Gadavist

1 INDICATIONS AND USAGE GADAVIST is indicated for: Magnetic resonance imaging (MRI) of the central nervous system (CNS) to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity in adult and pediatric patients including term neonates MRI of the breast to assess the presence and extent of malignant breast disease in adult patients Magnetic resonance angiography (MRA) to evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients including term neonates Cardiac MRI (CMRI) to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD) GADAVIST is a gadolinium-based contrast agent indicated for use with magnetic resonance imaging (MRI): To detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system in adult and pediatric patients including term neonates To assess the presence and extent of malignant breast disease in adult patients To evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients including term neonates To assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD) ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended dose for adults and pediatric patients, including term neonates, is 0.1 mmol/kg actual body weight (equivalent to 0.1 mL/kg) administered by intravenous bolus injection. ( 2.1 , 2.2 ) See Full Prescribing Information for administration, imaging, and handling. ( 2.2 , 2.3 ) 2.1 Recommended Dose The recommended dose of GADAVIST for adult and pediatric patients, including term neonates, is 0.1 mmol/kg actual body weight (equivalent to 0.1 mL/kg) administered intravenously. For CMRI, the dose is divided into two separate, equal injections [see Dosage and Administration (2.2) ] . Refer to Table 1 for volumes to be administered for example body weights. Table 1: Volume of GADAVIST for Example Body Weights Body Weight (kg) Volume to be Administered (mL) 2.5 0.25 5 0.5 10 1 15 1.5 20 2 25 2.5 30 3 35 3.5 40 4 45 4.5 50 5 60 6 70 7 80 8 90 9 100 10 110 11 120 12 130 13 140 14 2.2 Administration and Imaging Instructions General GADAVIST is formulated at a higher concentration (1 mmol/mL) compared to certain other gadolinium-based contrast agents, resulting in a lower volume of administration [see Dosage and Administration (2.1) ]. GADAVIST is for intravenous use only and must not be administered intrathecally [see Warnings and Precautions (5.1) ]. Use aseptic technique when preparing and administering GADAVIST. Visually inspect GADAVIST for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored, if particulate matter is present, or if the container appears damaged. If solidification occurs due to cold exposure, bring GADAVIST to room temperature before use and inspect to ensure that the solution is clear and colorless to pale yellow. Do not mix GADAVIST with other medications and do not administer GADAVIST in the same intravenous line simultaneously with other medications. MRI of the CNS in Adult and Pediatric Patients Including Term Neonates Administer GADAVIST as an intravenous injection, manually or by power injector, at a flow rate of approximately 2 mL/sec. Follow GADAVIST injection with a flush of 0.9% Sodium Chloride Injection to ensure complete administration of the contrast. Post contrast MRI can commence immediately following contrast administration. MRI of the Breast in Adults Administer GADAVIST as an intravenous bolus by power injector, followed by a flush of 0.9% Sodium Chloride Injection to ensure complete administration of the contrast. Start image acquisition following GADAVIST administration and then repeat sequentially to determine peak intensity and wash-out. MR Angiography in Adult and Pediatric Patients Including Term Neonates Image acquisition should coincide with peak arterial concentration, which varies among patients. For adults, administer GADAVIST as an intravenous injection by power injector, at a flow rate of approximately 1.5 mL/sec, followed by a 30 mL flush of 0.9% Sodium Chloride Injection at the same rate to ensure complete administration of the contrast. For pediatric patients including term neonates, administer GADAVIST as an intravenous injection by power injector or manually, followed by a flush of 0.9% Sodium Chloride Injection to ensure complete administration of the contrast. Cardiac MRI in Adults Administer GADAVIST through a separate intravenous line in the contralateral arm if concomitantly providing a continuous infusion of a pharmacologic stress agent. Administer GADAVIST as two separate bolus injections: 0.05 mmol/kg actual body weight (equivalent to 0.05 mL/kg) at peak pharmacologic stress followed by 0.05 mmol/kg (equivalent to 0.05 mL/kg) at rest. Administer GADAVIST via a power injector at a flow rate of approximately 4 mL/sec and follow each injection with a 20 mL flush of 0.9% Sodium Chloride Injection at the same flow rate. 2.3 Directions for Use of Single-Dose Containers Single-Dose Vials Draw GADAVIST into the syringe immediately before use. Pierce the rubber stopper only once. Discard any unused vial contents. Single-Dose Prefilled Syringes Remove the tip cap from the prefilled syringe immediately before use. Discard any unused syringe contents. 2.4 Directions for Use of Imaging Bulk Package GADAVIST Imaging Bulk Package (IBP) contains many single doses for use only with an automated contrast injection system, contrast management system, or contrast media transfer set approved or cleared for use with this contrast agent in this IBP. See drug and device labeling for information on devices indicated for use with this IBP and techniques to help assure safe use. The IBP is to be used only in a room designated for radiological procedures that involve intravascular administration of a contrast agent. Utilize aseptic technique for penetrating the container closure of the IBP and transferring GADAVIST. Penetrate the container closure only one time with a suitable sterile component of the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) approved or cleared for use with this contrast agent in this IBP. Once the IBP is punctured, do not remove it from the work area during the entire period of use. Storage temperature of GADAVIST IBP after the closure has been entered is 20°C to 25°C (68°F to 77°F). Maximum use time from puncture is 24 hours. Discard any unused portion 24 hours after puncture of the IBP. After the container closure is punctured, if the integrity of the IBP and the delivery system cannot be assured through direct continuous supervision, the IBP and all associated disposable components for the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) should be discarded.

4 CONTRAINDICATIONS GADAVIST is contraindicated in patients with history of severe hypersensitivity reactions to GADAVIST [see Warnings and Precautions (5.3) ] . History of severe hypersensitivity reaction to GADAVIST ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have occurred. Monitor patients closely during and after administration of GADAVIST. ( 5.3 ) Acute Respiratory Distress Syndrome: For patients demonstrating respiratory distress after administration, assess oxygen requirement and monitor for worsening respiratory function. ( 5.4 ) Gadolinium Retention: Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.5 ) 5.1 Risk Associated with Intrathecal Use Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of GADAVIST have not been established with intrathecal use. GADAVIST is not approved for intrathecal use [see Dosage and Administration (2.2) ]. 5.2 Nephrogenic Systemic Fibrosis GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GADAVIST among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following GADAVIST administration to Bayer Healthcare (1-888-842-2937) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended GADAVIST dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . The usefulness of hemodialysis in the prevention of NSF is unknown . 5.3 Hypersensitivity Reactions Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, have occurred following GADAVIST administration [see Adverse Reactions (6.1 , 6.2) ]. There have been reports of life-threatening and fatal outcomes from these adverse reactions. Most hypersensitivity reactions to GADAVIST have occurred within half an hour after administration. Delayed reactions can occur up to several days after administration. Before GADAVIST 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 GADAVIST. GADAVIST is contraindicated in patients with history of hypersensitivity reactions to GADAVIST [see Contraindications (4) ] . Administer GADAVIST only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. Observe patients for signs and symptoms of hypersensitivity reactions during and following GADAVIST administration. 5.4 Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) has been reported in patients administered GADAVIST and may be characterized by severe hypoxemia requiring oxygen support and mechanical ventilation. These manifestations may resemble an immediate hypersensitivity reaction with onset of respiratory distress within <30 minutes to 24 hours after GADAVIST administration. For patients demonstrating respiratory distress after GADAVIST administration, assess oxygen requirement and monitor for worsening respiratory function. 5.5 Gadolinium Retention Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (for example, 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. At equivalent doses, gadolinium retention varies among the linear agents with gadodiamide causing greater retention than other linear agents such as gadoxetate disodium and gadobenate dimeglumine. Retention is lowest and similar among the macrocyclic GBCAs such as gadoterate meglumine, gadobutrol, gadoteridol, and gadopiclenol. Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function [see Warnings and Precautions (5.2) ] . There are rare reports of pathologic skin changes in patients with normal renal function. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention [see Adverse Reactions (6.2) ] . While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing a GBCA for these patients. Minimize repetitive GBCA imaging studies particularly closely spaced studies, when possible. 5.6 Acute Kidney Injury In patients with chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses. 5.7 Extravasation and Injection Site Reactions Injection site reactions have been reported in clinical studies with GADAVIST [see Adverse Reactions (6.1) ]. Extravasation into tissues during GADAVIST administration may result in moderate irritation [see Nonclinical Toxicology (13.2) ]. Ensure catheter and venous patency before the injection of GADAVIST. 5.8 Overestimation of Extent of Malignant Disease in MRI of the Breast GADAVIST MRI of the breast overestimated the histologically confirmed extent of malignancy in the diseased breast in up to 50% of the patients [see Clinical Studies (14.2) ]. 5.9 Low Sensitivity for Significant Arterial Stenosis The performance of GADAVIST MRA for detecting arterial segments with significant stenosis (>50% renal, >70% supra-aortic) has not been shown to exceed 55%. Therefore, a negative MRA study alone should not be used to rule out significant stenosis [see Clinical Studies (14.3) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in labeling: Nephrogenic Systemic Fibrosis [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.3) ] Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence ≥ 0.5%) are headache, nausea, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 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 clinical practice. The safety of GADAVIST was evaluated in 7,713 subjects (including 184 pediatric population, ages 0 to 17 years) who received GADAVIST in clinical trials. Approximately 52% of the subjects were male and the racial and ethnic distribution was 62% White, 28% Asian, 5% Hispanic or Latino, 2.5% Black or African American, and 2.5% other ethnic groups. The average age was 56 years (range from 1 week to 93 years). Table 2 lists adverse reactions that occurred in ≥ 0.1% subjects who received GADAVIST. Table 2: Adverse Reactions Reported in ≥0.1% Subjects who Received GADAVIST in Clinical Trials Adverse Reaction GADAVIST n=7,713 Rate (%) Headache 1.7 Nausea 1.2 Dizziness 0.5 Dysgeusia 0.4 Feeling Hot 0.4 Injection site reactions 0.4 Vomiting 0.4 Rash (includes generalized, macular, papular, pruritic) 0.3 Erythema 0.2 Paresthesia 0.2 Pruritus (includes generalized) 0.2 Dyspnea 0.1 Urticaria 0.1 Adverse reactions that occurred with a frequency of < 0.1% in subjects who received GADAVIST include: hypersensitivity/anaphylactic reaction, loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold. Adverse Reactions in Pediatric Patients The frequency, type, and severity of adverse reactions observed in pediatric patients from the clinical studies were similar to adverse reactions in adults [ s ee Use in Specific Populations (8.4) ] . 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of GADAVIST or other GBCAs. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Cardiac arrest Gastrointestinal Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration General Disorders and Administration Site Conditions: Fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems with variable onset and duration after GBCA administration [see Warnings and Precautions (5.5) ] Immune System Disorders: Hypersensitivity reactions (anaphylactic shock, circulatory collapse, respiratory arrest, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor) Renal Disorders: Nephrogenic systemic fibrosis Respiratory, Thoracic, and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edema Skin Disorders: Gadolinium associated plaques

8.1 Pregnancy Risk Summary GBCAs cross the placenta and result in fetal exposure. In human placental imaging studies, contrast was visualized in the placenta and fetal tissues after maternal GBCA administration. Based on animal studies, use of GBCAs during pregnancy may result in fetal gadolinium retention. Published epidemiological studies on the association between GBCAs and adverse fetal outcomes have reported inconsistent findings and have important methodological limitations (see Data ) . In animal reproduction studies, although teratogenicity was not observed, embryolethality was observed in monkeys, rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 times and above the recommended human dose. Retardation of embryonal development was observed in rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 and 12 times, respectively, the recommended human dose (see Data ). Because of the potential risks of gadolinium to the fetus, use GADAVIST only if imaging is essential during pregnancy and cannot be delayed. The 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 Available data regarding exposure to GBCAs during pregnancy from published epidemiological studies are not sufficient to assess the risk of adverse fetal and neonatal effects that may be associated with GBCAs. A retrospective cohort study of over 1.4 million pregnancies in Ontario, Canada, 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. Another retrospective cohort study of over 11 million pregnancies in the Medicaid database found no increased risk of fetal or neonatal death or Neonatal Intensive Care Unit admission when comparing pregnancies exposed to GBCA MRI versus non-contrast MRI. These two retrospective observational studies assessed a limited number of potential pregnancy outcomes and did not evaluate the full spectrum of potential fetal risk. 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 Embryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 8 times the recommended single human dose (based on body surface area); gadobutrol was not maternally toxic or teratogenic at this dose. Embryolethality and retardation of embryonal development also occurred in pregnant rats receiving maternally toxic doses of gadobutrol (≥ 7.5 mmol/kg body weight; equivalent to 12 times the human dose based on body surface area) and in pregnant rabbits (≥ 2.5 mmol/kg body weight; equivalent to 8 times the recommended human dose based on body surface area). In rabbits, this finding occurred without evidence of pronounced maternal toxicity and with minimal placental transfer (0.01% of the administered dose detected in the fetuses). Because pregnant animals received repeated daily doses of GADAVIST, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.