Gadoteric acid

Dotarem

1.8845GM/5ML, 3.769GM/10ML, 37.69GM/100ML … solutionVereinigte StaatenIm HandelZugelassen am 20. März 2013

Inhalt auf Englisch

Anwendungsgebiete

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 and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity. 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 and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity.

Gegenanzeigen

History of clinically important hypersensitivity reactions to DOTAREM [see Warnings and Precautions ( 5.2 )]. Clinically important hypersensitivity reactions to DOTAREM.

Warnhinweise und Vorsichtsmaßnahmen

Hypersensitivity Reactions: 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. ( 5.3 ) Gadolinium Retention: Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.4 )

5.1Risk 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 )].

5.2Nephrogenic Systemic Fibrosis

Anwendungsgebiete

Warnhinweise und Vorsichtsmaßnahmen

5.1Risk Associated with Intrathecal Use

5.2Nephrogenic Systemic Fibrosis

Schwangerschaft und Stillzeit

8.1Pregnancy Risk Summary

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 of 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, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively.

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 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. 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 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 of 0, 1, 3 and 7 mmol/kg/day (3, 10 and 23 times the RHD on 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 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.

Nebenwirkungen

The following clinically significant adverse reactions are described elsewhere in the labeling: Nephrogenic systemic fibrosis [see Warnings and Precautions ( 5.2 )] . Hypersensitivity reactions [see Warnings and Precautions ( 5.3 )] . Gadolinium Retention [see Warnings and Precautions ( 5.4 )] 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 .

6.1Clinical Trials 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. Table 2: Adverse Reactions in Clinical Trials Reaction Rate (%) n=2867 Nausea 0.6% Headache 0.4% Injection Site Pain 0.4% Injection Site Coldness 0.2% Rash 0.2% 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.

6.2Postmarketing Experience

The following additional adverse reactions have been identified during postmarketing use of DOTAREM or other GBCAs. 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. 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 Disorders muscle contracture, muscle weakness Gastrointestinal Disorders diarrhea, salivary hypersecretion, acute pancreatitis with onset within 48 hours after GBCA administration General Disorders and Administration Site Conditions malaise, fever Adverse reactions with variable onset and duration have been reported after GBCA administration.

These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems. Respiratory, Thoracic and Mediastinal Disorders Acute respiratory distress syndrome, pulmonary edema Skin and Subcutaneous Tissue Disorders NSF, in patients whose reports were confounded by the receipt of other 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

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Packung	Code	Status
GADOTERATE MEGLUMINE 1.8845GM/5ML (376.9MG/ML)	NDA204781-005	Prescription
GADOTERATE MEGLUMINE 5.6535GM/15ML (376.9MG/ML)	NDA204781-003	Prescription
GADOTERATE MEGLUMINE 37.69GM/100ML (376.9MG/ML)	NDA204781-001	Prescription
GADOTERATE MEGLUMINE 7.538GM/20ML (376.9MG/ML)	NDA204781-004	Prescription
GADOTERATE MEGLUMINE 3.769GM/10ML (376.9MG/ML)	NDA204781-002	Prescription

Dotarem

Anwendungsgebiete

Gegenanzeigen

Warnhinweise und Vorsichtsmaßnahmen

5.1Risk Associated with Intrathecal Use

5.2Nephrogenic Systemic Fibrosis

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Dotarem

Anwendungsgebiete

Gegenanzeigen

Warnhinweise und Vorsichtsmaßnahmen

5.1Risk Associated with Intrathecal Use

5.2Nephrogenic Systemic Fibrosis

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5.3Hypersensitivity Reactions Anaphylactic

5.4Gadolinium Retention

5.5Acute Kidney Injury

5.6Extravasation and Injection Site Reactions

Wechselwirkungen

Schwangerschaft und Stillzeit

8.1Pregnancy Risk Summary

Nebenwirkungen

6.1Clinical Trials Experience

6.2Postmarketing Experience

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