Included as part of the PRECAUTIONS section.
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
Report any diagnosis of NSF following Clariscan
administration to GE Healthcare at (1-800-654-0118) or FDA at (1-800-FDA-1088
or www.fda.gov/medwatch ) .
Screen patients for acute kidney injury and other
conditions that may reduce renal function. Features of acute kidney injury
consist of rapid (over hours to days), and usually reversible, decrease in
kidney function, commonly in the setting of surgery, severe infection, injury
or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may
not reliably assess renal function in the setting of acute kidney injury. For
patients at risk for chronically reduced renal function (e.g., age > 60
years, diabetes mellitus or chronic hypertension), estimate the GFR through
The factors that may increase the risk for NSF are
repeated or higher than recommended doses of a GBCA, and the degree of renal
impairment at the time of exposure. Record the specific GBCA and the dose
administered to a patient. For patients at highest risk for NSF, do not exceed
the recommended Clariscan dose and allow a sufficient period of time for
elimination of the drug prior to re-administration. For patients receiving
hemodialysis, physicians may consider the prompt initiation of hemodialysis
following the administration of a GBCA in order to enhance the contrast agent's
elimination. The usefulness of hemodialysis in the prevention of NSF is unknown
[see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Anaphylactic and anaphylactoid reactions have been
reported with Clariscan, involving cardiovascular, respiratory, and/or
cutaneous manifestations. Some patients experienced circulatory collapse and
died. In most cases, initial symptoms occurred within minutes of Clariscan
administration and resolved with prompt emergency treatment [see ADVERSE
- Before Clariscan administration, assess all patients for
any history of a reaction to contrast media, bronchial asthma and/or allergic
disorders. These patients may have an increased risk for a hypersensitivity
reaction to Clariscan.
- Administer Clariscan only in situations where trained
personnel and therapies are promptly available for the treatment of
hypersensitivity reactions, including personnel trained in resuscitation.
- During and following Clariscan administration, observe
patients for signs and symptoms of hypersensitivity reactions.
Gadolinium is retained for months or years in several
organs. The highest concentrations (nanomoles per gram of tissue) have been
identified in the bone, followed by other organs (e.g. brain, skin, kidney,
liver and spleen). The duration of retention also varies by tissue and is
longest in bone. Linear GBCAs cause more retention than macrocyclic GBCAs. At
equivalent doses, gadolinium retention varies among the linear agents with
Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention
than other linear agents [Eovist (gadoxetate disodium), Magnevist
(gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine)]. Retention is
lowest and similar among the macrocyclic GBCAs [Clariscan (gadoterate meglumine),
Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)].
Consequences of gadolinium retention in the brain have
not been established. Pathologic and clinical consequences of GBCA
administration and retention in skin and other organs have been established in
patients with impaired renal function [see Nephrogenic Systemic Fibrosis].
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].
While clinical consequences of gadolinium retention have
not been established in patients with normal renal function, certain patients
might be at higher risk. These include patients requiring multiple lifetime
doses, pregnant and pediatric patients, and patients with inflammatory
conditions. Consider the retention characteristics of the agent when choosing a
GBCA for these patients. Minimize repetitive GBCA imaging studies, particularly
closely spaced studies when possible.
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
Extravasation And Injection Site Reactions
Ensure catheter and venous patency before the injection
of Clariscan. Extravasation into tissues during Clariscan administration may
result in tissue irritation [see Nonclinical Toxicology].
Patient Counseling Information
- Advise the patient to read the FDA-approved patient
labeling (Medication Guide)
Nephrogenic Systemic Fibrosis
Instruct patients to inform their healthcare provider if
- have a history of kidney disease, or
- 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
Instruct the patients to contact their physician if they
develop signs or symptoms of NSF following Clariscan administration, such as
burning, itching, swelling, scaling, hardening and tightening of the skin; red
or dark patches on the skin; stiffness in joints with trouble moving, bending
or straightening the arms, hands, legs or feet; pain in the hip bones or ribs;
or muscle weakness.
Common Adverse Reactions
Inform patients that they may experience:
- Reactions along the venous injection site, such as mild
and transient burning or pain or feeling of warmth or coldness at the injection
- Side effects of headache, nausea, abnormal taste and
- Pregnancy: Advise pregnant women of the potential risk of
fetal exposure to gadoterate [see Use In Specific Population]
- Gadolinium Retention: Advise patients that gadolinium is
retained for months or years in brain, bone, skin, and other organs in patients
with normal renal function. The clinical consequences of retention are unknown.
Retention depends on multiple factors and is greater following administration
of linear GBCAs than following administration of macrocyclic GBCAs [see
WARNINGS AND PRECAUTIONS].
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
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 Clariscan only if imaging is essential during
pregnancy and cannot be delayed.
The estimated background risk of major birth defects and
miscarriage for the indicated population(s) are unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
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.
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.
Gadoterate meglumine was administered in intravenous
doses of 0, 2, 4 and 10 mmol/kg/day [3, 7 and 16 times the recommended human dose
(RHD) based on body surface area (BSA)] to female rats for 14 days before
mating, throughout the mating period and until gestation day (GD) 17. Pregnant rabbits
were administered gadoterate meglumine in intravenous doses levels of 0, 1, 3
and 7 mmol/kg/day (3, 10 and 23 times the RHD based on BSA) from GD6 to GD19.
No effects on embryo-fetal development were observed at doses up to 10
mmol/kg/day in rats or 3 mmol/kg/day in rabbits. Maternal toxicity was observed
in rats at 10 mmol/kg/day and in rabbits at 7 mmol/kg/day. This maternal
toxicity was characterized in rats by a slightly lower litter size and gravid
uterus weight compared to the control group, and in rabbits by a reduction in
body weight and food consumption.
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 present in breast milk. Additionally, there is
limited GBCA gastrointestinal absorption in the breastfed infant. Gadoterate is
present in goat milk ( see Data). The developmental and health benefits
of breastfeeding should be considered along with the mother's clinical need for
Clariscan and any potential adverse effects on the breastfed infant from
Clariscan or from the underlying maternal condition.
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 administered dose was absorbed and eliminated in urine).
The safety and efficacy of Clariscan at a single dose of
0.1 mmol/kg have been established in pediatric patients from 2 to 17 years of
age based on clinical data in 133 pediatric patients 2 years of age and older.
Adverse reactions in pediatric patients were similar to those reported in
adults [see ADVERSE REACTIONS] . No dosage adjustment
according to age is necessary in pediatric patients [See DOSAGE AND
ADMINISTRATION, Pharmacokinetics] . The safety of Clariscan has not
been established in preterm neonates.
No cases of NSF associated with Clariscan or any other
GBCA have been identified in pediatric patients age 6 years and younger [see WARNINGS
AND PRECAUTIONS] . Normal estimated GFR (eGFR) is approximately 30
mL/minute/1.73 m² at birth and increases to adult values by 2 years of age.
Juvenile Animal Data
Single and repeat-dose toxicity studies in neonatal and
juvenile rats did not reveal findings suggestive of a specific risk for use in
Additional pediatric use information is approved for
Guerbet, LLC's Dotarem (gadoterate meglumine injection). However, due to
Guerbet LLC's marketing exclusivity, this drug product is not labeled with that
In clinical studies of Clariscan, 900 patients were 65
years of age and over, and 304 patients were 75 years of age and over. No
overall differences in safety or efficacy were observed between these subjects
and younger subjects. In general, use of Clariscan in elderly patients should
be cautious, reflecting the greater frequency of impaired renal function and
concomitant disease or other drug therapy. No age-related dosage adjustment is
No Clariscan dosage adjustment is recommended for
patients with renal impairment. Gadoterate meglumine can be removed from the
body by hemodialysis [see WARNINGS AND PRECAUTIONS and CLINICAL