ProHance by is a Prescription medication manufactured, distributed, or labeled by Bracco Diagnostics Inc, BRACCO IMAGING SPA, BIPSO GmbH, Labor LS SE & Co. KG, BioChem Labor für biologishe und chemische. Drug facts, warnings, and ingredients follow.
Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs.
Warnings and Precautions, Gadolinium Retention (5.3) | 04/2018 |
ProHance Multipack is a gadolinium-based paramagnetic MRI contrast agent indicated for intravenous use to visualize:
Injection: Each mL of ProHance contains 279.3 mg of gadoteridol (3).
Allergic or hypersensitivity reactions to ProHance (4).
The most commonly reported adverse reactions are nausea and taste perversion with an incidence of 1.4% (6.1)
To report SUSPECTED ADVERSE REACTIONS, Contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Pregnancy: Use only if imaging is essential during pregnancy and cannot be delayed. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 8/2018
Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs [see Warnings and Precautions (5.1)].
MRI of Extracranial/Extraspinal
Tissues
Adults:
Pediatric Use: Safety and efficacy for extracranial/extraspinal tissues have not been established.
NOT FOR DIRECT INFUSION
The pharmacy bulk package is used as a multiple dose container with
an appropriate transfer device to fill empty sterile syringes. Use
the following procedures when transferring ProHance from the pharmacy
bulk package to individual syringes:
ProHance is contraindicated in patients with known allergic or hypersensitivity reactions to ProHance [see Warnings and Precautions (5.2)].
Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following ProHance Multipack administration to Bracco Diagnostics (1-800-257-5181) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).
Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.
Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. [see Clinical Pharmacology (12)].
Severe and fatal hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products, including ProHance. Prior to ProHance administration, ensure the availability of trained personnel and medications to treat hypersensitivity reactions. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders should be closely monitored during the procedure and for several hours after drug administration. If a reaction occurs, stop ProHance and immediately begin appropriate therapy including resuscitation.
Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (e.g. brain, skin, kidney, liver, and spleen). The duration of retention also varies by tissue and is longest in bone. Linear GBCAs cause more retention than macrocyclic GBCAs. At equivalent doses, retention varies among the linear agents with Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention than other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)].
Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function [see Warnings and Precautions (5.1)]. There are rare reports of pathologic skin changes in patients with normal renal function. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention[see Adverse Reactions (6.2)].
While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing a GBCA for these patients. Minimize repetitive GBCA imaging studies, particularly closely spaced studies when possible.
In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging.
The following adverse reactions are discussed in greater detail in other sections of the prescribing information:
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.
The adverse events described in this section were observed in clinical trials involving 1,251 patients (670 males and 581 females). Adult patients ranged in age from 18 to 91 yrs. Pediatric patients ranged from 2 to 17 years. The racial breakdown was 83% Caucasian, 8% Black, 3% Hispanic, 2% Asian, and 1% other. In 2% of the patients, race was not reported.
The most commonly noted adverse experiences were nausea and taste perversion with an incidence of 1.4%.
These events were mild to moderate in severity.
The following additional adverse events occurred in less than 1% of the patients:
Body as a Whole: | Facial Edema; Neck Rigidity; Pain; Pain at Injection Site; Injection Site Reaction; Chest Pain; Headache; Fever; Itching; Watery Eyes; Abdominal Cramps; Tingling Sensation in Throat; Laryngismus; Flushed Feeling; Vasovagal Reaction; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms) |
Cardiovascular: | Prolonged P-R Interval; Hypotension; Elevated Heart Rate; A-V Nodal Rhythm |
Digestive: | Edematous and/or itching tongue; Gingivitis; Dry Mouth; Loose Bowel; Vomiting |
Nervous System: | Anxiety; Dizziness; Paresthesia; Mental Status Decline; Loss of Coordination in Arm; Staring Episode; Seizure; Syncope |
Respiratory System: | Dyspnea; Rhinitis; Cough |
Skin and Appendages: | Pruritus; Rash; Rash Macular Papular; Urticaria; Hives; Tingling Sensation of Extremity and Digits |
Special Senses: | Tinnitus |
The following adverse reactions have been identified during post approval use of ProHance that were not observed in the clinical trials. 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.
General Disorders and Administration Site Conditions | Adverse events with variable onset and duration have been reported after GBCA administration [see Warnings and Precautions (5.3)]. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems. |
Body as a Whole: | Generalized Edema; Laryngeal Edema; Malaise; Anaphylactoid Reactions (characterized by cardiovascular, respiratory and cutaneous symptoms, and rarely resulting in Death) |
Cardiovascular: | Cardiac Arrest; Bradycardia; Hypertension; and Death in association with pre-existing cardiovascular disorders |
Digestive: | Increased Salivation; Dysphagia |
Nervous System: | Stupor; Tremor; Loss of Consciousness |
Respiratory: | Apnea; Wheezing |
Skin and Appendages: | Gadolinium associated plaques, Sweating; and Cyanosis |
Special Senses: | Voice Alteration; Transitory Deafness |
Urogenital: | Urinary Incontinence |
GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive. Because of the potential risks of gadolinium to the fetus, use ProHance only if imaging is essential during pregnancy and cannot be delayed. Contrast enhancement is visualized in the human placenta and fetal tissues after maternal GBCA administration.
Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported a clear association between GBCAs and adverse effects in the exposed neonates. However, a retrospective cohort study, comparing pregnant women who had a GBCA MRI to pregnant women who did not have an MRI, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include a lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.
GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least 7 months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age.
Gadoteridol administered to rats at 10 mmol/kg/day (33 times the maximum recommended human dose of 0.03 mmol/kg or 6 times the human dose based on a mmol/m2 comparison) for 12 days during gestation doubled the incidence of postimplantation loss. When rats were administered 6.0 or 10.0 mmol/ kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. Gadoteridol increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/ kg/day (20 times the maximum recommended human dose or 7 times the human dose based on a mmol/m2comparison) for 13 days during gestation.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ProHance is administered to a nursing woman.
Safety and efficacy in pediatric patients under the age of 2 years have not been established. The safety and efficacy of > 0.1 mmol/kg; and sequential and/or repeat procedures have not been studied in pediatric patients [see Indications and Usage (1) and Dosage and Administration (2)].
Of the total number of 2673 adult subjects in clinical studies of ProHance, 22% were 65 and over. No overall differences in safety were observed between these elderly subjects and the younger subjects.
ProHance is known to be substantially excreted by the kidneys, and the risk of toxic reactions from ProHance may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function it may be useful to monitor renal function.
ProHance (gadoteridol) injection, a gadolinium-based paramagnetic MRI contrast agent, is a colorless to slightly yellow aqueous, sterile, nonpyrogenic injectable solution available in a 50 mL Pharmacy Bulk Package for intravenous administration.
Each mL of ProHance contains 279.3 mg gadoteridol, 0.23 mg calteridol calcium, 1.21 mg tromethamine and water for injection. ProHance contains no antimicrobial preservative.
Gadoteridol is the gadolinium complex of 10-(2-hydroxy-propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid with a molecular weight of 558.7, an empirical formula of C17H29N4O7Gd and has the following structural formula:
ProHance has a pH of 6.5 to 8.0. Pertinent physiochemical parameters are provided below:
Osmolality | 630 mOsmol/kg water at 37 °C |
Viscosity | 1.3 cP at 37 °C |
Density | 1.137 g/mL at 25 °C |
ProHance has an osmolality that is 2.2 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use.
Gadoteridol is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent.
In MRI, visualization of normal and pathologic brain tissue depends, in part, on variations in the radiofrequency signal intensity that occur with: 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoteridol decreases T1 relaxation times in the target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.
Gadoteridol affects proton relaxation times and consequently the MR signal. The enhancement of the signal intensity is effected by the dose and relaxivity of the gadoterate molecule. Consistently, for all gadolinium based contrast agents, the relaxivity of gadoteridol decreases with the increase of the magnetic field strength used in clinical MRI (0.2 –3.0T).
Disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadoteridol in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetics of gadoteridol in various lesions is not known.
The pharmacokinetics of intravenously administered gadoteridol in normal subjects conforms to a two-compartment open model with mean distribution and elimination half-lives (reported as mean ± SD) of about 0.20 ± 0.04 hours and 1.57 ± 0.08 hours, respectively. Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)].
Elimination
Gadoteridol is eliminated in the urine with 94.4 ± 4.8% (mean ±
SD) of the dose excreted within 24 hours post-injection. It is unknown
if biotransformation or decomposition of gadoteridol occur in vivo. The renal and plasma clearance rates (1.41 ± 0.33
mL/ min/kg and 1.50 ± 0.35 mL/ min/kg, respectively) of gadoteridol
are essentially identical, indicating no alteration in elimination
kinetics on passage through the kidneys and that the drug is essentially
cleared through the kidney. The volume of distribution (204 ± 58 mL/kg)
is equal to that of extracellular water, and clearance is similar
to that of substances which are subject to glomerular filtration.
It is unknown if protein binding of gadoteridol occurs in vivo.
No animal studies have been performed to evaluate the carcinogenic potential of gadoteridol or potential effects on fertility.
Gadoteridol did not demonstrate genotoxic activity in: bacterial reverse mutation assays using Salmonella typhimurium and Escherichia coli; a mouse lymphoma forward mutation assay; an in vitro cytogenetic assay measuring chromosomal aberration frequencies in Chinese hamster ovary cells; and an in vivo mouse micronucleus assay at intravenous doses up to 5.0 mmol/kg.
ProHance was evaluated in two blinded read trials in a total of 133 adults who had an indication for head and neck extracranial or extraspinal MRI. These 133 adults (74 men, 59 women) had a mean age of 53 with a range of 19 to 76 years. Of these patients, 85% were Caucasian, 13% Black, 2% Asian, and < 1% other. The results of the non-contrast and gadoteridol MRI scans were compared. In this database, approximately 75-82% of the scans were enhanced, 45-48% of the scans provided additional diagnostic information, and 8-25% of the diagnoses were changed. The relevance of the findings to disease sensitivity and specificity has not been fully evaluated.
ProHance was evaluated in a multicenter clinical trial of 103 pediatric patients who had an indication for a brain or spine MRI. These 103 pediatric patients, (54 boys and 49 girls) had a mean age of 8.7 years with an age range of 2 to 20 years. Of these 103 pediatric patients, 54 were between 2 and 12 years of age. Also, of these 103 pediatric patients, 74% were Caucasian, 11% Black, 12% Hispanic, 2% Asian, and 2% other. The results of the non-contrast and gadoteridol MRI scans were compared. ProHance was given in one single 0.1 mmol/kg dose. Repeat dosing was not studied. In this database, MRI enhancement was noted in approximately 60% of the scans and additional diagnostic information in 30-95% of the scans.
In early studies, ProHance was evaluated in two multicenter trials of 310 evaluable patients suspected of having neurological pathology. After the administration of ProHance 0.1 mmol/kg IV, the results were similar to those described above.
In another multicenter study of 49 evaluable adult patients with known intracranial tumor with high suspicion of having cerebral metastases, two doses of ProHance were administered. First ProHance 0.1 mmol/kg was injected followed 30 minutes later with 0.2 mmol/kg. In comparison to the 0.1 mmol/kg dose alone, the addition of the 0.2 mmol/kg dose improved visualization in 67% and improved border definition in 56% of patients. In comparison to non-contrast MRI, the number of lesions after 0.1 mmol/kg increased in 34% of patients. After ProHance 0.2 mmol/kg, this increased to 44%.
How Supplied
ProHance Multipack (gadoteridol) injection is a colorless
to slightly yellow solution containing 279.3 mg/mL of gadoteridol
in rubber stoppered vials. ProHance Multipack is supplied in boxes
of five 50 mL Pharmacy Bulk Packages (NDC: 0270-1111-70).
Storage and Handling
Store at 25°C (77° F). Excursions permitted to 15°C
to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect
from light. DO NOT FREEZE. Should freezing occur in the vial, ProHance
Multipack should be brought to room temperature before use. If allowed
to stand at room temperature for a minimum of 60 minutes, ProHance
Multipack (Gadoteridol) Injection should return to a clear, colorless
to slightly yellow solution. Before use, examine the product to assure
that all solids are redissolved and that the container and closure
have not been damaged. Should solids persist, discard vial.
Nephrogenic Systemic
Fibrosis
Instruct patients to inform their physician
if they:
GBCAs increase the risk for NSF in patients with impaired elimination of the drugs. To counsel patients at risk for NSF:
Instruct the patients to contact their physician if they develop signs or symptoms of NSF following ProHance administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness.
General
Precautions
Instruct patients to inform their physician
if they;
This product is covered by U.S. Patent No. 5,846,519
Manufactured for:
Bracco
Diagnostics Inc.
Monroe Twp., NJ 08831
This Medication Guide has been approved by the U.S. Food and Drug Administration | Issued: 04/2018 COEB503 |
MEDICATION GUIDE PROHANCE®(prō-ˈhan(t)s) (Gadoteridol) Injection for intravenous use |
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What is PROHANCE?
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What is the
most important information I should know about PROHANCE?
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Do not receive PROHANCE if you have had a severe allergic reaction to PROHANCE. | |
Before receiving
PROHANCE, tell your healthcare provider about all your medical conditions,
including if you:
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What are the
possible side effects of PROHANCE?
These are not all the possible side effects of PROHANCE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
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General information
about the safe and effective use of PROHANCE.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your healthcare provider for information about PROHANCE that is written for health professionals. |
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What are the
ingredients in PROHANCE?
Active ingredient: gadoteridol Inactive ingredients: calteridol calcium, tromethamine Manufactured by: BIPSO GmbH-78224 Singen (Germany) Manufactured for: Bracco Diagnostics Inc., Monroe Township, NJ 08831 US Patent No. 5,474,756; 5,846,519; and 6,143,274. For more information, go to www.imaging.bracco.com or call 1-800-257-5181. |
PROHANCE
gadoteridol injection, solution |
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Labeler - Bracco Diagnostics Inc (849234661) |
Registrant - Bracco Diagnostics Inc (849234661) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
BRACCO IMAGING SPA | 434384007 | API MANUFACTURE(0270-1111) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
BIPSO GmbH | 342104149 | MANUFACTURE(0270-1111) , ANALYSIS(0270-1111) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
---|---|---|---|
Lacor LS SE & Co. KG | 314929072 | ANALYSIS(0270-1111) |
Mark Image Registration | Serial | Company Trademark Application Date |
---|---|
PROHANCE 97264281 not registered Live/Pending |
JAMOCHA TECH PRIVATE LIMITED 2022-02-11 |
PROHANCE 97182054 not registered Live/Pending |
JAMOCHA TECH PRIVATE LIMITED 2021-12-21 |
PROHANCE 75572308 not registered Dead/Abandoned |
United Agri Products 1998-10-19 |
PROHANCE 74392033 1820972 Live/Registered |
BRACCO DIAGNOSTICS INC. 1993-05-19 |
PROHANCE 74222866 not registered Dead/Abandoned |
E. R. Squibb & Sons, Inc. 1991-11-14 |
PROHANCE 74032581 not registered Dead/Abandoned |
E. R. Squibb & Sons, Inc. 1990-02-26 |
PROHANCE 73809193 1582205 Live/Registered |
E. R. SQUIBB & SONS, INC. 1989-06-26 |