Drug: Dotarem

DOTAREM (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. 92943-93-6 DOTAREM Injection is a sterile, nonpyrogenic, clear, colorless to yellow, aqueous solution of 0.5 mmol/mL of gadoterate meglumine. No preservative is added. Each mL of DOTAREM contains 376.9 mg of gadoterate meglumine, 0.25 mg of DOTA and water for injection. DOTAREM has a pH of 6.5 to 8.0. The main physiochemical properties of DOTAREM are provided below: Table 4: Physicochemical Properties
Parameter Value Density @ 20°C 1.1753 g/cm³ Viscosity @ 20°C 3.4 mPas Viscosity @ 37°C 2.4 mPas Osmolality 1350 mOsm/kg water The thermodynamic stability constants for gadoterate (log Ktherm and log Kcond at pH 7.4) are 25.6 and 19.3, respectively. Last reviewed on RxList: 4/5/2013
This monograph has been modified to include the generic and brand name in many instances.

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GBCAs have been associated with a risk for NSF [see WARNINGS AND PRECAUTIONS]. NSF has not been reported in patients with a clear history of exposure to DOTAREM alone. Hypersensitivity reactions and acute kidney injury are described in other sections of the labeling [see WARNINGS AND PRECAUTIONS]. 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 DOTAREM exposure in 2813 patients, representing 2672 adults and 141 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 0.1 to 97 years). Overall, 3.9% of patients reported at least one adverse reaction, primarily occurring immediately or several days following DOTAREM 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 DOTAREM. Table 2: Adverse Reactions in Clinical Trials
Reaction Rate (%)
n = 2813 Nausea 0.6% Headache 0.5% Injection Site Pain 0.4% Injection Site Coldness 0.2% Burning Sensation 0.2% Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, oropharyngeal discomfort, serum creatinine increased and injection site reactions, including site inflammation, extravasation, pruritus, and warmth. Adverse Reactions in Pediatric Patients During clinical trials, 141 pediatric patients (7 aged < 24 months, 33 aged 2 - 5 years, 58 aged 6 - 11 years and 43 aged 12 - 17) received DOTAREM. Overall, 6 pediatric patients (4.3%) reported at least one adverse reaction following DOTAREM administration. The most frequently reported adverse reaction was headache (1.5%). Most adverse events were mild in severity and transient in nature, and all patients recovered without treatment. Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of DOTAREM. 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 General Disorders and Administration Site Conditions malaise, fever Skin and Subcutaneous Tissue Disorders NSF, 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 DOTAREM. Vascular Disorders superficial phlebitis Read the Dotarem (gadoterate meglumine for use with magnetic resonance imaging) Side Effects Center for a complete guide to possible side effectsLearn More »

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Dosing Guidelines For adult and pediatric patients (2 years and older), the recommended dose of DOTAREM 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 DOTAREM Injection by Body Weight
Body Weight Volume Milliliters (mL) Pounds (lb) Kilograms (kg) 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 DOTAREM the injection may be followed by normal saline flush. Contrast MRI can begin immediately following DOTAREM injection. Drug Handling Visually inspect DOTAREM for particulate matter prior to administration. Do not use the solution if particulate matter is present or if the container appears damaged. DOTAREM should be a clear, colorless to yellow solution. Do not mix with other drugs or parenteral nutrition. Discard any unused portions of the drug. When DOTAREM is to be injected using plastic disposable syringes, the contrast medium should be drawn into the syringe and used immediately.

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DOTAREM does not interfere with serum and plasma calcium measurements determined by colorimetric assays. Specific drug interaction studies with DOTAREM have not been conducted. Last reviewed on RxList: 4/5/2013
This monograph has been modified to include the generic and brand name in many instances.

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DOTAREM 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 (2 years of age and older) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity.

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History of clinically important hypersensitivity reactions to DOTAREM [see WARNINGS AND PRECAUTIONS]. Last reviewed on RxList: 4/5/2013
This monograph has been modified to include the generic and brand name in many instances.

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DOTAREM administered to healthy volunteers and to patients at cumulative doses up to 0.3 mmol/kg was tolerated in a manner similar to lower doses. Adverse reactions to overdosage with DOTAREM have not been reported. Gadoterate meglumine can be removed from the body by hemodialysis [See CLINICAL PHARMACOLOGY].

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Dosage Forms And Strengths DOTAREM 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 and pre-filled syringes. Storage And Handling DOTAREM Injection is a clear, colorless to yellow solution containing 0.5 mmol/mL of gadoterate meglumine. It is supplied in vials and prefilled syringes.
  • DOTAREM Injection is supplied in 10 mL vials containing 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 shrink wrapped package of 10, in the following configurations: 10 mL in glass vial (NDC 67684-200-01)
15 mL in glass vial (NDC 67684-200-02)
20 mL in glass vial (NDC 67684-200-03) DOTAREM Injection is supplied in 10 mL pre-filled syringes containing 10 mL of solution and 20 mL pre-filled syringes containing 15 mL or 20 mL of solution. Each syringe is sealed with rubber closures and the contents are sterile. Syringes, including plunger rod, are packaged in a shrink wrapped package of 5, in the following configurations: 10 mL in glass pre-filled syringe (NDC 67684-300-01)
15 mL in glass pre-filled syringe (NDC 67684-300-02)
20 mL in glass pre-filled syringe (NDC 67684-300-03) 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 (CRT)]. Pre-filled syringes must not be frozen. Frozen syringes should be discarded. Should solidification occur in the vial because of exposure to the cold, DOTAREM should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 90 minutes, DOTAREM should return to a clear, colorless to yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard the vial. Directions for Use of the DOTAREM (gadoterate meglumine) Injection glass pre-filled syringe
  1. Screw the threaded tip of the plunger rod clockwise into the cartridge plunger and push forward a few millimeters to break any friction between the cartridge plunger and syringe barrel.
  2. Holding the syringe vertically so the rubber cap is pointed upward, aseptically remove the rubber cap from the tip of the syringe and attach either a sterile, disposable needle or compatible needleless luer lock tubing set using a push-twist action. At this point, the tubing set is not attached to a patient's intravenous connection.
    • If using a needleless luer lock tubing set, check the connection between the syringe and the tubing as the fluid flows. Ensure that the connection is successful before administration of Dotarem Injection.
    • If using a needle, hold the syringe vertically and push plunger forward until all of the air is evacuated and fluid either appears at the tip of the needle or the tubing is filled. Following the usual venous blood aspiration procedure, complete the DOTAREM injection.
  3. To ensure complete delivery of the contrast medium, the injection may be followed by a normal saline flush.
  4. Properly dispose of the syringe and any other materials used.
Guerbet LLC, 1185 West 2nd street, Bloomington, IN 47403, Pre-filled syringes manufactured by Catalent, Belgium for Guerbet, Vials manufactured by Recipharm, France for Guerbet. Revised: 3/2013 Last reviewed on RxList: 4/5/2013
This monograph has been modified to include the generic and brand name in many instances.

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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/1.73m²) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73m²) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73m²). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following DOTAREM 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 > 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 DOTAREM 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 and CLINICAL PHARMACOLOGY]. Hypersensitivity Reactions Anaphylactic and anaphylactoid reactions have been reported with DOTAREM, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of DOTAREM administration and resolved with prompt emergency treatment [see ADVERSE REACTIONS].
  • Before DOTAREM 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 DOTAREM.
  • Administer DOTAREM 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 DOTAREM administration, observe patients for signs and symptoms of hypersensitivity reactions.
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. Extravasation and Injection Site Reactions Ensure catheter and venous patency before the injection of DOTAREM. Extravasation into tissues during DOTAREM administration may result in tissue irritation [see Nonclinical Toxicology]. Nonclinical Toxicology 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. Use In Specific Populations Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with DOTAREM conducted in pregnant women. Limited published human data on exposure to other GBCAs during pregnancy did not show adverse effects in exposed neonates. No effects on embryo fetal development were observed in rats or rabbits at doses up to 10 mmol/kg/day in rats or 3 mmol/kg/day in rabbits. The doses in rats and rabbits were respectively 16 and 10 times the recommended human dose based on body surface area. DOTAREM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human Data While it is unknown if DOTAREM crosses the human placenta, other GBCAs do cross the placenta in humans and result in fetal exposure. Animal Data Reproductive and developmental toxicity studies were conducted with gadoterate meglumine in rats and rabbits. Gadoterate meglumine was administered intravenously in doses of 0, 2, 4 and 10 mmol/kg/day (or 3.2, 6.5 and 16.2 times the recommended human dose based on body surface area) to female rats for 14 days before mating throughout the mating period and until gestation day (GD) 17. Pregnant rabbits were intravenously administered gadoterate meglumine at the dose levels of 0, 1, 3 and 7 mmol/kg/day (or 3.3, 10 and 23 times the human doses based on body surface area) from GD6 to GD19. No effects on embryo fetal development were observed in rats or rabbits 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 (or 16 times the human dose based on body surface area) and in rabbits at 7 mmol/kg/day (23 times the human dose based on body surface area). Nursing Mothers It is not known whether DOTAREM is excreted in human milk. Limited case reports on use of GBCAs in nursing mothers indicate that 0.01 to 0.04% of the maternal gadolinium dose is excreted in human breast milk. Because many drugs are excreted in human milk, exercise caution when DOTAREM is administered to a nursing woman. Nonclinical data show that gadoterate meglumine is excreted into breast milk in very small amounts ( < 0.1% of the dose intravenously administered) and absorption via the gastrointestinal tract is poor. Pediatric Use The safety and efficacy of DOTAREM at a single dose of 0.1 mmol/kg have been established in pediatric patients from 2 to 17 years of age. No dosage adjustment according to age is necessary in this population [See DOSAGE AND ADMINISTRATION and Clinical Studies]. The safety and efficacy of DOTAREM have not been established in pediatric patients below 2 years of age. GFR does not reach adult levels until 1 year of age [see WARNINGS AND PRECAUTIONS]. Geriatric Use In clinical studies of DOTAREM, 900 patients were 65 years of age and over, and 312 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 DOTAREM 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. Renal Impairment No DOTAREM dosage adjustment is recommended for patients with renal impairment. Gadoterate meglumine can be removed from the body by hemodialysis [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 4/5/2013
This monograph has been modified to include the generic and brand name in many instances.

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