Dotarem

Dosage Forms And Strengths

DOTAREM 0.5 mmol/mL is a sterile, clear, colorless to yellow, aqueous solution for intravenous injection containing 376.9 mg/mL gadoterate meglumine and is available in vials and pre-filled syringes.

Storage And Handling

DOTAREM Injection is a clear, colorless to yellow solution containing 0.5 mmol/mL of gadoterate meglumine. It is supplied in vials and prefilled syringes.

• DOTAREM Injection is supplied in 10 mL vials containing 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. Vials are individually packaged in a shrink wrapped package of 10, in the following configurations:

5 mL in glass vial (NDC 67684-2000-0)
10 mL in glass vial (NDC 67684-2000-1)
15 mL in glass vial (NDC 67684-2000-2)
20 mL in glass vial (NDC 67684-2000-3)

• DOTAREM Injection is supplied in 10 mL pre-filled syringes containing 10 mL of solution and 20 mL prefilled syringes containing 15 mL or 20 mL of solution.

Each syringe is sealed with rubber closures and the contents are sterile. Syringes, including plunger rod, are packaged in a shrink wrapped package of 5, in the following configurations:

10 mL in glass pre-filled syringe (NDC 67684-2000-5)
15 mL in glass pre-filled syringe (NDC 67684-2000-6)
20 mL in glass pre-filled syringe (NDC 67684-2000-7)

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 to yellow 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.

Guerbet LLC 821 Alexander Road, Suite 204, Princeton, New Jersey 08540 Vials manufactured by Recipharm, France for Guerbet.  Revised: Aug 2017

Gadoterate is a magnetic resonance imaging (MRI) contrast agent. Contrast agents are used to help create a clear picture of the body during MRI scans. MRI scans are a special kind of diagnostic procedure. They use magnets and computers to create images or “pictures” of certain areas inside the body. Unlike x-rays, they do not involve ionizing radiation. Gadoterate is a gadolinium-based contrast agent (GBCA).

Gadoterate is given by injection before MRI to help diagnose problems in the brain, spine, head, neck, and other parts of your body.

This medicine is to be used only by or under the direct supervision of a doctor.

It is very important that your doctor check the progress of you or your child while you are receiving this medicine and during the MRI scan. This will allow your doctor to see if the medicine is working properly and to check for unwanted effects.

The risk of having a very serious disease called nephrogenic systemic fibrosis (NSF) is increased in patients with severe kidney disease. Even if you have severe kidney problems, your doctor may decide that it is still important to use this medicine. Check with your doctor right away if you or your child have burning or itching of the skin, red or dark patches on the skin, swelling, hardening, or tightening of the skin, joint stiffness, limited range of motion in the arms and legs, pain that is deep in the hip bone or ribs, or muscle weakness. These may be symptoms of NSF.

This medicine may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Check with your doctor or nurse right away if you or your child have cold, clammy skin, confusion, dizziness, lightheadedness, a skin rash, itching, sweating, swelling of the face, tongue, and throat, trouble with breathing, or chest pain after you receive the medicine.

Tell your doctor right away if you or your child have mild, burning pain, feeling of warmth or coldness, peeling of the skin, redness, or swelling at the injection site.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Blurred vision
• dizziness
• fast, irregular, pounding, or racing heartbeat or pulse
• headache
• nervousness
• pounding in the ears
• slow or fast heartbeat

• Areas of the skin that turn red or dark or feel tight
• bluish color of the fingernails, lips, skin, palms, or nail beds
• bone pain in the hips or ribs
• burning, dry, or itching eyes
• change in consciousness
• chest pain or discomfort
• cough
• difficulty with swallowing
• discharge or excessive tearing
• fainting
• fever
• hives or welts
• increased sweating
• itching
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• lightheadedness, dizziness, or fainting
• loss of consciousness
• muscle weakness
• no blood pressure or pulse
• no breathing
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• redness of the skin
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• shakiness in the legs, arms, hands, or feet
• skin rash
• skin that burns or itches, swells, scales, or hardens
• stiff joints or muscles
• stopping of the heart
• trembling or shaking of the hands or feet
• trouble moving your arms or legs
• unconsciousness
• unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• change in taste
• discomfort in the throat
• fear
• loss of taste
• nausea
• pain in the arms or legs
• pain, burning, or cold sensation at the injection site
• sleepiness or unusual drowsiness
• vomiting

• Transient, mild, pleasant aromatic odor

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use Dotarem as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a vein.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Dotarem 0.5 mmol/mL is a sterile, clear, colorless to yellow, aqueous solution for intravenous injection containing 376.9 mg/mL gadoterate meglumine.

Dotarem Pharmacy Bulk Package is available in vials.

GBCAs have been associated with a risk for NSF [see Warnings and Precautions (5.1)]. 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 and Precautions (5.2) and (5.3)].

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 2867 patients, representing 2682 adults and 185 pediatric patients. 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.

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 events were mild in intensity and transient in nature.

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.

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 the radiofrequency signal intensity that occurs with:

1. differences in proton density
2. 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.

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).

Gadoterate does not cross the intact blood-brain barrier and, therefore, does not enhance normal brain or lesions that have a normal blood-brain barrier, e.g. cysts, mature post-operative scars. However, disruption of the blood-brain barrier or abnormal vascularity allows distribution of gadoterate in lesions such as neoplasms, abscesses, and infarcts.

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 a second 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 in female 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.

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 % and 85.4 ± 9.7 % (mean ± SD) eliminated within 48 hours, in female and male subjects, respectively. Similar values were achieved 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 and 1.74 ± 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.

Special 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.

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, and 4 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 from less than one week to 23.8 months (mean 9.9 months) and body weight ranged from 3 to 15 kg (mean 8.1 kg). Individual level 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 model with 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 in pediatric subjects aged less than 2 years was similar to that observed in healthy adults.

These highlights do not include all the information needed to use Dotarem safely and effectively. See full prescribing information for Dotarem.

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

See full prescribing information for complete boxed warning 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-contra sted MRI or other modalities.

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 (for example, age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.

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

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 a flow rate of approximately 2 mL/second for adults and 1-2 mL/second for pediatric patients. The dose is delivered by manual or power injection.

Dosage Forms and Strengths

Dotarem Injection 0.5 mmol/mL contains 376.9 mg/mL of gadoterate meglumine and is available in vials and pre-filled syringes.

Contraindications

Clinically important hypersensitivity reactions to Dotarem.

Warnings and Precautions

• Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appear to increase the risk.
• Hypersensitivity: Anaphylactoid/anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred. Monitor patients closely for need of emergency cardiorespiratory support.