GADOTERIDOL: 788 Adverse Event Reports & Safety Profile

Gadoteridol Injection, USP, a gadolinium-based paramagnetic MRI contrast agent, is a colorless to slightly yellow aqueous, sterile, non-pyrogenic injectable solution for intravenous use. Each mL contains 279.3 mg (0.5 mmol/mL) gadoteridol, 0.23 mg calteridol calcium, 1.21 mg tromethamine and water for injection; pH adjusted with hydrochloric acid and/or sodium hydroxide.

Gadoteridol

Injection, USP 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 C 17 H 29 N 4 O 7 Gd and has the following structural formula: Gadoteridol Injection, USP 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 Gadoteridol Injection, USP has an osmolality that is 2.2 times that of plasma (285 mOsmol/kg water) and is hypertonic under conditions of use. chemical structure

AND USAGE Gadoteridol Injection is a gadolinium-based contrast agent indicated for magnetic resonance imaging (MRI) to visualize: lesions with disrupted blood brain barrier and/or abnormal vascularity in the brain (intracranial lesions), spine and associated tissues in adults and pediatric patients, including term neonates (1.1 ) lesions in the head and neck in adults ( 1.2 )

1.1 MRI of the Central Nervous System (CNS)

Gadoteridol

Injection 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 Head and Neck Gadoteridol Injection is indicated for MRI in adults to visualize lesions in the head and neck.

AND ADMINISTRATION Dispense multiple single doses into separate sterile syringes for intravenous administration ( 2.3 ) Recommended dose in adult and pediatric patients is 0.2 mL/kg (0.1 mmol/kg) body weight administered as rapid intravenous infusion or bolus ( 2.1 ) Follow injection with a saline flush of at least 5 mL normal saline ( 2.1 )

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

Gadoteridol Injection is contraindicated in patients with known allergic or hypersensitivity reactions to Gadoteridol Injection [see Warnings and Precautions ( 5.3 )] . Allergic or hypersensitivity reactions to Gadoteridol Injection ( 4 )

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 ( 5.2 )] . Hypersensitivity reactions [see Contraindications ( 4 ) and Warnings and Precautions (5.3 )] . The most commonly reported adverse reactions are nausea and taste perversion with an incidence ≥ 0.9% ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 Gadoteridol Injection.

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 Gadoteridol Injection administration.

Table

2 lists adverse reactions that occurred in ≥ 0.4% subjects who received Gadoteridol Injection.

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 disorder: 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 Gadoteridol Injection 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. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span> . These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems. Cardiac disorders: Cardiac arrest, bradycardia, hypertension Gastrointestinal disorders: Acute pancreatitis with onset within 48 hours after GBCA administration Immune system disorders: Hypersensitivity/anaphylactoid reactions including cardiac arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, cough, sneezing, conjunctivitis, eyelid edema, hyperhidrosis, urticaria <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> . Nervous system disorders: Coma, loss of consciousness, vasovagal reaction, tremor Respiratory, thoracic and mediastinal disorders: Respiratory arrest, acute respiratory distress syndrome, pulmonary edema Renal and urinary system disorders: Acute renal failure Cases of acute renal failure have been reported in patients with pre-existing severe renal impairment.

AND PRECAUTIONS Hypersensitivity: anaphylactic/anaphylactoid reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe reactions including shock can occur. Monitor patients closely for need of emergency cardiorespiratory support ( 5.3 ) Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.4 )

5.1 Risk Associated with Intrathecal Use Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of Gadoteridol injection have not been established with intrathecal use. Gadoteridol injection is not approved for intrathecal use <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ) ]</span>.

5.2 Nephrogenic Systemic Fibrosis GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of Gadoteridol injection 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/1.73 m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73 m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73 m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following gadoteridol administration to Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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 gadoteridol 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12 )]</span>.

5.3 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 gadoteridol administration and resolved with prompt emergency treatment. Prior to gadoteridol 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 gadoteridol and immediately begin appropriate therapy. Observe patients for signs and symptoms of a hypersensitivity reaction during and for up to 2 hours after gadoteridol administration.

5.4 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), 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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.

5.5 Acute Kidney Injury 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.