Clinical consequences of overdosage with Optimark have not been reported. Treatment of overdose is directed toward supporting vital functions and prompt institution of symptomatic therapy. Optimark has been shown to be dialyzable.
Optimark is contraindicated in patients with:
The following adverse reactions are discussed in greater detail in other sections of the prescribing information:
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 practice.
The adverse reactions described in this section were observed in a total of 1,309 subjects (24 healthy volunteers and 1,285 patients in clinical trials). Patients ranged in age from 12 to 85 years (mean age of 50 years) and 680 subjects (52%) were men. The ethnic distribution was 84% White, 9% Black, 3% Asian, and 4% other.
Overall, 460 subjects (35%) reported at least one adverse reaction. Most adverse reactions were mild or moderate in severity. The most commonly noted adverse reactions were: injection associated discomfort (26%), headache (9.4%), vasodilatation (6.4%), taste perversion (6.2%), dizziness (3.7%), nausea (3.2%), and paresthesia (2.2%). Table 2 lists adverse reactions reported in 1% or greater of patients.
Table 2 Adverse Reactions Experienced by
≥1% of Patients
| Body System or Event | Optimark (N = 1309) |
| Injection associated discomfort | 26.4% |
| Headache | 9.4% |
| Vasodilatation | 6.4% |
| Taste Perversion | 6.2% |
| Dizziness | 3.7% |
| Nausea | 3.2% |
| Paresthesia | 2.2% |
| Diarrhea | 1.9% |
| Pain Abdomen | 1.8% |
| Asthenia | 1.5% |
| Injection Site Reaction | 1.5% |
| Rhinitis | 1.5% |
| Dyspepsia | 1.2% |
| Pain Back | 1.2% |
| Pain | 1.0% |
The following adverse reactions occurred in less than 1% of the patients:
Body As A Wholeallergic reaction, facial edema, fever, malaise, neck rigidity, neck pain, pelvic pain, increased sweating
Cardiovasculararrhythmia, chest pain, hypertension, hypotension, pallor, palpitation, syncope, tachycardia, vasospasm
Digestiveanorexia, constipation, dry mouth, dysphagia, eructation, increased salivation, thirst, vomiting
Metabolic And Nutritionalincreased creatinine, edema, hypercalcemia
Musculoskeletalarthralgia, leg cramps, myalgia, spasm
Nervous Systemagitation, anxiety, confusion, diplopia, dystonia, hypertonia, hypesthesia, somnolence, tremor, vertigo
Respiratory Systemcough, dyspnea, laryngismus, pharyngitis, sinusitis, voice alteration
Skin And Appendageserythema multiforme, pruritus, rash, thrombophlebitis, urticaria
Special Sensesparosmia, tinnitus
Urogenitaloliguria
Post-Marketing ExperienceThe following adverse reactions have been identified during post-approval use of Optimark. 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 Optimark.
Optimark is indicated for use with magnetic resonance imaging (MRI) in patients with abnormal bloodbrain barrier or abnormal vascularity of the brain, spine and associated tissues.
MRI Of LiverOptimark is indicated for use with MRI to provide contrast enhancement and facilitate visualization of lesions with abnormal vascularity in the liver of patients who are highly suspect for liver structural abnormalities on computed tomography.
In MRI, visualization of normal and pathological brain, spinal and hepatic tissue depends in part on variations in the radiofrequency signal intensity that occurs with: 1) changes in proton density; 2) alterations of the spin-lattice or longitudinal relaxation time (T1); and 3) variation of the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoversetamide decreases T1 and T2 relaxation times in tissues where it accumulates. At the recommended dose, the effect is primarily on T1 relaxation time, and produces an increase in signal intensity (brightness).
The pharmacokinetics of intravenously administered gadoversetamide in normal subjects conforms to a two-compartment open-model with mean distribution and elimination half-lives (reported as mean ± SD) of about 13.3 ± 6.8 and 103.6 ± 19.5 minutes.
DistributionGadoversetamide does not undergo protein binding in vitro. In pregnant and lactating rats which received Gd-labeled gadoversetamide, radioactivity was detected in the placenta, fetus, and maternal milk. The volume of distribution at steady state of gadoversetamide in normal subjects is 162 ± 25 mL/kg, roughly equivalent to that of extracellular water.
Gadoversetamide does not appear to cross the intact blood-brain barrier in early- or delayed- phase imaging. However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadoversetamide in the extravascular spaces of lesions.
Deposition with Repeated Dosing
Increased signal intensity on non-contrast T1-weighted images within the brain, mainly the globus pallidus and the dentate nucleus, has been observed after multiple administrations of linear (ionic and nonionic) gadolinium-based contrast agents due to gadolinium deposition.
Following repeated GBCA administration, gadolinium deposits may be present for months or years in bone, liver, skin, brain, and other organs. Deposition depends on multiple factors and may be greater following administration of gadoversetamide and other linear GBCAs than following administration of macrocyclic GBCAs. GBCAs have been assocated with the development of NSF in patients with renal impairment. The clinical significance of gadolinium retention in the body and brain is otherwise unknown.
MetabolismGadoversetamide is not metabolized.
EliminationGadoversetamide (0.1 mmol/kg) is eliminated primarily in the urine with 95.5 ± 17.4% (mean ± SD) of the administered dose eliminated by 24 hours. Animal data demonstrated that insignificant levels of Gd-labeled gadoversetamide are eliminated via the feces. In experimentally induced anephria in the rat, hepatobiliary excretion did not significantly compensate for the absence of urinary elimination. The renal and plasma clearance rates of gadoversetamide in normal subjects are similar (69 ± 15.4 and 72 ± 16.3 mL/hr/kg, respectively) indicating that the drug is cleared through the kidneys via glomerular filtration. Within the studied dose range (0.1 to 0.7 mmol/kg), the kinetics of gadoversetamide appear to be linear.
Gadoversetamide is removed from the body by hemodialysis. Approximately 98% of the administered dose (0.1 mmol/kg) was cleared from the circulation over the three dialysis sessions that occurred 2 hours, 48 hours, and 120 hours after injection. After each of three dialysis sessions, respectively, 70%, 93%, and 98% of the administered dose was cleared from the plasma. The mean dialysis clearance of gadoversetamide was 93.2 ± 17.1 mL/min, or 48% of the creatinine clearance (194 ± 18.6 mL/min), using a high flux PMMA membrane.
There are no adequate and well-controlled studies in pregnant women. Optimark should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Gadoversetamide administered to rats reduced neonatal weights from birth through weaning at maternal doses of 0.5 mmol/kg/day (1 times the human dose based on body surface area) for 5 weeks (including gestation) and paternal doses of 0.5 mmol/kg/day for 12 weeks. This effect was not observed at 0.1 mmol/kg (0.2 times the human dose based on body surface area). Maternal toxicity was not observed at any dose.
Gadoversetamide injection caused a reduced mean fetal weight, abnormal liver lobation, delayed ossification of sternebrae, and delayed behavioral development (startle reflex and air righting reflex) in fetuses from female rats dosed with 4.9 mmol/kg/day (10 times the human dose based on body surface area) on days 7 through 17 of gestation. These effects were not observed at 0.7 mmol/kg/day (1 times the human dose based on body surface area). Maternal toxicity was observed at 4.9 mmol/kg/day.
Gadoversetamide injection caused forelimb flexures and cardiovascular changes in fetuses from female rabbits dosed with 0.4 and 1.6 mmol/kg/day (respectively, 1 and 4 times the human dose based on body surface area) on gestation days 6 through 18. The cardiovascular changes were malformed thoracic arteries, a septal defect, and abnormal ventricle. These effects were not observed at 0.1 mmol/kg/day (0.3 times the human dose based on body surface area). Maternal toxicity was not observed at any dose.
Optimark is supplied as a clear, colorless to slightly yellow solution for injection containing 330.9 mg gadoversetamide per mL (equivalent to 0.5 mmol/mL).
Storage And HandlingOptimark is a clear, colorless to slightly yellow solution containing 330.9 mg/mL (equivalent to 0.5 mmol/mL) of gadoversetamide for injection. Optimark is supplied in 10 mL vials containing 5 mL or 10 mL of solution and is also provided in 20 mL vials containing 15 mL or 20 mL of solution. Each single dose vial is rubber stoppered with an aluminum seal and the contents are sterile. Optimark is supplied in 10 mL, 15 mL, 20 mL or 30 mL syringes containing 10 mL, 15 mL, 20 mL or 30 mL of solution respectively. Each syringe is sealed with rubber closures and the contents are sterile. Vials and syringes are contained in shipping cartons with the following configurations:
5 mL in glass vials in cartons of 10 vials (NDC Code 0019-1177-02)
10 mL in glass vials in cartons of 10 vials (NDC Code 0019-1177-04)
15 mL in glass vials in cartons of 10 vials (NDC Code 0019-1177-06)
20 mL in glass vials in cartons of 10 vials (NDC Code 0019-1177-08)
10 mL in plastic syringes in cartons of 10 syringes (NDC Code 0019-1177-11)
15 mL in plastic syringes in cartons of 10 syringes (NDC Code 0019-1177-16)
20 mL in plastic syringes in cartons of 10 syringes (NDC Code 0019-1177-21)
30 mL in plastic syringes in cartons of 10 syringes (NDC Code 0019-1177-31)
Optimark should be stored at 20°C to 25°C (68°F to 77°F) and protected from light and freezing. Optimark may be stored at 37°C for up to one month in a contrast media warmer utilizing circulating warm air. For periods longer than one month, store at 20°C to 25°C (68°F to 77°F).
Manufactured by: Liebel-Flarsheim Company LLC, Raleigh, NC 27616. Revised: Aug 2016
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS 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 among these patients unless the diagnostic information is essential and not available with non-contrast enhanced 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. Do not administer Optimark to these patients. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 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 Optimark administration to Liebel-Flarsheim Company LLC (1-855-266-5037) 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 chronic kidney disease (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. When administering Optimark, do not exceed the recommended dose and allow a sufficient period of time for elimination of the drug prior to any re-administration.
Acute Kidney Injury (AKI)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.
Hypersensitivity ReactionsSevere hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products including Optimark. Before administering Optimark ensure the availability of resuscitation equipment and personnel trained in resuscitation techniques. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders may be at greater risk and should be closely observed during the procedure and for several hours after drug administration. If a reaction occurs, stop Optimark and immediately begin appropriate therapy including resuscitation.
Interference With Laboratory TestingInterference by Optimark in the measurements of serum iron, copper and zinc has been observed. Optimark causes interference in the measurement of serum calcium using the ortho-cresophthalin complexone (OCP) colorimetric method. In the presence of Optimark, OCP produces an erroneous, low value for serum calcium. The magnitude of this artifact is proportional to the concentration of Optimark in the blood, and accurate values can be obtained approximately 90 minutes following injection. In patients with renal insufficiency, clearance of Optimark is slowed and the interference with calcium determination by OCP is prolonged. Neither the arsenazo III dye system nor the inductively coupled plasma mass spectroscopy methods for calcium assay are affected by Optimark.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityLong-term animal studies have not been performed to evaluate the carcinogenic potential of gadoversetamide. The results of the following genotoxicity assays were negative: Salmonella/E. Coli reverse mutation (Ames) assay, mouse lymphoma mutagenesis assay, and the in vivo mammalian micronucleus assay. The in vitro CHO chromosome aberration assay without metabolic activation was positive.
Gadoversetamide administered to rats in a fertility study was shown to have irreversible reduction and degeneration of spermatocytes in testes and epididymides, and impaired male fertility following intravenous doses of 2.0 mmol/kg/day (4 times the human dose based on body surface area) for 7 weeks. These effects were not observed at dose of 0.5 mmol/kg/day (1 times the human dose based on body surface area).
In a separate 28-day repeat dose study in rats, gadoversetamide was shown to have irreversible reduction of male reproductive organ weights, degeneration of the germinal epithelium of the testes, presence of germ cells in the epididymides, and reduced sperm count following daily intravenous doses of 3.0 mmol/kg/day (6 times the human dose based on body surface area). These effects were not observed at 0.6 mmol/kg/day (1 times the human dose based on surface area). These effects were not observed in similar studies conducted in dogs.
In a single dose study in rats, gadoversetamide did not produce adverse effects on the male reproductive system 24 hours and 14 days after intravenous administration of 0.5 to 15 mmol/kg (1 to 25 times the human dose based on body surface area).
Use In Specific Populations Pregnancy Pregnancy Category CThere are no adequate and well-controlled studies in pregnant women. Optimark should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Gadoversetamide administered to rats reduced neonatal weights from birth through weaning at maternal doses of 0.5 mmol/kg/day (1 times the human dose based on body surface area) for 5 weeks (including gestation) and paternal doses of 0.5 mmol/kg/day for 12 weeks. This effect was not observed at 0.1 mmol/kg (0.2 times the human dose based on body surface area). Maternal toxicity was not observed at any dose.
Gadoversetamide injection caused a reduced mean fetal weight, abnormal liver lobation, delayed ossification of sternebrae, and delayed behavioral development (startle reflex and air righting reflex) in fetuses from female rats dosed with 4.9 mmol/kg/day (10 times the human dose based on body surface area) on days 7 through 17 of gestation. These effects were not observed at 0.7 mmol/kg/day (1 times the human dose based on body surface area). Maternal toxicity was observed at 4.9 mmol/kg/day.
Gadoversetamide injection caused forelimb flexures and cardiovascular changes in fetuses from female rabbits dosed with 0.4 and 1.6 mmol/kg/day (respectively, 1 and 4 times the human dose based on body surface area) on gestation days 6 through 18. The cardiovascular changes were malformed thoracic arteries, a septal defect, and abnormal ventricle. These effects were not observed at 0.1 mmol/kg/day (0.3 times the human dose based on body surface area). Maternal toxicity was not observed at any dose.
Nursing MothersRadiolabeled gadoversetamide (153Gd) was excreted in the milk of lactating rats receiving a single intravenous dose of 0.1 mmol/kg. Women should discontinue nursing and discard breast milk up to 72 hours after Optimark administration.
Pediatric UseThe safety and effectiveness of Optimark in pediatric patients have not been established. Pediatric patients may be particularly vulnerable to adverse GBCA reactions due to renal immaturity or unrecognized renal insufficiency.
Geriatric UseSince gadoversetamide is cleared from the body by glomerular filtration, the risk of adverse reactions may be greater in patients with impaired renal function (GFR ≥30 and <90 mL/min/1.73m2 ). Due to the risk for NSF, estimate the GFR through laboratory testing for patients >60 years of age.
Renal ImpairmentA single intravenous dose of 0.1 mmol/kg of Optimark was administered to 28 patients (17 men and 11 women) with impaired renal function (mean serum creatinine of 2.4 mg/dL). Sixteen patients had concurrent central nervous system or liver pathology. Renal impairment was shown to delay the elimination of gadoversetamide (see Table 3). The mean cumulative urinary excretion of gadoversetamide at 72 hours was approximately 93.5% for renally impaired patients and 95.8% for subjects with normal renal function. Dose adjustments in renal impairment have not been studied. Optimark has been shown to be removed from the body by hemodialysis.
Hepatic ImpairmentA single intravenous dose of 0.1 mmol/kg of Optimark was administered to 4 patients (2 men and 2 women) with impaired hepatic function. Hepatically impaired patients with normal renal function had plasma kinetics similar to normal subjects (see Table 3).
Table 3 Elimination Profiles of Normal, Renally Impaired and Hepatically Impaired Men and
Women (mean ± SD)
| Population | Elimination t1/2 (hours ) | |
| Men (N = 52) | Women (N = 48) | |
| Healthy Volunteers | 1.73 ± 0.31 (N = 8) | 1.73 ± 0.40 (N = 4) |
| Normal Patients | 1.90 ± 0.50 (N = 25) | 1.94 ± 0.57 (N = 31) |
| Renally Impaired | 8.74 ± 5.14 (N = 17) | 6.91 ± 2.46 (N = 11) |
| Hepatically Impaired | 2.09 ± 0.03 (N = 2) | 2.35 ± 1.09 (N = 2) |
Table 1 Dosage Chart for
Optimark Injection
| Body Weight Kilograms (kg) | 0.1 mmol/kg Volume (mL) |
| 40 | 8 |
| 50 | 10 |
| 60 | 12 |
| 70 | 14 |
| 80 | 16 |
| 90 | 18 |
| 100 | 20 |
| 110 | 22 |
| 120 | 24 |
| 130 | 26 |
| 140 | 28 |
| 150 | 30 |
The following adverse reactions are discussed in greater detail in other sections of the prescribing information:
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 practice.
The adverse reactions described in this section were observed in a total of 1,309 subjects (24 healthy volunteers and 1,285 patients in clinical trials). Patients ranged in age from 12 to 85 years (mean age of 50 years) and 680 subjects (52%) were men. The ethnic distribution was 84% White, 9% Black, 3% Asian, and 4% other.
Overall, 460 subjects (35%) reported at least one adverse reaction. Most adverse reactions were mild or moderate in severity. The most commonly noted adverse reactions were: injection associated discomfort (26%), headache (9.4%), vasodilatation (6.4%), taste perversion (6.2%), dizziness (3.7%), nausea (3.2%), and paresthesia (2.2%). Table 2 lists adverse reactions reported in 1% or greater of patients.
Table 2 Adverse Reactions Experienced by
≥1% of Patients
| Body System or Event | Optimark (N = 1309) |
| Injection associated discomfort | 26.4% |
| Headache | 9.4% |
| Vasodilatation | 6.4% |
| Taste Perversion | 6.2% |
| Dizziness | 3.7% |
| Nausea | 3.2% |
| Paresthesia | 2.2% |
| Diarrhea | 1.9% |
| Pain Abdomen | 1.8% |
| Asthenia | 1.5% |
| Injection Site Reaction | 1.5% |
| Rhinitis | 1.5% |
| Dyspepsia | 1.2% |
| Pain Back | 1.2% |
| Pain | 1.0% |
The following adverse reactions occurred in less than 1% of the patients:
Body As A Wholeallergic reaction, facial edema, fever, malaise, neck rigidity, neck pain, pelvic pain, increased sweating
Cardiovasculararrhythmia, chest pain, hypertension, hypotension, pallor, palpitation, syncope, tachycardia, vasospasm
Digestiveanorexia, constipation, dry mouth, dysphagia, eructation, increased salivation, thirst, vomiting
Metabolic And Nutritionalincreased creatinine, edema, hypercalcemia
Musculoskeletalarthralgia, leg cramps, myalgia, spasm
Nervous Systemagitation, anxiety, confusion, diplopia, dystonia, hypertonia, hypesthesia, somnolence, tremor, vertigo
Respiratory Systemcough, dyspnea, laryngismus, pharyngitis, sinusitis, voice alteration
Skin And Appendageserythema multiforme, pruritus, rash, thrombophlebitis, urticaria
Special Sensesparosmia, tinnitus
Urogenitaloliguria
Post-Marketing ExperienceThe following adverse reactions have been identified during post-approval use of Optimark. 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 Optimark.
Drug interactions with other contrast agents and other drugs have not been studied.
