ProHance: Package Insert and Label Information

PROHANCE- gadoteridol injection, solution
Bracco Diagnostics Inc

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS

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.

  • The risk for NSF appears highest among patients with:
    • chronic, severe kidney disease (GFR less than 30 mL/min/1.73m2), or
    • acute kidney injury
  • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age greater than 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.
  • 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 from the body prior to re-administration [see Warnings and Precautions (5.1)].

1  INDICATIONS AND USAGE

1.1 MRI of the Central Nervous System (CNS)

ProHance is indicated for magnetic resonance imaging (MRI) in adults and pediatric patients including term neonates to visualize lesions with disrupted blood brain barrier and/or abnormal vascularity in the brain (intracranial lesions), spine and associated tissues.

1.2 MRI of Extracranial/Extraspinal Tissues

ProHance is indicated for MRI in adults to visualize lesions in the head and neck.

2  DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

The recommended dose for adult and pediatric patients, including term neonates, is 0.2 mL/kg (0.1 mmol/kg) administered as a rapid intravenous infusion (10 mL/min to 60 mL/min) or bolus (greater than 60 mL/min). Table 1 provides weight-adjusted recommended dose volumes.

Table 1: Recommended Volume of ProHance Injection by Body Weight
Body Weight (kg) Volume to be Administered (mL)
2.5 0.5
5 1
10 2
20 4
30 6
40 8
50 10
60 12
70 14
80 16
90 18
100 20
110 22
120 24
130 26
140 28
150 30

MRI of the CNS in Adults:

  • A supplementary dose of 0.4 mL/kg (0.2 mmol/kg) may be given up to 30 minutes after the first dose in adult patients with normal renal function suspected of having poorly visualized CNS lesions, in the presence of negative or equivocal scans
  • The safety and efficacy of supplementary dosing have not been established in pediatric patients

2.2 Administration

  • Visually inspect ProHance for particulate matter and discoloration prior to use
  • Do not administer the solution if it is discolored or particulate matter is present
  • Concurrent medications or parenteral nutrition should not be physically mixed with contrast agents and should not be administered in the same intravenous line because of the potential for chemical incompatibility
  • Inject at least a 5 mL normal saline flush immediately after ProHance injection to ensure complete administration
  • Imaging procedures should be completed within 1 hour

2.3 Directions for Proper Use of Pharmacy Bulk Package

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:

  • Use of this product is restricted to a suitable work area, such as a laminar flow hood, utilizing aseptic technique
  • Prior to entering the vial, remove the seal and cleanse the rubber closure with a suitable antiseptic agent
  • The container closure may be penetrated only one time, utilizing a suitable transfer device or dispensing set that allows measured dispensing of the contents
  • Once the pharmacy bulk package is punctured, it should not be removed from the aseptic work area during the entire period of use
  • Withdrawal of container contents should be accomplished without delay. A maximum time of 8 hours from initial closure entry is permitted to complete fluid transfer operations
  • Any unused contents must be discarded by 8 hours after initial puncture of the bulk package
  • Once drawn into syringe, administer transferred agent promptly for single-dose administration

3  DOSAGE FORMS AND STRENGTHS

ProHance Multipack is supplied as a sterile, nonpyrogenic, and colorless to slightly yellow solution available in 50 mL pharmacy bulk packages for intravenous administration. Each mL contains 279.3 mg (0.5 mmol/mL) of gadoteridol for injection.

4  CONTRAINDICATIONS

ProHance is contraindicated in patients with known allergic or hypersensitivity reactions to ProHance [see Warnings and Precautions (5.2)].

5  WARNINGS AND PRECAUTIONS

5.1 Nephrogenic Systemic Fibrosis (NSF)

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 MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR less than 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 (for example, age greater than 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 Page 4 elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see Clinical Pharmacology (12)].

5.2 Hypersensitivity Reactions

Anaphylactic and anaphylactoid reactions have been reported, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of ProHance administration and resolved with prompt emergency treatment.

Prior to ProHance administration, ensure the availability of trained personnel and medications to treat hypersensitivity reactions. Consider the risk for hypersensitivity reactions, especially in patients with a history of hypersensitivity reactions or a history of asthma or other allergic disorders. If such a reaction occurs, stop ProHance and immediately begin appropriate therapy. Observe patients for signs and symptoms of a hypersensitivity reaction during and for up to 2 hours after ProHance administration.

5.3 Gadolinium Retention

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.

5.4 Acute Kidney Injury (AKI)

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.

6  ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:

  • Nephrogenic systemic fibrosis [see Boxed Warning and Warnings and Precautions (5.1)]
  • Hypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

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 3174 subjects (including 2896 adults and 278 pediatric subjects ages 0 to 17 years) exposed to ProHance. Approximately 48% of the subjects were men and ethnic distribution was 78% Caucasian, 6% Black, 3% Hispanic, 6% Asian, and 2% other. In 5% of the subjects, race was not reported. Average age was 47 years (range from 1 day to 91 years) and the exposure ranged from 0.03 to 0.3 mmol/kg.

Overall, approximately 5.8% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after ProHance administration.

Table 2 lists adverse reactions that occurred in ≥ 0.4% subjects who received ProHance.
Table 2: More frequent adverse reactions in clinical trials
Reaction Rate (%)N = 3174
Nausea 1.4%
Dysgeusia 0.9%
Headache 0.7%
Dizziness 0.4%
Urticaria 0.4%
The following additional adverse events occurred in fewer than 0.4% of the subjects:
General disorders and administration site conditions: Asthenia; chest discomfort, facial edema, feeling hot, injection site coldness, injection site erythema, injection site pain, injection site warmth, pain, pyrexia
Cardiac: Angina pectoris, palpitations, atrio-ventricular block first degree
Ear and labyrinth disorders: Ear discomfort, tinnitus
Eye disorders: Eye pruritis, lacrimation increased
Gastrointestinal disorders: Abdominal discomfort, abdominal pain, diarrhea, dry mouth, gingival pain, oral pruritis, swollen tongue, vomiting
Infections and infestations: Gingivitis, rhinitis
Investigations: Alanine aminotransferase increased, aspartate aminotransferase increased, blood chloride increased, blood pressure immeasurable, blood urea decreased, hemoglobin decreased, heart rate increased
Metabolism and nutrition disorders: Decreased appetite, hypoglycemia
Musculoskeletal and connective tissue disorders: Back pain, musculoskeletal stiffness
Nervous system disorders: Formication, hypoesthesia, hypokinesia, lethargy, loss of consciousness, migraine, paresthesia, presyncope, seizure, syncope, taste disorder
Psychiatric disorders: Anxiety, mental status changes
Respiratory, thoracic and mediastinal disorders: Cough, dry throat, dyspnea, nasal discomfort, throat irritation
Skin and subcutaneous tissue disorders: Hyperhidrosis, pruritis, rash, rash morbilliform
Vascular disorders: Flushing, hypotension, peripheral coldness, vascular rupture, vasodilatation, vasospasm

6.2 Post-marketing Experience

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.

* Cases of acute renal failure have been reported in patients with pre-existing severe renal impairment.
The following adverse drug reactions have also been reported:
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.
Cardiac disorders: Cardiac arrest, bradycardia, hypertension
Immune system disorders: Hypersensitivity/anaphylactoid reactions including cardiac arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, cough, sneezing, conjunctivitis, eyelid edema, hyperhidrosis, urticaria [see Warnings and Precautions (5.2)].
Nervous system disorders: Coma, loss of consciousness, vasovagal reaction, tremor
Respiratory, thoracic and mediastinal disorders: Respiratory arrest, pulmonary edema
Renal and urinary system disorders: Acute renal failure *
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