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Black Box Warning
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF):
See full prescribing information for complete Boxed 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 DOTAREM dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration
Overview
Gadoterate is a Diagnostic Agent that is FDA approved for the diagnosis of areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity in brain (intracranial), spine and associated tissues with magnetic resonance imaging (MRI). There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, headache, injection site pain, injection site coldness, and burning sensation.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
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.
Dosage
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.
To ensure complete injection of DOTAREM the injection may be followed by normal saline flush. Contrast MRI can begin immediately following DOTAREM injection.
2.2 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.
3 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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Gadoterate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoterate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Indications
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.
Dosage
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.
To ensure complete injection of DOTAREM the injection may be followed by normal saline flush. Contrast MRI can begin immediately following DOTAREM injection.
2.2 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.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Gadoterate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoterate in pediatric patients.
Contraindications
History of clinically important hypersensitivity reactions to DOTAREM
Warnings
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF):
See full prescribing information for complete Boxed 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 DOTAREM dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration
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 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 (2) and Clinical Pharmacology (12)].
5.2 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 (6)].
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.
5.3 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.
5.4 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
Adverse Reactions
Clinical Trials Experience
GBCAs have been associated with a risk for NSF [see Warnings and Precautions (5.1)]. 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 (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 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.
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.
Drug Interactions
DOTAREM does not interfere with serum and plasma calcium measurements determined by colorimetric assays. Specific drug interaction studies with DOTAREM have not been conducted.
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).
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadoterate in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Gadoterate during labor and delivery.
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 the 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 (2.1) and Clinical Studies (14)]. 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
Geriatic 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.
Gender
There is no FDA guidance on the use of Gadoterate with respect to specific gender populations.
Race
There is no FDA guidance on the use of Gadoterate with respect to specific racial populations.
Renal Impairment
No DOTAREM dosage adjustment is recommended for patients with renal impairment. Gadoterate meglumine can be removed from the body by hemodialysis
Hepatic Impairment
There is no FDA guidance on the use of Gadoterate in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Gadoterate in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Gadoterate in patients who are immunocompromised.
Administration and Monitoring
Administration
Intravenous
Monitoring
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
IV Compatibility
There is limited information regarding IV Compatibility of Gadoterate in the drug label.
Overdosage
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
Pharmacology
There is limited information regarding Gadoterate Pharmacology in the drug label.
