural formula: DPPA has a molecular weight of 670, empirical formula of C35H68O8PNa, and following structural formula: DPPC has a molecular weight of 734, empirical formula of C40H80NO8P, and following structural formula: MPEG5000 DPPE has an approximate molecular weight of 5750 represented by empirical formula C265H527NO123PNa, and the following structural formula: Prior to VIALMIX® activation, the DEFINITY® vial contains 6.52 mg/mL octafluoropropane in the headspace. Each mL of the clear liquid contains 0.75 mg lipid blend (consisting of 0.045 mg DPPA, 0.401 mg DPPC, and 0.304 mg MPEG5000 DPPE), 103.5 mg propylene glycol, 126.2 mg glycerin, 2.34 mg sodium phosphate monobasic monohydrate, 2.16 mg sodium phosphate dibasic heptahydrate, and 4.87 mg sodium chloride in Water for Injection. The pH is 6.2-6.8. After activating the contents of the vial in a VIALMIX®, each mL of the milky white suspension contains a maximum of 1.2 X 1010 perflutren lipid microspheres, and about 150 microL/mL (1.1 mg/mL) octafluoropropane. The microsphere particle size parameters are listed in Table 11.1 below: Table 11.1: Microsphere Size Distribution
  Microsphere particle size parameters Mean diameter range 1.1 μm – 3.3 μm Percent less than 10 μm 98% Maximum diameter 20 μm Last reviewed on RxList: 11/4/2011
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Clinical Trials Experience 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 6.1). There were 26 serious adverse events and 15 (0.9%) subjects discontinued because of an adverse event. Deaths and Serious Adverse Events Among the 1716 activated DEFINITY® patients, 19 (1.1%) suffered serious cardiopulmonary adverse events including eight deaths. The deaths occurred several days after activated DEFINITY® administration and appeared to be related to the course of underlying disease. Of the 11 other serious adverse events, which appeared within days of the drug administration (2-15 days), all appeared to be a progression underlying cardiac and noncardiac disease. However, a role for DEFINITY® in the initiation or course of these adverse events cannot be ruled out. Discontinuations There were 15 discontinuations reported with a mean age of 41.5 years. Nine of these patients were discontinued after the first injection. One patient experienced a hypersensitivity reaction with urticaria and pruritus and all the other patients experienced dizziness, chest pain, dyspnea or back pain. These adverse reactions appeared within minutes (1 – 15 min) of the drug administration and were of moderate intensity resolving usually without treatment within minutes or hours after onset. 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 6.1 summarizes the most common adverse reactions. Table 6.1: New-Onset Adverse Reactions Occurring in ≥ 0.5% of All Activated DEFINITY®-Treated Subjects
  All activated DEFINITY ®
(N=1716) Total Number of Adverse Reactions 269   Total Number of Subjects with an Adverse Reaction 144 (8.4%) Body system Preferred term n (%) Application Site Disorders 11 (0.6)   Injection Site Reactions 11 (0.6) Body as a Whole 41 (2.4)   Back/renal pain 20 (1.2)   Chest pain 13 (0.8) Central and peripheral nervous system disorder 54 (3.1)   Headache 40 (2.3)   Dizziness 11 (0.6) Gastrointestinal system 31 (1.8)   Nausea 17 (1.0) Vascular (extracardiac) disorders 19 (1.1)   Flushing 19 (1.1) N=Sample size 1716 subjects who received activated DEFINITY®
n=Number of subjects reporting at least one Adverse Reaction 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 Postmarketing Experience 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 anaphylactoid events and other serious but non-fatal adverse reactions were uncommonly reported. These events typically occurred within 30 minutes of DEFINITY® administration. These serious events 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 [see WARNINGS AND PRECAUTIONS]. Reported reactions included: Cardiopulmonary 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. Anaphylactoid Anaphylactic/anaphylactoid reaction, anaphylactic shock, hypersensitivity, bronchospasm, throat tightness, angioedema, edema (pharyngeal, palatal, mouth, peripheral, localized), swelling (face, eye, lip, tongue, upper airway), facial hypoesthesia, rash, urticaria, pruritus, flushing, erythema. Neurologic Coma, loss of consciousness, convulsion, seizure, transient ischemic attack, agitation, tremor, vision blurred, dizziness, headache, fatigue. Read the Definity (perflutren lipid microsphere) Side Effects Center for a complete guide to possible side effectsLearn More »

Source: http://www.rxlist.com

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]. 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.

Source: http://www.rxlist.com

Drug-drug interactions for activated DEFINITY® have not been studied.Last reviewed on RxList: 11/4/2011
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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.

Source: http://www.rxlist.com

Do not administer DEFINITY® to patients with known or suspected:
  • Right-to-left, bi-directional, or transient right-to-left cardiac shunts,
  • Hypersensitivity to perflutren [see WARNINGS AND PRECAUTIONS].
Do not administer DEFINITY® by intra-arterial injection.Last reviewed on RxList: 11/4/2011
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

The clinical consequences of overdosing with activated DEFINITY® are not known. Treatment of an overdose should be directed toward the support of all vital functions and prompt institution of symptomatic therapy [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Source: http://www.rxlist.com

Dosage Forms And Strengths DEFINITY® is supplied as a single use 2-mL clear glass vial containing a clear liquid. Each package contains four (4) 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 [see DESCRIPTION]. DEFINITY® is supplied as a single use 2-mL clear glass vial containing clear liquid. Each package (clear plastic clamshell) contains four (4) single-use vials. NDC (11994-011-01), vial
NDC (11994-011-04), 4 vial kit Storage and Handling Store between 2-8°C (36°-46°F). 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. Manufacturer details: n/a. Revised: October, 2011 Last reviewed on RxList: 11/4/2011
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Serious Cardiopulmonary Reactions 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 [see ADVERSE REACTIONS]. Anaphylactoid Reactions In postmarketing use, uncommon but serious anaphylactoid reactions were observed during or shortly following perflutren-containing microsphere administration including: Shock, hypersensitivity, 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 [see ADVERSE REACTIONS]. Systemic Embolization of DEFINITY® in Patients with Cardiac Shunts In patients with right-to-left, bi-directional, or transient right-to-left cardiac shunts phospholipid-encapsulated microspheres can bypass the pulmonary particle-filtering mechanisms and directly enter the arterial circulation resulting in microvascular occlusion and ischemia. In an animal study utilizing intra-arterial administration of activated DEFINITY®, microsphere trapping was seen in small arterioles < 15 μm, especially at branch points and in capillaries at all doses tested, including doses directly applicable to those used in humans. An animal study utilizing intravenous administration did not result in arterial microvascular obstruction presumably because of filtering by the lungs. Do not administer DEFINITY® by intra-arterial injection [see CONTRAINDICATIONS]. High Ultrasound Mechanical Index 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. The safety of activated DEFINITY® at mechanical indices greater than 0.8 has not been evaluated [see DOSAGE AND ADMINISTRATION]. The safety of activated DEFINITY® with the use of end-systolic triggering has not been evaluated. QTc Prolongation ECG parameters for doses up to 10 microL/kg were monitored in 221 subjects at multiple time points from 1 hour to 72 hours after the first bolus injection. In the 221 subjects, QTc prolongations of > 30 msec were noted in 64 (29%) subjects. Forty-six out of 64 subjects with QTc prolongations were further evaluated and 39% (18/46) showed associated cardiac rhythm changes. The effects of concomitant drugs were not studied. Nonclinical Toxicology Carcinogenesis, Mutagenesis, and Impairment of Fertility 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). Use In Specific Populations 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]. 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. Last reviewed on RxList: 11/4/2011
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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