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Gadoterate Meglumine

FDA Drug Information • Also known as: Clariscan, Dotarem, Gadoterate Meglumine

Brand Names
Clariscan, Dotarem, Gadoterate Meglumine
Dosage Form
POWDER
Product Type
BULK INGREDIENT

⚠ Boxed Warning (Black Box)

WARNING: RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS Risk Associated with Intrathecal Use Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. Gadoterate Meglumine Injection is not approved for intrathecal use [see Warnings and Precautions ( 5.1 )]. Nephrogenic Systemic Fibrosis GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of Gadoterate Meglumine Injection 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 m 2 ), 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 Gadoterate Meglumine Injection 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 ( 5.2 )] . WARNING: RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS See full prescribing information for complete boxed warning.

Description

11 DESCRIPTION Gadoterate Meglumine Injection, USP 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 C 23 H 42 O 13 N 5 Gd (anhydrous basis). The structural formula of gadoterate meglumine in solution is as follows: CAS Registry No. 92943-93-6 Gadoterate Meglumine Injection, USP is a sterile, nonpyrogenic, clear, colorless to yellow, aqueous solution of 0.5 mmol/mL of gadoterate meglumine, for intravenous use. No preservative is added. Each mL of Gadoterate Meglumine Injection, USP contains 376.9 mg of gadoterate meglumine, 0.25 mg of DOTA and water for injection. Gadoterate Meglumine Injection, USP has a pH of 6.5 to 8.0. The main physiochemical properties of Gadoterate Meglumine Injection, USP are provided below: Table 4: Physicochemical Properties Parameter Value Density @ 20°C 1.1753 g/cm 3 Viscosity @ 20°C 3.4 mPa·s Viscosity @ 37°C 2.4 mPa·s Osmolality 1350 mOsm/kg water The thermodynamic stability constants for gadoterate (log K therm and log K cond at pH 7.4) are 25.6 and 19.3, respectively. structural formula

What Is Gadoterate Meglumine Used For?

1 INDICATIONS AND USAGE Gadoterate Meglumine Injection 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 (including term neonates) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity. Gadoterate Meglumine Injection 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 (including term neonates) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Adult and pediatric patients: The recommended dose of Gadoterate Meglumine Injection is 0.2 mL/kg (0.1 mmol/kg) body weight administered as an intravenous bolus injection at a flow rate of approximately 2 mL/second for adults and 1-2 mL/second for pediatric patients (including term neonates). The dose is delivered by manual or power injection. ( 2 ) 2.1 Dosing Guidelines For adult and pediatric patients (including term neonates), the recommended dose of Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection by Body Weight Body Weight Volume Pounds (lb) Kilograms (kg) Milliliters (mL) 5.5 2.5 0.5 11 5 1 22 10 2 44 20 4 66 30 6 88 40 8 110 50 10 132 60 12 154 70 14 176 80 16 198 90 18 220 100 20 242 110 22 264 120 24 286 130 26 308 140 28 330 150 30 To ensure complete injection of Gadoterate Meglumine the injection may be followed by normal saline flush. Contrast MRI can begin immediately following Gadoterate Meglumine Injection. 2.2 Drug Handling Visually inspect Gadoterate Meglumine Injection for particulate matter prior to administration. Do not use the solution if particulate matter is present or if the container appears damaged. Gadoterate Meglumine Injection should be a clear, colorless to yellow solution. Do not mix with other drugs or parenteral nutrition. Discard any unused portions of the drug. Directions for Use of the Gadoterate Meglumine Injection Glass vial: Aseptically draw up the contrast medium into a disposable syringe and use immediately.

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Nephrogenic systemic fibrosis [see Warnings and Precautions ( 5.2 )] . Hypersensitivity reactions [see Warnings and Precautions ( 5.3 )]. Gadolinium Retention [see Warnings and Precautions ( 5.4 )] . The most frequent (≥ 0.2%) adverse reactions in clinical studies were nausea, headache, injection site pain, injection site coldness, and rash. ( 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 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 Injection exposure in 2867 patients, representing 2682 adults and 185 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded, the ethnic distribution was 81% Caucasian, 11% Asian, 4% Black, and 4% 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 Injection administration. Most adverse reactions were mild or moderate in severity and transient in nature. Table 2 lists adverse reactions that occurred in ≥ 0.2% patients who received Gadoterate Meglumine Injection. Table 2: Adverse Reactions in Clinical Trials Reaction Rate (%) n=2867 Nausea 0.6% Headache 0.4% Injection Site Pain 0.4% Injection Site Coldness 0.2% Rash 0.2% Adverse reactions that occurred with a frequency < 0.2% in patients who received Gadoterate Meglumine Injection 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. Adverse Reactions in Pediatric Patients During clinical trials, 185 pediatric patients (52 aged < 24 months, 33 aged 2 - 5 years, 57 aged 6 – 11 years and 43 aged 12 - 17 years) received Gadoterate Meglumine Injection. Overall, 7 pediatric patients (3.8%) reported at least one adverse reaction following Gadoterate Meglumine Injection administration. The most frequently reported adverse reaction was headache (1.1%). Most adverse events were mild in intensity and transient in nature. 6.2 Post-Marketing Experience The following additional adverse reactions have been identified during postmarketing use of Gadoterate Meglumine Injection. 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 Experience System Organ Class Adverse Reaction Cardiac Disorders bradycardia, tachycardia, arrhythmia Immune System Disorders hypersensitivity/anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticaria Nervous System Disorders coma, convulsion, syncope, presyncope, parosmia, tremor Musculoskeletal and Connective Tissue Disorders muscle contracture, muscle weakness Gastrointestinal Disorders diarrhea, salivary hypersecretion, acute pancreatitis with onset within 48 hours after GBCA administration General Disorders and Administration Site Conditions malaise, fever Adverse events with variable onset and duration have been reported after GBCA...

Drug Interactions

7 DRUG INTERACTIONS Gadoterate does not interfere with serum and plasma calcium measurements determined by colorimetric assays. Specific drug interaction studies with Gadoterate Meglumine Injection have not been conducted.

Contraindications

4 CONTRAINDICATIONS History of clinically important hypersensitivity reactions to Gadoterate Meglumine Injection [see Warnings and Precautions ( 5.3 )] . Clinically important hypersensitivity reactions to Gadoterate Meglumine Injection. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary GBCAs 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 Gadoterate Meglumine Injection 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 Data Contrast 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 Retention GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in...

Overdosage

10 OVERDOSAGE Gadoterate Meglumine Injection 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 Injection have not been reported. Gadoterate meglumine can be removed from the body by hemodialysis [see Clinical Pharmacology (12.3)] .

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Gadoterate Meglumine Injection, USP is a clear, colorless to yellow solution containing 0.5 mmol/mL of gadoterate meglumine. It is supplied in vials. Gadoterate Meglumine Injection, USP is supplied in 10 mL vials containing 5 mL or 10 mL of solution, 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 box of 10, in the following configurations: 5 mL in glass vial (NDC 70436-123-31) 10 mL in glass vial (NDC 70436-123-33) 15 mL in glass vial (NDC 70436-123-34) 20 mL in glass vial (NDC 70436-123-35) Storage Store 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, Gadoterate Meglumine Injection, USP should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 90 minutes, Gadoterate Meglumine Injection, USP 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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.