NDC 0407-2943 Clariscan

Gadoterate Meglumine

NDC Product Code 0407-2943

NDC 0407-2943-01

Package Description: 10 VIAL, GLASS in 1 BOX > 10 mL in 1 VIAL, GLASS

NDC 0407-2943-02

Package Description: 10 VIAL, GLASS in 1 BOX > 15 mL in 1 VIAL, GLASS

NDC 0407-2943-05

Package Description: 10 VIAL, GLASS in 1 BOX > 20 mL in 1 VIAL, GLASS

NDC Product Information

Clariscan with NDC 0407-2943 is a a human prescription drug product labeled by Ge Healthcare. The generic name of Clariscan is gadoterate meglumine. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: Ge Healthcare

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Clariscan Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • GADOTERATE MEGLUMINE 376.9 mg/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • WATER (UNII: 059QF0KO0R)
  • TETRAXETAN (UNII: 1HTE449DGZ)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.
  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Gadolinium-based Contrast Agent - [EPC] (Established Pharmacologic Class)
  • Magnetic Resonance Contrast Activity - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Ge Healthcare
Labeler Code: 0407
FDA Application Number: ANDA210016 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 11-01-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Clariscan Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: 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 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 fibrosis affecting the skin, muscle, and internal organs.The risk for NSF appears highest among patients with:-Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2), 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 > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.1).For patients at highest risk for NSF, do not exceed the recommended Clariscan dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)].

1 Indications And Usage

Clariscan is a gadolinium-based contrast agent indicated for intravenous use with magnetic resonance imaging (MRI) in brain (intracranial), spine and associated tissues in adult and pediatric patients to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity. Additional pediatric use information is approved for Guerbet, LLC's Dotarem (gadoterate meglumine injection). However, due to Guerbet LLC's marketing exclusivity, this drug product is not labeled with that pediatric information.

2.1 Dosing Guidelines

For adult and pediatric patients, the recommended dose of Clariscan is 0.2 mL/kg (0.1 mmol/kg) body weight administered as an intravenous bolus injection, manually or by power injector, at a flow rate of approximately 2 mL/second for adults and 1-2 mL/second for pediatric patients. Table 1 provides weight-adjusted dose volumes. Table 1: Volumes of Clariscan Injection by Body WeightBody WeightVolumePounds (lb)Kilograms (kg)Milliliters (mL)2210244204663068840811050101326012154701417680161989018220100202421102226412024286130263081402833015030To ensure complete injection of Clariscan, the injection may be followed by normal saline flush. Contrast MRI can begin immediately following Clariscan injection.Additional pediatric use information is approved for Guerbet, LLC's Dotarem (gadoterate meglumine injection). However, due to Guerbet LLC's marketing exclusivity, this drug product is not labeled with that pediatric information.

2.2 Drug Handling

  • Visually inspect Clariscan for particulate matter prior to administration. Do not use the solution if particulate matter is present or if the container appears damaged. Clariscan should be a clear, colorless to yellow solution.Do not mix with other drugs or parenteral nutrition.Discard any unused portions of the drug.

Other

Directions for Use of Clariscan (gadoterate meglumine) Injection

Glass vial:Aseptically draw up the contrast medium into a disposable syringe and use immediately.

Adverse Reactions in Pediatric PatientsDuring clinical trials, 140 pediatric patients (7 aged < 24 months, 33 aged 2 - 5 years, 57 aged 6 - 11 years and 43 aged 12 – 17 years) received gadoterate meglumine. Overall, 6 pediatric patients (4.3%) reported at least one adverse reaction following gadoterate meglumine administration. The most frequently reported adverse reaction was headache (1.1%). Most adverse events were mild in intensity and transient in nature.Additional pediatric use information is approved for Guerbet, LLC's Dotarem (gadoterate meglumine injection). However, due to Guerbet LLC's marketing exclusivity, this drug product is not labeled with that pediatric information.

Risk SummaryGBCAs cross the human 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 (see Data). In animal reproduction studies, there were no adverse developmental effects observed in rats or rabbits with intravenous administration of gadoterate meglumine during organogenesis at doses up to 16 and 10 times, respectively, the recommended human dose (see Data). Because of the potential risks of gadolinium to the fetus, use Clariscan only if imaging is essential during pregnancy and cannot be delayed. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human DataContrast enhancement is visualized in the 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 material 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.

Animal Data

Gadolinium RetentionGBCAs 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.

Reproductive ToxicologyGadoterate meglumine was administered in intravenous doses of 0, 2, 4 and 10 mmol/kg/day [3, 7 and 16 times the recommended human dose (RHD) based on body surface area (BSA)] to female rats for 14 days before mating, throughout the mating period and until gestation day (GD) 17. Pregnant rabbits were administered gadoterate meglumine in intravenous doses levels of 0, 1, 3 and 7 mmol/kg/day (3, 10 and 23 times the RHD based on BSA) from GD6 to GD19. No effects on embryo-fetal development were observed at doses up to 10 mmol/kg/day in rats or 3 mmol/kg/day in rabbits. Maternal toxicity was observed in rats at 10 mmol/kg/day and in rabbits at 7 mmol/kg/day. This maternal toxicity was characterized in rats by a slightly lower litter size and gravid uterus weight compared to the control group, and in rabbits by a reduction in body weight and food consumption.

Risk SummaryThere are no data on the presence of gadoterate in human milk, the effects on the breastfed infant, or the effects on milk production. However, published lactation data on other GBCAs indicate that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk. Additionally, there is limited GBCA gastrointestinal absorption in the breastfed infant. Gadoterate is present in goat milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Clariscan and any potential adverse effects on the breastfed infant from Clariscan or from the underlying maternal condition.

DataNonclinical data demonstrate that gadoterate is detected in goat milk in amounts < 0.1% of the dose intravenously administered. Furthermore, in rats, absorption of gadoterate via the gastrointestinal tract is poor (1.2% of the administered dose was absorbed and eliminated in urine).

Juvenile Animal DataSingle and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients.Additional pediatric use information is approved for Guerbet, LLC's Dotarem (gadoterate meglumine injection). However, due to Guerbet LLC's marketing exclusivity, this drug product is not labeled with that pediatric information.

DistributionThe volume of distribution at steady state of total gadolinium in normal subjects is 179 ± 26 and 211 ± 35 mL/kg in female and male subjects respectively, roughly equivalent to that of extracellular water. Gadoterate does not undergo protein binding in vitro. The extent of blood cell partitioning of gadoterate is not known.Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)].

MetabolismGadoterate is not known to be metabolized.

EliminationFollowing a 0.1 mmol/kg dose of gadoterate meglumine, total gadolinium is excreted primarily in the urine with 72.9 ± 17.0% and 85.4 ± 9.7% (mean ± SD) eliminated within 48 hours, in female and male subjects, respectively. Similar values were achieved after a cumulative dose of 0.3 mmol/kg (0.1 + 0.2 mmol/kg, 20 minutes later), with 85.5 ± 13.2% and 92.0 ± 12.0% recovered in urine within 48 hours in female and male subjects, respectively.In healthy subjects, the renal and total clearance rates of total gadolinium are comparable (1.27 ± 0.32 and 1.74 ± 0.12 mL/min/kg in females; and 1.40 ± 0.31 and 1.64 ± 0.35 mL/min/kg in males, respectively) indicating that the drug is primarily cleared through the kidneys. Within the studied dose range (0.1 to 0.3 mmol/kg), the kinetics of total gadolinium appear to be linear.

Special Populations

Renal ImpairmentA single intravenous dose of 0.1 mmol/kg of gadoterate meglumine was administered to 8 patients (5 men and 3 women) with impaired renal function (mean serum creatinine of 498 ± 98 µmol/L in the 10-30 mL/min creatinine clearance group and 192 ± 62 µmol/L in the 30-60 mL/min creatinine clearance group). Renal impairment delayed the elimination of total gadolinium. Total clearance decreased as a function of the degree of renal impairment. The distribution volume was unaffected by the severity of renal impairment (Table 5). No changes in renal function test parameters were observed after gadoterate meglumine injection. The mean cumulative urinary excretion of total gadolinium was approximately 76.9 ± 4.5% in 48 hours in patients with moderate renal impairment, 68.4 ± 3.5% in 72 hours in patients with severe renal impairment and 93.3 ± 4.7% in 24 hours for subjects with normal renal function.Table 5: Pharmacokinetic Profile of Total Gadolinium in Normal and Renally Impaired PatientsPopulationElimination Half-life(hr)Plasma Clearance(L/h/kg)Distribution Volume(L/kg)Healthy volunteers1.6 ± 0.20.10 ± 0.010.246 ± 0.03Patients with moderate renal impairment5.1 ± 1.00.036 ± 0.0070.236 ± 0.01Patients with severe renal impairment13.9 ± 1.20.012 ± 0.0010.234 ± 0.01Gadoterate was shown to be dialyzable after an IV injection of gadoterate meglumine in 10 patients with end-stage renal failure who required hemodialysis treatment. Gd serum concentration decreased over time by 88%, 93% and 97% at 0.5 hours, 1.5 hours, and 4 hours after start of dialysis, respectively. A second and third hemodialysis session further removed Gd. After the third dialysis, Gd serum concentration decreased by 99.7%.

Pediatric PopulationAdditional pediatric use information is approved for Guerbet, LLC's Dotarem (gadoterate meglumine injection). However, due to Guerbet LLC's marketing exclusivity, this drug product is not labeled with that pediatric information.

CNS ImagingEfficacy and safety of gadoterate meglumine were evaluated in a multi-center clinical trial (Study A) that enrolled 364 adult and 38 pediatric patients (aged ≥ 2 years) with known or suspected CNS lesions. Adults were randomized 2 to 1 to receive either gadoterate meglumine or gadopentetate dimeglumine, each administered at a dose of 0.1 mmol/kg. All pediatric patients received gadoterate meglumine, also at a dose of 0.1 mmol/kg. In the trial, patients first underwent a baseline (pre-contrast) MRI examination followed by the assigned GBCA administration and a post-contrast MR examination. The images (pre-contrast, post-contrast and "paired pre- and post-contrast") were interpreted by three independent off-site readers blinded to clinical information. The primary efficacy analysis compared three patient-level visualization scores (paired images) to baseline MRI (pre-contrast images) for adults who received gadoterate meglumine. The three primary visualization components were: contrast enhancement, border delineation and internal morphology. For each of these components there was a pre-defined scoring scale. Lesion counting (up to five per patient) was also reflected within each component's patient-level visualization score.Among the adult patients, 245 received gadoterate meglumine and their data comprised the primary efficacy population. There were 114 (47%) men and 131 (53%) women with a mean age of 53 years (range 18 to 85 years), the racial and ethnic representations were 84% Caucasian, 11% Asian, 4% Black, and 1% other.Table 6 displays a comparison of paired images (pre-and post-contrast) to pre-contrast images with respect to the proportion of patients who had paired image scores that were greater "better", or same/worse "not better" than the pre- contrast scores and with respect to the difference in the mean patient level visualization score. Across the three readers 56% to 94% of patients had improved lesion visualization for paired images compared to pre-contrast images. Gadoterate meglumine provided a statistically significant improvement for all three primary visualization components. More lesions were seen on the paired images than the pre-contrast images.Table 6: Study A. Improvement in Patient-level Lesion Visualization Scores, Paired versus Pre-contrast ImagesBetter: number of patients with paired (pre-and post-contrast) score greater than the pre-contrast scoreNot better: number of patients with paired score same as or worse than the pre-contrast scoreMissing: number of patients with missing scoreLesion ScoresReader 1Reader 2Reader 3n = 231n = 232n = 237Border Delineation  Better195 (84%)215 (93%)132 (56%)  Not Better28 (12%)7 (3%)88 (37%)  Missing8 (4%)10 (4%)17 (7%)Difference in Mean Score Difference = paired mean score minus pre-contrast mean score2.26Statistically significant improvement by paired t-test2.891.17Internal Morphology  Better218 (94%)214 (93%)187 (79%)  Not Better5 (2%)8 (3%)33 (14%)  Missing8 (4%)10 (4%)17 (7%)Difference in Mean Score 2.742.751.54Contrast Enhancement  Better208 (90%)216 (93%)208 (88%)  Not Better15 (6%)6 (3%)12 (5%)  Missing8 (4%)10 (4%)17 (7%)Difference in Mean Score 3.093.692.92In secondary analyses, post-contrast images were improved in comparison to pre-contrast images. Gadoterate meglumine lesion visualization scores were similar to those for gadopentetate dimeglumine. Gadoterate meglumine imaging results in the pediatric patients were also similar to those seen in adults.In a second clinical trial (Study B), MR images were reread from 150 adult patients with known CNS lesions who had participated in a previously conducted clinical trial. Gadoterate meglumine administration and image interpretation was performed in the same manner as in Study A. Similar to Study A, this trial also demonstrated improved lesion visualization with gadoterate meglumine.Additional pediatric use information is approved for Guerbet, LLC's Dotarem (gadoterate meglumine injection). However, due to Guerbet LLC's marketing exclusivity, this drug product is not labeled with that pediatric information.

Distributed by GE Healthcare Inc. Marlborough, MA 01752 U.S.A.Product of Norwegian Origin.GE and the GE Monogram are trademarks of General Electric Company.1197884 BK

3 Dosage Forms And Strengths

Clariscan 0.5 mmol/mL is a sterile, clear, colorless to yellow, aqueous solution for intravenous injection containing 376.9 mg/mL gadoterate meglumine and is available in vials.

4 Contraindications

History of clinically important hypersensitivity reactions to Clariscan [see Warnings and Precautions (5.2)].

5.1 Nephrogenic Systemic Fibrosis

Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (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 < 30 mL/min/1.73 m2) 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 m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73 m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle, and internal organs. Report any diagnosis of NSF following Clariscan administration to GE Healthcare at (1-800-654-0118) or FDA at (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.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 Clariscan 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 Dosage and Administration (2) and Clinical Pharmacology (12)].

5.2 Hypersensitivity Reactions

  • Anaphylactic and anaphylactoid reactions have been reported with gadoterate meglumine, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of gadoterate meglumine administration and resolved with prompt emergency treatment [see Adverse Reactions (6)].Before Clariscan 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 Clariscan.Administer Clariscan 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 Clariscan administration, observe patients for signs and symptoms of hypersensitivity reactions.

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, gadolinium 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 [Clariscan (gadoterate meglumine), 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

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. Screen all patients for renal impairment by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction.

5.5 Extravasation And Injection Site Reactions

Ensure catheter and venous patency before the injection of Clariscan. Extravasation into tissues during Clariscan administration may result in tissue irritation [see Nonclinical Toxicology (13.2)].

6 Adverse Reactions

GBCAs have been associated with a risk for NSF [see Warnings and Precautions (5.1)]. Confirmed diagnosis of NSF has not been reported in patients with a clear history of exposure to gadoterate meglumine alone.Hypersensitivity reactions and acute kidney injury are described in other sections of the labeling [see Warnings and Precautions (5.2) and (5.3)].

6.1 Clinical Studies 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 data described below reflect gadoterate meglumine exposure in 2822 patients, representing 2682 adults and 140 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded, the ethnic distribution was 74% Caucasian, 12% Asian, 4% Black, and 10% others. The average age was 53 years (range from < 1 week to 97 years).Overall, 4% of patients reported at least one adverse reaction, primarily occurring immediately or within 24 hours following gadoterate meglumine administration. Most adverse reactions were mild or moderate in intensity and transient in nature.Table 2 lists adverse reactions that occurred in ≥ 0.2% patients who received gadoterate meglumine.Table 2: Adverse Reactions in Clinical TrialsReactionRate (%)n= 2867Nausea0.6%Headache0.4%Injection Site Pain0.4%Injection Site Coldness0.2%Rash0.2%Adverse reactions that occurred with a frequency < 0.2% in patients who received gadoterate meglumine include: feeling cold, feeling hot, burning sensation, somnolence, pain, dizziness, dysgeusia, blood creatinine increased, hypotension, hypertension, asthenia, fatigue, injection site reactions (inflammation, extravasation, pruritus, swelling, warmth), paresthesia, pruritus, laryngeal discomfort, pain in extremity, vomiting, anxiety and palpitations.

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during postmarketing use of gadoterate meglumine. 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.Table 3: Adverse Reactions in the Postmarketing ExperienceSystem Organ ClassAdverse ReactionCardiac Disordersbradycardia, tachycardia, arrhythmiaImmune System Disordershypersensitivity / anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticariaNervous System Disorderscoma, convulsion, syncope, presyncope, parosmia, tremorMusculoskeletal and Connective Tissue Disordersmuscle contracture, muscle weaknessGastrointestinal Disordersdiarrhea, salivary hypersecretionGeneral Disorders and Administration Site Conditionsmalaise, fever 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.Skin and Subcutaneous Tissue DisordersNSF, in patients whose reports were confounded by the receipt of other GBCAs or in situations where receipt of other GBCAs could not be ruled out.No unconfounded cases of NSF have been reported with gadoterate meglumine. Gadolinium-associated plaques.Vascular Disorderssuperficial phlebitis

7 Drug Interactions

Gadoterate does not interfere with serum and plasma calcium measurements determined by colorimetric assays. Specific drug interaction studies with gadoterate meglumine have not been conducted.

8.4 Pediatric Use

The safety and efficacy of gadoterate meglumine at a single dose of 0.1 mmol/kg have been established in pediatric patients from 2 to 17 years of age based on clinical data in 133 pediatric patients 2 years of age and older. Adverse reactions in pediatric patients were similar to those reported in adults [see Adverse Reactions (6.1)]. No dosage adjustment according to age is necessary in pediatric patients [See Dosage and Administration (2.1), Pharmacokinetics (12.3)]. The safety of gadoterate meglumine has not been established in preterm neonates.No cases of NSF associated with gadoterate meglumine or any other GBCA have been identified in pediatric patients age 6 years and younger [see Warnings and Precautions (5.1)]. Normal estimated GFR (eGFR) is approximately 30 mL/minute/1.73 m2 at birth and increases to adult values by 2 years of age.

8.5 Geriatric Use

In clinical studies of gadoterate meglumine, 900 patients were 65 years of age and over, and 304 patients were 75 years of age and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects. In general, use of Clariscan in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No age-related dosage adjustment is necessary.

8.6 Renal Impairment

No Clariscan dosage adjustment is recommended for patients with renal impairment. Gadoterate meglumine can be removed from the body by hemodialysis [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

10 Overdosage

Clariscan administered to healthy volunteers and to adult patients at cumulative doses up to 0.3 mmol/kg was tolerated in a manner similar to lower doses. Adverse reactions to overdosage with gadoterate meglumine have not been reported. Gadoterate meglumine can be removed from the body by hemodialysis [See Clinical Pharmacology (12.3)].

11 Description

Clariscan (gadoterate meglumine) is a paramagnetic macrocyclic ionic contrast agent administered for magnetic resonance imaging. The chemical name for gadoterate meglumine is D-glucitol, 1-deoxy-1-(methylamino)-, [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceto(4-)-.kappa.N1, .kappa.N4, .kappa.N7, .kappa.N10, .kappa.O1, .kappa.O4, .kappa.O7, .kappa.O10]gadolinate(1-)(1:1); it has a formula weight of 753.9 g/mol and empirical formula of C23H42O13N5Gd (anhydrous basis).The structural formula of gadoterate meglumine in solution is as follows: CAS Registry No. 92943-93-6Clariscan Injection is a sterile, nonpyrogenic, clear, colorless to yellow, aqueous solution of 0.5 mmol/mL of gadoterate meglumine. Each vial contains 5 mmol per 10 mL, 7.5 mmol per 15 mL and 10 mmol per 20 mL. No preservative is added. Each mL of Clariscan contains 376.9 mg of gadoterate meglumine, 0.25 mg of DOTA and water for injection. Clariscan has a pH of 6.5 to 8.0.The main physiochemical properties of Clariscan are provided below:Table 4: Physicochemical PropertiesParameterValueDensity @ 20°C1.1753 g/cm3Viscosity @ 20 °C3.4 mPa.sViscosity @ 37°C2.4 mPa.sOsmolality1350 mOsm/kg waterThe thermodynamic stability constants for gadoterate (log Ktherm and log Kcond at pH 7.4) are 25.6 and 19.3, respectively.

12.1 Mechanism Of Action

  • Gadoterate is a paramagnetic molecule that develops a magnetic moment when placed in a magnetic field. The magnetic moment enhances the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues.In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with:1)differences in proton density2)differences of the spin-lattice or longitudinal relaxation times (T1)3)differences in the spin-spin or transverse relaxation time (T2)When placed in a magnetic field, gadoterate shortens the T1 and T2 relaxation times in target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.

12.2 Pharmacodynamics

Gadoterate affects proton relaxation times and consequently the MR signal, and the contrast obtained is characterized by the relaxivity of the gadoterate molecule. The relaxivity values for gadoterate are similar across the spectrum of magnetic field strengths used in clinical MRI (0.2-1.5 T).Disruption of the blood-brain barrier or abnormal vascularity allows distribution of gadoterate in lesions such as neoplasms, abscesses, and infarcts.

12.3 Pharmacokinetics

The pharmacokinetics of total gadolinium assessed up to 48 hours following an intravenously administered 0.1 mmol/kg dose of gadoterate meglumine in healthy adult subjects demonstrated a mean elimination half-life (reported as mean ± SD) of about 1.4 ± 0.2 hours and 2.0 ± 0.7 hours in female and male subjects, respectively. Similar pharmacokinetic profile and elimination half-life values were observed after intravenous injection of 0.1 mmol/kg of gadoterate meglumine followed 20 minutes later by a second injection of 0.2 mmol/kg (1.7 ± 0.3 hours and 1.9 ± 0.2 hours in female and male subjects, respectively).

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadoterate meglumine. Gadoterate meglumine did not demonstrate mutagenic potential in in vitro bacterial reverse mutation assays (Ames test) using Salmonella typhimurium, in an in vitro chromosome aberration assay in Chinese hamster ovary cells, in an in vitro gene mutation assay in Chinese hamster lung cells, nor in an in vivo mouse micronucleus assay.No impairment of male or female fertility and reproductive performance was observed in rats after intravenous administration of gadoterate meglumine at the maximum tested dose of 10 mmol/kg/day (16 times the maximum human dose based on surface area), given during more than 9 weeks in males and more than 4 weeks in females. Sperm counts and sperm motility were not adversely affected by treatment with the drug.

13.2 Animal Toxicology And/Or Pharmacology

Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells were observed after perivenous injection in rabbits suggesting the possibility of local irritation if the contrast medium leaks around the veins in a clinical setting [see Warnings and Precautions (5.5)].Toxicity of gadoterate meglumine was evaluated in neonatal and juvenile (pre- and post-weaning) rats following a single or repeated intravenous administration at doses 1, 2, and 4 times the MHD based on BSA. Gadoterate meglumine was well tolerated at all dose levels tested and had no effect on growth, pre-weaning development, behavior and sexual maturation.

16 How Supplied/Storage And Handling

  • Clariscan Injection is a clear, colorless to yellow solution containing 0.5 mmol/mL of gadoterate meglumine. It is supplied in vials.Clariscan Injection is supplied in 10 mL vials containing 10 mL of solution and in 20 mL vials containing 15 mL or 20 mL of solution.Each single-dose vial is closed with a rubber stopper and sealed with an aluminum cap and the contents are sterile. Vials are individually packaged in a package of 10, in the following configurations:5 mmol per 10 mL (0.5 mmol per mL) in glass vial (NDC 0407-2943-01)7.5 mmol per 15 mL (0.5 mmol per mL) in glass vial (NDC 0407-2943-02)10 mmol per 20 mL (0.5 mmol per mL) in glass vial (NDC 0407-2943-05)

Storage And Handling

StorageStore at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP, Controlled Room Temperature].Should solidification occur in the vial because of exposure to the cold, bring Clariscan to room temperature before use. If allowed to stand at room temperature for a minimum of 90 minutes, Clariscan should return to a clear, colorless to yellow solution. Before use, examine the product to assure that all solids are dissolved and that the container and closure have not been damaged. Discard the vial if solids persist.

17 Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Medication Guide)

17.1 Nephrogenic Systemic Fibrosis

  • Instruct patients to inform their healthcare provider if they:have a history of kidney disease, orhave recently received a GBCA.GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF:Describe the clinical manifestations of NSF.Describe procedures to screen for the detection of renal impairment.Instruct the patients to contact their physician if they develop signs or symptoms of NSF following Clariscan 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.

17.2 Common Adverse Reactions

  • Inform patients that they may experience:Reactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site.Side effects of headache, nausea, abnormal taste and feeling hot.

17.3 General Precautions

  • Pregnancy: Advise pregnant women of the potential risk of fetal exposure to gadoterate [see Use in Specific Population (8.1)]Gadolinium Retention: Advise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs [see Warnings and Precautions (5.3)].

Spl Medguide

  • MEDICATION GUIDECLARISCAN™ (kla-ri'-skan)(gadoterate meglumine) injection for intravenous useWhat is Clariscan?Clariscan is a prescription medicine called a gadolinium-based contrast agent (GBCA). Clariscan, like other GBCAs, is injected into your vein and used with a magnetic resonance imaging (MRI) scanner.An MRI exam with a GBCA, including Clariscan, helps your doctor to see problems better than an MRI exam without a GBCA.Your doctor has reviewed your medical records and has determined that you would benefit from using a GBCA with your MRI exam.What is the most important information I should know about Clariscan?Clariscan contains a metal called gadolinium. Small amounts of gadolinium can stay in your body including the brain, bones, skin and other parts of your body for a long time (several months to years).It is not known how gadolinium may affect you, but so far, studies have not found harmful effects in patients with normal kidneys.Rarely patients have reported pains, tiredness, and skin, muscle or bone ailments for a long time, but these symptoms have not been directly linked to gadolinium.There are different GBCAs that can be used for your MRI exam. The amount of gadolinium that stays in the body is different for different gadolinium medicines. Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist or MultiHance. Gadolinium stays in the body the least after Clariscan, Dotarem, Gadavist or ProHance.People who get many doses of gadolinium medicines, women who are pregnant and young children may be at increased risk from gadolinium staying in the body.Some people with kidney problems who get gadolinium medicines can develop a condition with severe thickening of the skin, muscles and other organs in the body (nephrogenic systemic fibrosis). Your healthcare provider should screen you to see how well your kidneys are working before you receive Clariscan.Do not receive Clariscan if you have had a severe allergic reaction to Clariscan.Before receiving Clariscan, tell your healthcare provider about all your medical conditions, including if you:have had any MRI procedures in the past where you received a GBCA. Your healthcare provider may ask you for more information including the dates of these MRI procedures.are pregnant or plan to become pregnant. It is not known if Clariscan can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if a GBCA such as Clariscan is received during pregnancy.have kidney problems, diabetes, or high blood pressure.have had an allergic reaction to dyes (contrast agents) including GBCA.What are possible side effects of Clariscan?See "What is the most important information I should know about Clariscan?" Allergic reactions. Clariscan can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.The most common side effects of Clariscan include: nausea, headache, pain, or cold feeling at the injection site, and rash. These are not all the possible side effects of Clariscan.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective uses of Clariscan. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your healthcare provider for information about Clariscan that is written for health professionals.What are the ingredients in Clariscan?Active ingredient: gadoterate meglumine Inactive ingredients: DOTA, water for injectionManufactured by: GE Healthcare AS Oslo, Norway GE and the GE Monogram are trademarks of General Electric Company. For more information, go to www.GEHealthcare.com or call 1-800-654-0118.This Medication Guide has been approved by the U.S. Food and Drug Administration.11/2019

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