HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DOTAREM safely and effectively. See full prescribing information for
DOTAREM.

DOTAREM Injection 0.5 mmol/mL contains 376.9 mg/mL of gadoteratemeglumine and is available in vials and pre-filled syringes. (3)

DOTAREM® (gadoterate meglumine) Injection for intravenous use
Initial U.S. Approval: 2013------------------------- CONTRAINDICATIONS ------------------------Clinically important hypersensitivity reactions to DOTAREM. (4)------------------ DOSAGE FORMS AND STRENGTHS ---------------WARNING: RISK ASSOCIATED WITH INTRATHECAL USE andNEPHROGENIC SYSTEMIC FIBROSIS----------------- WARNINGS AND PRECAUTIONS -----------------

See full prescribing information for complete boxed warning•• Intrathecal administration of gadolinium-based contrast agents(GBCAs) can cause serious adverse reactions including death,coma, encephalopathy, and seizures. DOTAREM is not approved for
intrathecal use. (5.1)

Hypersensitivity: Anaphylactoid/anaphylactic reactions withcardiovascular, respiratory or cutaneous manifestations, ranging from mild
to severe, including death, have uncommonly occurred. Monitor patientsclosely for need of emergency cardiorespiratory support. (5.3)•

Gadolinium is retained for months or years in brain, bone, and otherorgans. (5.4)• GBCAs increase the risk for nephrogenic systemic fibrosis (NSF)
among patients with impaired elimination of the drugs. Avoid use of
DOTAREM in these patients unless the diagnostic information isessential and not available with non-contrasted MRI or othermodalities. The risk for NSF appears highest among patients with:o Chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), oro Acute kidney injury.
Screen patients for acute kidney injury and other conditions that
may reduce renal function. For patients at risk for chronicallyreduced renal function (for example, age > 60 years, hypertension ordiabetes), estimate the glomerular filtration rate (GFR) throughlaboratory testing (5.2).

------------------------ ADVERSE REACTIONS -----------------------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 GUERBET
LLC at 1-877-729-6679 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.

-------------------------- RECENT MAJOR CHANGES --------------------------------------------------- USE IN SPECIFIC POPULATIONS ----------------------Pregnancy: Use only if imaging is essential during pregnancy and cannot bedelayed. (8.1)

Boxed Warning
1/2024
Warnings and Precautions, Risk Associated with Intrathecal Use (5.1) 1/2024

See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 5/2024---------------------- INDICATIONS AND USAGE --------------------DOTAREM is a gadolinium-based contrast agent indicated: for intravenous
use with magnetic resonance imaging (MRI) in brain (intracranial), spine andassociated tissues in adult and pediatric patients (including term neonates) todetect and visualize areas with disruption of the blood brain barrier (BBB)
and/or abnormal vascularity. (1)------------------ DOSAGE AND ADMINISTRATION ---------------Adult and pediatric patients: The recommended dose of DOTAREM is 0.2 mL/kg(0.1 mmol/kg) body weight administered as an intravenous bolus injection at aflow rate of approximately 2 mL/second for adults and 1-2 mL/second for pediatricpatients (including term neonates). The dose is delivered by manual or power
injection. (2)FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK ASSOCIATED WITH INTRATHECAL
USE and NEPHROGENIC SYSTEMIC FIBROSIS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Dosing Guidelines
2.2
Drug Handling
3
DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS5WARNINGS AND PRECAUTIONS
5.1
Risk Associate with Intrathecal Use
5.2
Nephrogenic Systemic Fibrosis
5.3
Hypersensitivity Reactions
5.4
Gadolinium Retention
5.5
Acute Kidney Injury
5.6
Extravasation and Injection Site Reactions
6
ADVERSE REACTIONS
6.1
Clinical Studies Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
8USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.4
Pediatric Use

10
11
12

13
14
16
17

8.5
Geriatric Use
8.6
Renal Impairment
OVERDOSAGEDESCRIPTION
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2
Animal Toxicology and/or Pharmacology
CLINICAL STUDIESHOW SUPPLIED/STORAGE AND HANDLINGPATIENT COUNSELING INFORMATION
17.1
Nephrogenic Systemic Fibrosis
17.2
Common Adverse Reactions
17.3
General Precautions*Sections or subsections omitted from the full prescribing information are notlisted.

Page 1 of 16

FULL PRESCRIBING INFORMATIONWARNING: RISK ASSOCIATED WITH INTRATHECAL USE andNEPHROGENIC 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. DOTAREM 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 DOTAREM in these patients unless the diagnostic information isessential and not available with non-contrasted MRI or other modalities. NSF may result in fatal ordebilitating 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/1.73m2), 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 [seeWarnings and Precautions (5.2)].
1

INDICATIONS AND USAGE

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 (including term neonates) to detect andvisualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity.
2

DOSAGE AND ADMINISTRATION

2.1
Dosing Guidelines
For adult and pediatric patients (including term neonates), 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 rateof approximately 2 mL/second for adults and 1-2 mL/second for pediatric patients. Table 1 provides weight-adjusted dosevolumes.
Table 1: Volumes of DOTAREM Injection by Body Weight
Body Weight
VolumePounds (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
Page 2 of 16

242
264
286
308
330

110
120
130
140
150

22
24
26
28
30

To ensure complete injection of DOTAREM the injection may be followed by normal saline flush. Contrast MRI canbegin immediately following DOTAREM injection.
2.2
•
•
•

Drug Handling
Visually inspect DOTAREM for particulate matter prior to administration. Do not use the solution if particulatematter 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.

Directions for Use of the DOTAREM (gadoterate meglumine) Injection
Glass vial:
Aseptically draw up the contrast medium into a disposable syringe and use immediately.
Glass or plastic pre-filled syringe:
1) Holding the syringe barrel firmly, screw the threaded tip of the plunger rod clockwise into the cartridge plunger.
•

For glass pre-filled syringe: Push forward a few millimeters to break any friction between the cartridge plunger
and syringe barrel.

•

For plastic pre-filled syringe: After screwing the push rod into the syringe cartridge plunger, turn the push rod
clockwise an additional ½ turn so that the cartridge plunger rotates freely.

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 pushtwist 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.

Glass pre-filled syringe

Plastic pre-filled syringe

Page 3 of 16

3

DOSAGE FORMS AND STRENGTHSDOTAREM 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.
4

CONTRAINDICATIONSHistory of clinically important hypersensitivity reactions to DOTAREM [see Warnings and Precautions (5.3)].
5

WARNINGS AND PRECAUTIONS

5.1 Risk Associated with Intrathecal Use

Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy,
and seizures. The safety and effectiveness of DOTAREM have not been established with intrathecal use.
DOTAREM is not approved for intrathecal use [see Dosage and Administration (2.1)].
5.2
Nephrogenic Systemic Fibrosis
GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs.
Avoid use of DOTAREM among these patients unless the diagnostic information is essential and not available with noncontrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidneydisease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients withchronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidneydisease (GFR 60 - 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle andinternal 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 notreliably 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 degreeof 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 timefor 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)].
5.3
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 thetreatment of hypersensitivity reactions, including personnel trained in resuscitation.

•

During and following DOTAREM administration, observe patients for signs and symptoms of hypersensitivity
reactions.

5.4

Gadolinium Retention

Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue)
Page 4 of 16have been identified in the bone, followed by other organs (e.g. brain, skin, kidney, liver and spleen). The duration ofretention 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 themacrocyclic GBCAs [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 (5.2)]. 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 pediatricpatients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing a
GBCA for these patients. Minimize repetitive GBCA imaging studies, particularly closely spaced studies when possible.
5.5
Acute Kidney Injury
In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of
GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; 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.
5.6
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 (13.2)].
6

ADVERSE REACTIONS

GBCAs have been associated with a risk for NSF [see Warnings and Precautions (5.2)]. Confirmed diagnosis of 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 andPrecautions (5.3,5.4)].
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 observedin clinical practice.
The data described below reflect DOTAREM exposure in 2867 patients, representing 2682 adults and 185 pediatricpatients. 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 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 = 2867
Nausea0.6%
Headache
0.4%
Injection Site Pain
0.4%
Injection Site Coldness
0.2%
Rash
0.2%
Page 5 of 16

Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM 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 DOTAREM. Overall, 7 pediatric patients (3.8%) reported at least one adverse reaction following
DOTAREM administration. The most frequently reported adverse reaction was headache (1.1%). Most adverse eventswere mild in intensity and transient in nature.

Page 6 of 16

6.2
Postmarketing Experience
The following additional adverse reactions have been identified during postmarketing use of DOTAREM. Because thesereactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate theirfrequency 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
Disordersmuscle contracture, muscle weakness

Gastrointestinal Disorders

diarrhea, salivary hypersecretion, acute pancreatitis with onset
within 48 hours after GBCA administration
malaise, fever
Adverse events with variable onset and duration have beenreported after GBCA administration [see Warnings andPrecautions (5.4)]. These include fatigue, asthenia, pain
syndromes, and heterogeneous clusters of symptoms in theneurological, cutaneous, and musculoskeletal systems.

General Disorders and Administration
Site Conditions

Skin and Subcutaneous Tissue Disorders

NSF, in patients whose reports were confounded by the receipt ofother GBCAs or in situations where receipt of other GBCAs could
not be ruled out.
No unconfounded cases of NSF have been reported with
DOTAREM.
Gadolinium-associated plaques.

Vascular Disorders

superficial phlebitis

7

DRUG INTERACTIONS

Gadoterate does not interfere with serum and plasma calcium measurements determined by colorimetric assays. Specificdrug interaction studies with DOTAREM have not been conducted.
8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary
GBCAs cross the human placenta and result in fetal exposure and gadolinium retention. The human data on theassociation 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 ofgadoterate 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 DOTAREM 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, theestimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 1520% respectively.

Page 7 of 16

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 andneonatal deaths in the group receiving GBCA MRI. Limitations of this study include a lack of comparison with noncontrast MRI and lack of information about the material indication for MRI. Overall, these data preclude a reliableevaluation 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 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 Toxicology
Gadoterate meglumine was administered in intravenous doses of 0, 2, 4 and 10 mmol/kg/day [3, 7 and 16 times therecommended 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 inintravenous doses 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 and 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 wascharacterized 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.
8.2
Lactation
Risk Summary
There 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 excreted in breast milk. Additionally, there is limited GBCA gastrointestinal absorption in the breast-fed infant.
Gadoterate is present in goat milk (see Data). The developmental and health benefits of breastfeeding should beconsidered along with the mother’s clinical need for DOTAREM and any potential adverse effects on the breastfed infantfrom DOTAREM or from the underlying maternal condition.
Data
Nonclinical 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 administereddose was absorbed and eliminated in urine).
8.4
Pediatric Use
The safety and efficacy of DOTAREM at a single dose of 0.1 mmol/kg have been established in pediatric patients frombirth (term neonates ≥ 37 weeks gestational age) to 17 years of age based on clinical data in 133 pediatric patients 2 yearsof age and older, and clinical data in 52 pediatric patients birth to less than 2 years of age that supported extrapolationfrom adult data [see Clinical Studies (14)]. 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 andAdministration (2.1), Pharmacokinetics (12.3)]. The safety of DOTAREM has not been established in preterm neonates.
No cases of NSF associated with DOTAREM or any other GBCA have been identified in pediatric patients age 6 years
and younger [see Warnings and Precautions (5.2)]. Normal estimated GFR (eGFR) is approximately
30 mL/minute/1.73m2 at birth and increases to adult values by 2 years of age.
Page 8 of 16Juvenile Animal Data
Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk foruse in pediatric patients including term neonates and infants.
8.5
Geriatric Use
In clinical studies of DOTAREM, 900 patients were 65 years of age and over, and 304 patients were 75 years of age andover. 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 andconcomitant disease or other drug therapy. No age-related dosage adjustment is necessary.
8.6
Renal Impairment
No DOTAREM dosage adjustment is recommended for patients with renal impairment. Gadoterate can be removed fromthe body by hemodialysis [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
10

OVERDOSAGE

DOTAREM 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 DOTAREM have not been reported. Gadoteratemeglumine can be removed from the body by hemodialysis [See Clinical Pharmacology (12.3)].
11

DESCRIPTIONDOTAREM (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)-,[1,4,7,10tetraazacyclododecane-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 ofgadoterate 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 mPa.s

Viscosity @ 37°C

2.4 mPa.s

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.

Page 9 of 16

12

CLINICAL PHARMACOLOGY

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 theradiofrequency 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 DOTAREM in healthy adult subjects demonstrated a mean elimination half-life (reported as mean ± SD) of about
1.4 ± 0.2 hr and 2.0 ± 0.7 hr 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 DOTAREM followed 20 minutes later by asecond injection of 0.2 mmol/kg (1.7 ± 0.3 hr and 1.9 ± 0.2 hr in female and male subjects, respectively).
Distribution
The volume of distribution at steady state of total gadolinium in healthy subjects is 179 ± 26 and 211 ± 35 mL/kg infemale 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 [seeWarnings and Precautions (5.4)].
Metabolism
Gadoterate is not known to be metabolized.
Elimination
Following a 0.1 mmol/kg dose of DOTAREM, total gadolinium is excreted primarily in the urine with 72.9 ± 17.0% and85.4 ± 9.7% (mean ± SD) eliminated within 48 hours, in female and male subjects, respectively. Similar values wereachieved 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 hrs in female and male subjects respectively.
In healthy subjects, the renal and total clearance rates of total gadolinium are comparable (1.27 ± 0.32 and1.74 ± 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.

Page 10 of 16

Specific Populations
Renal Impairment
A single intravenous dose of 0.1 mmol/kg of DOTAREM 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
DOTAREM injection. The mean cumulative urinary excretion of total gadolinium was approximately 76.9 ± 4.5% in 48
hrs in patients with moderate renal impairment, 68.4 ± 3.5% in 72 hrs in patients with severe renal impairment and 93.3 ±
4.7% in 24 hrs for subjects with normal renal function.
Table 5: Pharmacokinetic Profile of Total Gadolinium in Normal and Renally Impaired Patients
Population
Healthy volunteers
Patients with moderate
renal impairment
Patients with severe renal
impairment

Elimination Half-life(hr)
1.6 ± 0.2

Plasma Clearance(L/h/kg)
0.10 ± 0.01

Distribution Volume(L/kg)
0.246 ± 0.03

5.1 ± 1.0

0.036 ± 0.007

0.236 ± 0.01

13.9 ± 1.2

0.012 ± 0.001

0.234 ± 0.01

Gadoterate was shown to be dialyzable after an IV injection of DOTAREM 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 hr, 1.5 hr, and4 hrs 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 population
The pharmacokinetics of gadoterate in pediatric patients receiving DOTAREM aged birth (term neonates) to 23 months,
was investigated in an open label, multicenter study, using a population pharmacokinetics approach. A total of 45 subjects(22 males, 23 females) received a single intravenous dose of DOTAREM 0.1 mmol/kg (0.2 mL/kg). The age ranged fromless than one week to 23.8 months (mean 9.9 months) and body weight ranged from 3 to 15 kg (mean 8.1 kg). Individuallevel of renal maturity in the study population, as expressed by eGFR ranged between 52 and 281 mL/min/1.73 m² and 11
patients had an eGFR below 100 mL/min/1.73 m2 (range 52 to 95 mL/min/1.73 m2).
Gadoterate concentrations obtained up to 8 hours after DOTAREM administration were best fitted using a biphasic modelwith linear elimination from the intravascular space. The mean clearance adjusted to body weight was estimated at 0.16 ±0.07 L/h/kg and increased with eGFR. The estimated mean elimination half-life was
1.47 ± 0.45 hr.
The body weight adjusted clearance of gadoterate after single intravenous injection of 0.1 mmol/kg of DOTAREM inpediatric subjects aged less than 2 years was similar to that observed in healthy adults.
13

NONCLINICAL TOXICOLOGY

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 humandose 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.
Page 11 of 16

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 theveins 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. Gadoteratemeglumine was well tolerated at all dose levels tested and had no effect on growth, pre-weaning development,
behavior and sexual maturation.
14

CLINICAL STUDIESCNS Imaging
Efficacy and safety of DOTAREM 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
DOTAREM or gadopentetate dimeglumine, each administered at a dose of 0.1 mmol/kg. All pediatric patients received
DOTAREM, 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 (precontrast, 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) tobaseline MRI (pre-contrast images) for adults who received DOTAREM. The three primary visualization components
were: contrast enhancement, border delineation and internal morphology. For each of these components there was a predefined scoring scale. Lesion counting (up to five per patient) was also reflected within each component’s patient-levelvisualization score.
Among the adult patients, 245 received DOTAREM and their data comprised the primary efficacy population. There were114 (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 precontrast 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.
DOTAREM provided a statistically significant improvement for all three primary visualization components. More lesions
were seen on the paired images than the pre-contrast images.

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Table 6: Study A. Improvement in Patient-level Lesion Visualization Scores, Paired versus Pre-contrast Images(a)Lesion Scores
Border Delineation
BetterNot Better
MissingDifference in Mean Score (b)Internal Morphology
BetterNot Better
MissingDifference in Mean Score (b)Contrast Enhancement
BetterNot Better
MissingDifference in Mean Score (b)Reader 1
n = 231

Reader 2
n = 232

Reader 3
n = 237

195 (84%)
28 (12%)8 (4%)
2.26*

215 (93%)
7 (3%)
10 (4%)
2.89*

132 (56%)
88 (37%)17 (7%)
1.17*

218 (94%)
5 (2%)
8 (4%)
2.74*

214 (93%)
8 (3%)
10 (4%)
2.75*

187 (79%)
33 (14%)17 (7%)
1.54*

208 (90%)
15 (6%)
8 (4%)
3.09*

216 (93%)
6 (3%)
10 (4%)
3.69*

208 (88%)
12 (5%)
17 (7%)
2.92*(a) Better: number of patients with paired (pre-and post-contrast) score greater than the pre-contrast score
Not better: number of patients with paired score same as or worse than the pre-contrast score
Missing: number of patients with missing score(b) Difference = paired mean score minus pre-contrast mean score*Statistically significant improvement by paired t-test

In secondary analyses, post-contrast images were improved in comparison to pre-contrast images. DOTAREM lesion
visualization scores were similar to those for gadopentetate dimeglumine. DOTAREM imaging results in the pediatricpatients 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 hadparticipated in previously conducted clinical trial. DOTAREM 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
DOTAREM.
CNS Imaging in the Sub-population of Pediatric Patients < 2 years old
A non-randomized study (Study C) with 28 pediatric patients under 2 years of age who were referred for contrast MRI of
the CNS supported extrapolation of CNS efficacy findings from adults and older children. CNS lesions were identified in
16 of these 28 patients on paired pre- and post-contrast images compared to 15 patients on pre-contrast images alone. In
the 16 patients who had identifiable lesions, the scores for the co-endpoints of lesion visualization were improved for atleast one lesion on paired pre- and post-contrast images compared to pre-contrast images in 8 out of 16 (50%) patients forlesion border delineation, 8 out of 16 (50%) patients for lesion internal morphology, and 14 out of 16 (88%) patients forlesion contrast enhancement.
16

HOW SUPPLIED/STORAGE AND HANDLINGDOTAREM 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 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.

Page 13 of 16

Vials are individually packaged in a shrink wrapped package of 10, in the following configurations:
5 mL in glass vial
10 mL in glass vial
15 mL in glass vial
20 mL in glass vial

(NDC 67684-2000-0)(NDC 67684-2000-1)(NDC 67684-2000-2)(NDC 67684-2000-3)

Vials are also packaged in a box of 10, in the following configurations:
5 mL in glass vial
10 mL in glass vial
15 mL in glass vial
20 mL in glass vial•

(NDC 67684-2001-0)(NDC 67684-2001-1)(NDC 67684-2001-2)(NDC 67684-2001-3)

DOTAREM Injection is supplied in 10 mL glass pre-filled syringes containing 10 mL of solution and 20 mL glass
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 ashrink wrapped package of 5, in the following configurations:
10 mL in glass pre-filled syringe
15 mL in glass pre-filled syringe
20 mL in glass pre-filled syringe•(NDC 67684-2000-5)(NDC 67684-2000-6)(NDC 67684-2000-7)

DOTAREM Injection is supplied in 20 mL plastic pre-filled syringes containing 10 mL, 15 mL or 20 mL ofsolution

Each syringe is sealed with rubber closures and the contents are sterile. Syringes, including plunger rod, are packaged in abox of 10, in the following configurations:
10 mL in plastic pre-filled syringe
15 mL in plastic pre-filled syringe
20 mL in plastic pre-filled syringe(NDC 67684-3001-1)(NDC 67684-3001-2)(NDC 67684-3001-3)

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, bring DOTAREM 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 toyellow 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•

17.1

Advise the patient to read the FDA-approved patient labeling (Medication Guide)
Nephrogenic Systemic Fibrosis
Page 14 of 16

Instruct patients to inform their healthcare provider if they:
1. have a history of kidney disease, or
2. have 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 DOTAREM
administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on theskin; 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 orcoldness 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
Populations (8.1)]
Gadolinium Retention: Advise patients that gadolinium is retained for months or years in brain, bone, skin, andother 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 (5.4)].

Rx Only

Guerbet LLC
214 Carnegie Center, Suite 300,
Princeton, New Jersey 08540
Glass pre-filled syringes manufactured by Catalent, Belgium for Guerbet
Plastic pre-filled syringes manufactured by Liebel-Flarsheim Company LLC, USA for Guerbet
Vials manufactured by Recipharm, France and Liebel-Flarsheim Company LLC, USA for Guerbet

Page 15 of 16

MEDICATION GUIDEDOTAREM® (doh TAH rem)(gadoterate meglumine)
Injection for intravenous use
What is DOTAREM?
• DOTAREM is a prescription medicine called a gadolinium-based contrast agent (GBCA). DOTAREM, like other
GBCAs, is injected into your vein and used with a magnetic resonance imaging (MRI) scanner.
• An MRI exam with a GBCA, including DOTAREM, 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 DOTAREM?
•
GBCAs like DOTAREM may cause serious side effects including death, coma, encephalopathy, and seizures when it
is given intrathecally (injection given into the spinal canal). It is not known if DOTAREM is safe and effective withintrathecal use. DOTAREM is not approved for this use.
• DOTAREM contains a metal called gadolinium. Small amounts of gadolinium can stay in your body including thebrain, 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 withnormal 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 isdifferent 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 Dotarem, Gadavist or ProHance.
• People who get many doses of gadolinium medicines, women who are pregnant and young children may be atincreased 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 DOTAREM.
Do not receive DOTAREM if you have had a severe allergic reaction to DOTAREM.
Before receiving DOTAREM, 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 formore information including the dates of these MRI procedures.
• are pregnant or plan to become pregnant. It is not known if DOTAREM can harm your unborn baby. Talk to yourhealthcare provider about the possible risks to an unborn baby if a GBCA such as DOTAREM is received during
pregnancy.
• have kidney problems, diabetes, or high blood pressure.
• have had an allergic reaction to dyes (contrast agents) including GBCAs.
What are possible side effects of DOTAREM?
• See “What is the most important information I should know about DOTAREM?”• Allergic reactions. DOTAREM 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 DOTAREM include: nausea, headache, pain, or cold feeling at the injection
site, and rash.
These are not all the possible side effects of DOTAREM.
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 DOTAREM.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask yourhealthcare provider for information about DOTAREM that is written for health professionals.
What are the ingredients in DOTAREM?
Active ingredient: gadoterate meglumine
Inactive ingredients: DOTA, water for injection
Manufactured by: Catalent (glass pre-filled syringes), Liebel-Flarsheim Company LLC (plastic pre-filled syringes andvials) and Recipharm (vials) for Guerbet
For more information, go to www.guerbet-us.com or call 1-877-729-6679.
This Medication Guide has been approved by the U.S. Food and Drug Administration.

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Rev. 1/2024