MultiHance (Page 3 of 7)

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)]

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 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 DisordersNausea	67 (1.3%)
General Disorders and Administration Site DisordersInjection Site ReactionFeeling Hot	54 (1.1%)49 (1.0%)
Nervous System DisordersHeadacheDysgeusiaParesthesiaDizziness	60 (1.2%)33 (0.7%)24 (0.5%)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)].

Adverse events with variable onset and duration have been reported after GBCA administration [see Warnings and Precautions (5.3)]. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.

Skin: Gadolinium associated plaques.

7  DRUG INTERACTIONS

7.1  Transporter-Based Drug-Drug Interactions

MultiHance and other drugs may compete for the canalicular multispecific organic anion transporter (MOAT also referred to as MRP2 or ABCC2). Therefore MultiHance may prolong the systemic exposure of drugs such as cisplatin, anthracyclines (e.g. doxorubicin, daunorubicin), vinca alkaloids (e.g. vincristine), methotrexate, etoposide, tamoxifen, and paclitaxel. In particular, consider the potential for prolonged drug exposure in patients with decreased MOAT activity (e.g. Dubin Johnson syndrome).

8  USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

Risk Summary
GBCAs cross the 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, gadobenate dimeglumine has been shown to be teratogenic in rabbits following repeated intravenous administration during organogenesis at doses up to 6 times the recommended human dose. There were no adverse developmental effects observed in rats with intravenous administration of gadobenate dimeglumine during organogenesis at doses up to three times the recommended human dose (see Data). Because of the potential risks of gadolinium to the fetus, use MultiHance only if imaging is essential and cannot be delayed.

The estimated background risk of major birth defects and miscarriage for the indicated population is 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 to 4% and is 15 to 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 maternal 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
Gadobenate dimeglumine has been shown to be teratogenic in rabbits when administered intravenously at 2 mmol/kg/day (6 times the recommended human dose based on body surface area) during organogenesis (day 6 to 18) inducing microphthalmia/small eye and/or focal retinal fold in 3 fetuses from 3 separate litters. In addition, MultiHance administered intravenously at 3 mmol/kg/day (10 times the recommended human dose based on body surface area) has been shown to increase intrauterine deaths in rabbits. There was no evidence that MultiHance induced teratogenic effects in rats at doses up to 2 mmol/kg/day (3 times the recommended human dose based on body surface area), however, rat dams exhibited no systemic toxicity at this dose. There were no adverse effects on the birth, survival, growth, development and fertility of the F1 generation at doses up to 2 mmol/kg in a rat peri- and post-natal (Segment III) study.