6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Nephrogenic systemic fibrosis [see Warnings and Precautions (5.1)] Hypersensitivity reactions [see Warnings and Precautions (5.2)] The most commonly reported adverse reactions are nausea (1.3%) and headache (1.2%). (6) To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical 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 practice. Adults In all clinical trials with MultiHance, a total of 4967 adult subjects (137 healthy volunteers and 4830 patients) received MultiHance at doses ranging from 0.005 to 0.4 mmol/kg. There were 2838 (57%) men and 2129 (43%) women with a mean age of 56.5 years (range 18 to 93 years). A total of 4403 (89%) subjects were Caucasian, 134 (3%) Black, 275 (6%) Asian, 40 (1%) Hispanic, 70 (1%) in other racial groups, and for 45 (1%) subjects, race was not reported. The most commonly reported adverse reactions in adult subjects who received MultiHance were nausea (1.3%) and headache (1.2%). Most adverse reactions were mild to moderate in intensity. One subject experienced a serious anaphylactoid reaction with laryngeal spasm and dyspnea [see Warnings and Precautions (5.2)]. Serious adverse reactions consisting of convulsions, pulmonary edema, acute necrotizing pancreatitis, and anaphylactoid reactions were reported in 0.1% of subjects in clinical trials. Adverse reactions that occurred in at least 0.5% of 4967 adult subjects who received MultiHance are listed below (Table 2), in decreasing order of occurrence within each system. TABLE 2: ADVERSE REACTIONS REPORTED IN ≥ 0.5% OF ADULT SUBJECTS WHO RECEIVED MULTIHANCE IN CLINICAL TRIALS Number of subjects dosed 4967 Number of subjects with any adverse reaction 517 (10.4%) Gastrointestinal Disorders Nausea 67 (1.3%) General Disorders and Administration Site Disorders Feeling Hot 49 (1.0%) Injection Site Reaction 58 (1.2%) Nervous System Disorders Headache 60 (1.2%) Dysgeusia 33 (0.7%) Paresthesia 24 (0.5%) Dizziness 24 (0.5%) The following adverse reactions occurred in less than 0.5% of the 4967 adult subjects who received MultiHance. Serious adverse reactions described above are not repeated below. Blood and Lymphatic System Disorders: Basophilia; Cardiac Disorders: Atrioventricular block first degree; Eye Disorders: Eye pruritus, eye swelling, ocular hyperemia, visual disturbance; Gastrointestinal Disorders: Abdominal pain or discomfort diarrhea, dry mouth, lip swelling, paraesthesia oral, tongue edema, vomiting; General Disorders and Administration Site Conditions: Chest pain or discomfort, chills, malaise; Immune System Disorders: Hypersensitivity; Investigations: Nonspecific changes in laboratory tests (including hematology, blood chemistry, liver enzymes and urinalysis), blood pressure and electrocardiogram parameters (including PR, QRS and QT intervals and ST-T segment changes). Musculoskeletal and Connective Tissue Disorders: Myalgia; Nervous System Disorders: Parosmia, tremor; Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, laryngospasm, nasal congestion, sneezing, wheezing; Skin and Subcutaneous Tissue Disorders: Hyperhidrosis, pruritus, rash, swelling face, urticaria. Pediatric Patients In clinical trials of MultiHance in MRI of the CNS, 307 pediatric subjects received MultiHance at a dose of 0.1 mmol/kg. A total of 160 (52%) subjects were male and the overall mean age was 6.0 years (range, 2 days to 17 years). A total of 211 (69%) subjects were Caucasian, 24 (8%) Black, 15 (5%) Asian, 39 (13%), Hispanic, 2 (<1%) in other racial groups, and for 16 (5%), race was not reported. Adverse reactions were reported for 14 (4.6%) of the subjects. The frequency and the nature of the adverse reactions were similar to those seen in the adult patients. The most commonly reported adverse reactions were vomiting (1.0%), pyrexia (0.7%), and hyperhidrosis (0.7%). No subject died during study participation. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of MultiHance. 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. Immune System Disorders: Anaphylactic, anaphylactoid and hypersensitivity reactions manifested with various degrees of severity up to anaphylactic shock, loss of consciousness and death. The reactions generally involved signs or symptoms of respiratory, cardiovascular, and/or mucocutaneous abnormalities. General Disorders and Administration Site Conditions: Extravasation of MultiHance may lead to injection site reactions, characterized by local pain or burning sensation, swelling, blistering, and necrosis[see Warnings and Precautions (5.4)]. Gadolinium retention: In patients with normal renal function, adverse events with variable onset and duration have been reported. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems [see Warnings and Precautions (5.3)]. Skin: Gadolinium associated plaques.