USA

Dotarem® (gadoterate meglumine) Injection

For more information about Dotarem, please see the Full Prescribing Information and Medication Guide (also available: Spanish Version Medication Guide)

Dear Health Care Provider Letter-Gadolinium Retention.

Guerbet’s research team designed Dotarem® (gadoterate meglumine) with a unique profile, providing the highest molecular stability to minimize the risk of gadolinium release.1

Dotarem’s unique profile features:

    • The first and only macrocyclic & ionic GBCA molecule2
    • Patented manufacturing process3
    • More than 75 million global doses administered with zero unconfounded cases of NSF2,4,5
    • Following repeated administrations, no visible T1 signal intensity detected on noncontrast images within the brain6-10

Important Safety Information2

WARNING: NEPHROGENIC FIBROSIS (NSF)
Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with noncontrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.

  • The risk for NSF appears highest among patients with:
    • Chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), 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.
  • 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.

Indications and Usage
DOTAREM® (gadoterate meglumine) injection is a prescription 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 and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity.

Contraindications
History of clinically important hypersensitivity reactions to DOTAREM.

Warnings and Precautions

  • 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
  • Before DOTAREM administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to DOTAREM.
  • Administer DOTAREM only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation.
  • Gadolinium Retention: Gadolinium is retained for months or years in several organs. The highest concentrations have been identified in the bone, followed by 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.
  • Consequences of gadolinium retention in the brain have not been established. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention.
  • 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.
  • Extravasation and Injection Site Reactions: Ensure catheter and venous patency before the injection of DOTAREM. Extravasation into tissues during DOTAREM administration may result in tissue irritation.

Adverse Reactions

  • The most common adverse reactions associated with DOTAREM in clinical trials were nausea, headache, injection site pain, injection site coldness and rash.
  • Serious adverse reactions in the Postmarketing experience have been reported with DOTAREM. These serious adverse reactions include but are not limited to: arrhythmia, cardiac arrest, respiratory arrest, pharyngeal edema, laryngospasm, bronchospasm, coma and convulsion.

Use in Specific Populations

  • Pregnancy: GBCAs cross the human placenta and result in fetal exposure andgadolinium retention. Use only if imaging is essential during pregnancy and cannot be delayed.
  • Lactation: 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.
  • Pediatric Use: The safety and efficacy of DOTAREM at a single dose of 0.1 mmol/kg has been established in pediatric patients from birth (term neonates ≥ 37 weeks gestational age) to 17 years of age based on clinical data. 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.

You are encouraged to report negative side effects of prescription drugs to the FDA.Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see the full Prescribing Information, including the patient Medication Guide, for additional important safety information.

Physical Characteristics

(Please see Prescribing Information)

Osmolality mOsm/kg H2O

Viscosity mPa*s at 20˚C

Viscosity mPa*s at 37˚C

Thermodynamic Stability Log Ktherm*

Thermodynamic Stability Log Kcond† at pH 7.4

Kinetic Stability11 (Dissociation Half-life) T1/2 at pH 1.0 at 25˚C

Dotarem ®

1350

3.4

2.4

25.6

19.3

> 338 h

* Log Ktherm = absolute thermodynamic stability constant
† Log Kcond = conditional thermodynamic stability constant depending on pH

Packaging

DOTAREM® Vials1

DOTAREM Prefilled Syringes1

DOTAREM Pharmacy Bulk Package Vials2

Unit of Sale

5 mL, 10 mL, 15 mL or 20 mL available in glass vials

10mL, 15 mL, or 20 mL solution available in glass prefilled syringes

Pharmacy Bulk Package is supplied in 100 mL vials containing 100 mLof solution.

Unit/Carton

Vials are individually packaged in a shrinkwrapped package of 10.

Syringes, including plunger rod, are packaged in a shrink- wrapped package of 5.

Pharmacy Bulk Package is individually packaged in a shrink-wrapped package of 6.

Wholesale Minimum Order

1 Carton of 10 Vials

1 Carton of 5 Prefilled Syringes

1 Carton of 6 Vials

Storage

Store at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see United States Pharmacopeia (USP), Controlled Room Temperature (CRT)].

Store at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see United StatesPharmacopeia (USP), Controlled Room Temperature (CRT)]. Prefilled syringes must not be frozen. Frozen syringes should be discarded.

Store at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP, Controlled Room Temperature (CRT)].

Dotarem (gadoterate meglumine) Injection, 0.5 mmol/mL
5 mL in glass vials in a shrink wrapped package of 10 (NDC 67684-2000-0)
10 mL in glass vials in a shrink wrapped package of 10 (NDC 67684-2000-1)
15 mL in glass vials in a shrink wrapped package of 10 (NDC 67684-2000-2)
20 mL in glass vials in a shrink wrapped package of 10 (NDC 67684-2000-3)
100 mL in glass vials in a shrink wrapped package of 6 (NDC 67684-2000-4)
10 mL in glass pre-filled syringe in a shrink wrapped package of 5 (NDC 67684-2000-5)
15 mL in glass pre-filled syringe in a shrink wrapped package of 5 (NDC 67684-2000-6)
20 mL in glass pre-filled syringe in a shrink wrapped package of 5 (NDC 67684-2000-7)

Pharmacy Bulk Package: NOT FOR DIRECT INFUSION

Reimbursement Information*

For U.S. Reimbursement Information, please see attached information for Hospital Outpatient settings and Freestanding/Independent Diagnostic Testing Facility (IDTF) settings.

For further assistance, please contact DOTAREM Reimbursement Support at 1-855-368-2736, Monday–Friday, 7 am–7 pm ET.

Dotarem® is a registered trademark of Guerbet LLC or its affiliates, and is available by prescription only.

Legal Copyright 2018 Guerbet

REFERENCES

  1. Meyer D et al. Gd-DOTA, a potential MRI contrast agent. Current status of physicochemical knowledge. Invest Radiol. 1988 Sep;23 Suppl 1:S232-5.
  2. Dotarem [package insert]. Princeton, NJ: Guerbet LLC; Aug 2018.
  3. Patent US 9,655,983.
  4. Internal data as of January 2018.
  5. de Kerviler E et al. Adverse reactions to gadoterate meglumine: review of over 25 years of clinical use and more than 50 million doses. Invest Radiol. 2016 Sep;51(9):544-51.
  6. Radbruch A et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology. 2015 Jun;275(3):783-91.
  7. Radbruch A et al. Intraindividual analysis of signal intensity changes in the dentate nucleus after consecutive serial applications of linear and macrocyclic gadolinium-based contrast agents. Invest Radiol. 2016 Nov;51(11):683-690.
  8. Eisele P et al. Lack of increased signal intensity in the dentate nucleus after repeated administration of a macrocyclic contrast agent in multiple sclerosis: An observational study. Medicine (Baltimore). 2016 Sep;95(39): e4624.
  9. Radbruch A et al. Pediatric brain: no increased signal intensity in the dentate nucleus on unenhanced T1-weighted MR images after consecutive exposure to a macrocyclic gadolinium-based contrast agent. Radiology. 2017 Jun;283(3):828-836.
  10. Tibussek D et al. Gadolinium brain deposition after macrocyclic gadolinium administration: a pediatric case-control study. Radiology. 2017 Oct;285(1):223-30. Epub 2017 Jun 21.
  11. Hao D. et al. MRI contrast agents: basic chemistry and safety. J Magn Reson Imaging. 2012:36(5):1060-1071.

* Reimbursement information provided is for illustrative purposes only and does not constitute legal advice. Information provided is gathered from third party sources and is subject to change without notice due to frequently changing laws, rules and regulations. Guerbet makes no guarantee that the use of this information will prevent differences of opinion or disputes with Medicare or other third party payers as to the correct form of billing or the amount that will be paid to providers of service. The provider of service has the responsibility to determine medical necessity and to submit appropriate codes and charges for care provided. Please contact your local payers, reimbursement specialists and/or legal counsel for interpretation of coding, coverage, and payment policies. Guerbet does not promote the use of its products outside FDA-approved labeling.

GU12171115-A