GADOPICLENOL: 148 Adverse Event Reports & Safety Profile

ELUCIREM is a gadolinium-based contrast agent, which contains gadopiclenol, a paramagnetic macrocyclic non-ionic complex of gadolinium. The chemical name for gadopiclenol is rac -[(2R,2'Ξ,2''Ξ)-2,2',2''-(3,6,9-triaza-κ 3 N 3 ,N 6 ,N 9 -1(2,6)-pyridina-κN 1 -cyclodecaphane-3,6,9-triyl)tris(5-{[(2Ξ)-2,3-dihydroxypropyl]amino}-5-oxopentanoato-κ 3 O 1 ,O 1 ',O 1 '')(3−)]gadolinium with a molecular weight of 970.11 g/mol and a molecular formula of 970.11 g/mol and a molecular formula of C 35 H 54 GdN 7 O 15 ELUCIREM is a sterile, nonpyrogenic, clear, colorless to yellow aqueous solution for intravenous use. Each mL contains 485.1 mg of gadopiclenol (equivalent to 0.5 mmol of gadopiclenol and 78.6 mg of gadolinium) and the following inactive ingredients: 0.404 mg tetraxetan, 1.211 mg trometamol, hydrochloric acid and/or sodium hydroxide (for pH adjustment, if needed), and water for injection. The main physicochemical properties of ELUCIREM are provided in Table 2.

Table

2. Physicochemical properties of ELUCIREM Parameter Value Density at 20°C 1.211 g/cm 3 Mean viscosity at 20°C 12.6 mPa.s Mean viscosity at 37°C 7.6 mPa.s Osmolality at 37°C 850 mOsm/kg water pH 7.0 – 7.8 structure

AND USAGE ELUCIREM TM is indicated in adult and pediatric patients aged 2 years and older for use with magnetic resonance imaging (MRI) to detect and visualize lesions with abnormal vascularity in: the central nervous system (brain, spine, and associated tissues), the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system). ELUCIREM is a gadolinium-based contrast agent indicated in adult and pediatric patients aged 2 years and older for use with magnetic resonance imaging (MRI) to detect and visualize lesions with abnormal vascularity in: the central nervous system (brain, spine, and associated tissues), the body (head and neck, thorax, abdomen, pelvis, and musculoskeletal system). (1)

AND ADMINISTRATION The recommended dose for adult and pediatric patients aged 2 years and older is 0.05 mmol/kg actual body weight (equivalent to 0.1 mL/kg) administered intravenously at approximately 2 mL/sec. ( 2.1 )

2.1 Recommended Dosage The recommended dose of ELUCIREM for adult and pediatric patients aged 2 years and older is 0.05 mmol/kg actual body weight (equivalent to 0.1 mL/kg) administered intravenously at approximately 2 mL/sec.

2.2 Administration and Imaging Instructions Use aseptic technique for all handling and administration of ELUCIREM. Visually inspect ELUCIREM for particulate matter and discoloration prior to administration. Do not use the solution if any particulate matter is present or the solution is discolored. Do not mix with other medications because of the potential for chemical incompatibility. Prime intravenous line before use. Administer ELUCIREM as an intravenous bolus injection, manually or by compatible power injector. The recommended injection rate is approximately 2 mL/second. Flush the intravenous line with 0.9% Sodium Chloride Injection, USP after the administration of ELUCIREM. Contrast MRI can begin immediately following the injection of ELUCIREM.

2.3 Directions for Use of Single-Dose Vial and Pre-filled Syringe Vial Do not pierce the rubber stopper more than once. Aseptically draw up ELUCIREM into a disposable syringe and use immediately. If solidification occurs in the vial because of exposure to the cold, bring the vial of ELUCIREM to room temperature before use and inspect that the solution is clear, colorless to yellow without any particulate matter and discoloration. Discard any unused portion. Pre-filled syringe Remove the tip cap of the syringe, screw the plunger rod and use immediately. All luer connections should be gently hand tightened without over tightening, to ensure secure connections and to prevent damage to the device. Pre-filled syringes must not be frozen. Frozen pre-filled syringes of ELUCIREM should be discarded. Discard any unused portion.

2.4 Directions for Use of Pharmacy Bulk Package Do not use the Pharmacy Bulk Package for direct infusion. Perform the transfer of ELUCIREM from the Pharmacy Bulk Package in an aseptic work area, such as laminar flow hood, using aseptic technique and suitable transfer device for filling empty syringes. Penetrate the closure only one time. Once the container closure is punctured, do not remove the Pharmacy Bulk Package from the aseptic work area.

The Pharmacy Bulk

Package is used with an appropriate transfer device for filling empty sterile syringes. Use each individual dose of ELUCIREM promptly following withdrawal from the Pharmacy Bulk Package. Use the contents of the Pharmacy Bulk Package within 24 hours at room temperature after initial puncture. If solidification occurs in the vial because of exposure to the cold, bring the vial of ELUCIREM to room temperature before use and inspect that the solution is clear, colorless to yellow without any particulate matter and discoloration.

2.5 Directions for Use of Imaging Bulk Package ELUCIREM Imaging Bulk Package (IBP) is for intravenous use and not for direct infusion. The IBP is a container of a sterile preparation for parenteral use that contains multiple single doses of ELUCIREM for multiple patients for use with an automated contrast injection system, contrast management system, or contrast media transfer set approved or cleared for use with this contrast agent in this IBP. See drug and device labeling for information on devices indicated for use with this IBP and techniques to help assure safe use. The ELUCIREM IBP is to be used only in a room designated to perform radiological procedures that involve administration of a contrast agent. Utilize aseptic technique for penetrating the container closure of the IBP and transferring ELUCIREM. Penetrate the container closure only one time with a suitable sterile component of the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) approved or cleared for use with this IBP. During the entire period of use, ensure that the contents of the ELUCIREM IBP container are in continuous contact with the automated contrast injector system, contrast management system or contrast media transfer set. Do not remove the dispensing set from the IBP container closure to ensure that the protection of the contrast media against any possible contamination. Once the ELUCIREM IBP container is punctured, do not remove it from the work area. Store the ELUCIREM IBP at 25° C (77° F); excursions permitted from 15°C to 30°C (59°F to 86°F) <span class="opacity-50 text-xs">[see USP Controlled Room Temperature]</span>. A maximum use time from initial puncture is 24 hours. Discard any unused ELUCIREM 24 hours after initial puncture of the IBP. After the container closure is punctured, if the integrity of IBP and the delivery system cannot be assured through direct continuous supervision, the IBP and all associated disposables for the automated contrast injection system, contrast management system, or contrast media transfer set should be discarded. If solidification occurs in the IBP because of exposure to the cold, bring the IBP container of ELUCIREM to room temperature, before use and inspect that the solution is clear, colorless to yellow without any particulate matter and discoloration.

ELUCIREM is contraindicated in patients with history of hypersensitivity reactions to ELUCIREM. History of hypersensitivity reactions to ELUCIREM ( 4 )

REACTIONS The following clinically significant adverse reactions are discussed elsewhere in labeling: Nephrogenic Systemic Fibrosis [see Warnings and Precautions ( 5.2 )]

Hypersensitivity

Reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] Most common adverse reactions (incidence >0.2%) in patients who received ELUCIREM are injection site pain, headache, nausea, injection site warmth and coldness, dizziness, and localized swelling. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS contact GUERBET LLC at 1-877-729-6679 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 clinical practice. The safety of ELUCIREM was evaluated in 1,047 patients who received ELUCIREM at doses ranging from 0.025 mmol/kg (one half the recommended dose) to 0.3 mmol/kg (six times the recommended dose). A total of 708 patients received the recommended dose of 0.05 mmol/kg. Among patients who received the recommended dose, the average age was 51 years (range 2 years to 88 years) and 56% were female. The ethnic distribution was 79% White, 10% Asian, 7% American Indian or Alaska native, 2% Black, and 2% patients of other or unspecified ethnic groups. Overall, approximately 4.7% of subjects receiving the labeled dose reported one or more adverse reactions.

Table

1 lists adverse reactions that occurred in > 0.2% of patients who received 0.05 mmol/kg ELUCIREM.

Table

1.

Adverse Reactions

Reported in > 0.2% of Patients Receiving ELUCIREM in Clinical Trials Adverse Reaction ELUCIREM 0.05 mmol/kg (n=708) (%) Injection site pain

0.7 Headache

0.7 Nausea

0.4 Injection site warmth

0.4 Injection site coldness

0.3 Dizziness

0.3 Localized swelling

0.3 Adverse reactions that occurred with a frequency ≤ 0.2% in patients who received 0.05 mmol/kg ELUCIREM included: maculopapular rash, vomiting, worsened renal impairment, feeling hot, pyrexia, oral paresthesia, dysgeusia, diarrhea, pruritus, allergic dermatitis, erythema, injection site paresthesia, Cystatin C increase, and blood creatinine increase.

Adverse

Reactions in Pediatric Patients One study with a single dose of ELUCIREM (0.05 mmol/kg) was conducted in 80 pediatric patients aged 2 years to 17 years, including 60 patients who underwent a central nervous system (CNS) MRI and 20 patients who underwent a body MRI. One adverse reaction (maculopapular rash of moderate severity) in one patient (1.3%) was reported in the CNS cohort.

6.2 Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of ELUCIREM or other GBCAs. 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.

Gastrointestinal

Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration. Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edema.

6.2 Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of ELUCIREM or other GBCAs. 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.

Gastrointestinal

Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration. Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edema.

AND PRECAUTIONS Hypersensitivity Reactions: Serious hypersensitivity reactions have occurred with GBCAs. Monitor patients closely for need of emergency cardiorespiratory support. ( 5.3 )

Gadolinium

Retention: 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 ELUCIREM have not been established with intrathecal use. ELUCIREM 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 ELUCIREM 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 &lt;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 ELUCIREM administration to Guerbet LLC (1-877-729-6679) 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 &gt;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 ELUCIREM 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span>. The usefulness of hemodialysis in the prevention of NSF is unknown.

5.3 Hypersensitivity Reactions With GBCAs, serious hypersensitivity reactions have occurred. In most cases, initial symptoms occurred within minutes of GBCA administration and resolved with prompt emergency treatment. Before ELUCIREM administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to ELUCIREM. ELUCIREM is contraindicated in patients with history of hypersensitivity reactions to ELUCIREM <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Administer ELUCIREM only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. During and following ELUCIREM administration, observe patients for signs and symptoms of hypersensitivity reactions.

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, gadolinium retention varies among the linear agents with gadodiamide causing greater retention than other linear agents such as gadoxetate disodium and gadobenate dimeglumine. Retention is lowest and similar among the macrocyclic GBCAs such as gadoterate meglumine, gadobutrol, gadoteridol, and gadopiclenol. 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. 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. Do not exceed the recommended dose.

5.6 Extravasation and Injection Site Reactions Injection site reactions such as injection site pain have been reported in the clinical studies with ELUCIREM <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Extravasation during ELUCIREM administration may result in tissue irritation <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.2 )]</span> . Ensure catheter and venous patency before the injection of ELUCIREM.

5.7 Interference with Visualization of Lesions Visible with Non-Contrast MRI As with any GBCA, ELUCIREM may impair the visualization of lesions seen on non-contrast MRI. Therefore, caution should be exercised when Gadopiclenol MRI scans are interpreted without a companion non-contrast MRI scan.

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 ELUCIREM have not been established with intrathecal use. ELUCIREM 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 ELUCIREM 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 &lt;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 ELUCIREM administration to Guerbet LLC (1-877-729-6679) 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 &gt;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 ELUCIREM 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span>. The usefulness of hemodialysis in the prevention of NSF is unknown.