ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions (>=1%) are headache, nausea, injection site coldness/localized coldness, and dizziness. (6)To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals at 1-888-84-BAYER (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The mean age of the 1272 patients who received Magnevist injection in pre-market clinical trials was 46.4 years (range to 93 years). Of these patients, 55% (700) were male and 45% (572) were female. Of the 1271 patients who received Magnevist injection and for whom race was reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3% (67) were Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were other.The most common adverse reaction was headache (4.8%). The majority of headaches were transient and of mild to moderate severity. Other adverse reactions that occurred in >= 1% of patients included: nausea (2.7%), injection site coldness/localized coldness (2.3%) and dizziness (1%).The following additional adverse reactions occurred in less than 1% of the patients:General Disorders: Injection site reactions, including phlebitis, pain, localized warmth, localized edema, and burning sensation [see Warnings and Precautions (5.5)]. Substernal chest pain, back pain, pyrexia, asthenia, feeling cold, generalized warmth, fatigue, and chest tightness, and anaphylactoid reactions characterized by cardiovascular, respiratory and/or cutaneous symptoms, such as dyspnea, bronchospasm, and cough. Cardiovascular: Hypotension, hypertension, tachycardia, migraine, syncope, vasodilatation, pallor.Gastrointestinal: Abdominal discomfort, teeth pain, increased salivation, abdominal pain, vomiting, diarrhea.Nervous System: Agitation, anxiety, thirst, somnolence, diplopia, loss of consciousness, convulsions (including grand mal), paresthesia.Respiratory System: Throat irritation, rhinitis, sneezing.Skin: Rash, sweating (hyperhidrosis), pruritus, urticaria (hives), facial edema.Special Senses: Conjunctivitis, taste abnormality, dry mouth, lacrimation, eye irritation, eye pain, ear pain.. 6.2 Postmarketing Experience. The following additional adverse reactions have been identified during postmarketing use of Magnevist. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.oAnaphylactic shock, respiratory distress, and laryngeal edema [see Warnings and Precautions (5.2)]oCardiac/respiratory arrest, shockoNephrogenic systemic fibrosis [see Warnings and Precautions (5.1)oGeneral Disorders and Administration Site Conditions: 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.oSkin: Gadolinium associated plaquesThe most frequently reported adverse reactions in the postmarketing experience were nausea, vomiting, urticaria, and rash.General Disorders and Administration Site Conditions: Nephrogenic systemic fibrosis [see Warnings and Precautions (5.1)], body temperature decreased, tremor, shivering (chills), injection site reactions including skin and soft tissue necrosis.Hypersensitivity Reactions: Anaphylactic/anaphylactoid reactions that may be fatal and include cardiac or respiratory arrest, respiratory distress, cyanosis, laryngeal edema, laryngospasm, pharyngeal edema, and angioedema [see Warnings and Precautions (5.2)].Delayed hypersensitivity reactions have been reported up to several hours after administration of Magnevist.Renal and Urinary: Acute renal failure, worsening renal impairment [see Warnings and Precautions (5.4)] urinary incontinence, urinary urgency.Vascular: Thrombophlebitis, deep vein thrombophlebitis, compartment syndrome requiring surgical intervention.Cardiac: Cardiac arrest, heart rate decreased, arrhythmia.Ear and Labyrinth Disorders: Hearing impairment.Eye Disorders: Visual disturbance.Musculoskeletal and Connective Tissue Disorder: Arthralgia.Nervous System Disorders: Coma, anosmia, speech disorder.Respiratory System: Respiratory arrest, pulmonary edema.Skin: Erythema multiforme, pustules oAnaphylactic shock, respiratory distress, and laryngeal edema [see Warnings and Precautions (5.2)]. oCardiac/respiratory arrest, shock. oNephrogenic systemic fibrosis [see Warnings and Precautions (5.1). oGeneral Disorders and Administration Site Conditions: 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.. oSkin: Gadolinium associated plaques.

BOXED WARNING SECTION.

WARNING: NEPHROGENIC SYSTEMIC 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 non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle, and internal organs.oDo not administer Magnevist to patients with:ochronic, severe kidney disease (GFR 30 mL/min/1.73m2), oroacute kidney injury [see Contraindications (4)]. oScreen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example, age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.Do not exceed the recommended Magnevist dose and allow sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)]. oDo not administer Magnevist to patients with:. ochronic, severe kidney disease (GFR 30 mL/min/1.73m2), or. oacute kidney injury [see Contraindications (4)]. oScreen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example, age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.. WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)See full prescribing information for complete boxed warning.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 non-contrasted MRI or other modalities.oDo not administer Magnevist to patients with:ochronic, severe kidney disease (GFR 30 mL/min/1.73m2), oroacute kidney injury. (4)oScreen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example, age 60 years, hypertension, or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. Do not exceed the recommended Magnevist dose and allow sufficient period of time for elimination of the drug from the body prior to any re-administration. (5.1). oDo not administer Magnevist to patients with:ochronic, severe kidney disease (GFR 30 mL/min/1.73m2), or. ochronic, severe kidney disease (GFR 30 mL/min/1.73m2), or. oacute kidney injury. (4). oScreen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example, age 60 years, hypertension, or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Gadopentetate dimeglumine is paramagnetic agent and, as such, it develops magnetic moment when placed in magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent.. 12.2 Pharmacodynamics. In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) changes in proton density; 2) alteration of the spin-lattice or longitudinal relaxation time (T1); and 3) variation of the spin-spin or transverse relaxation time (T2). When placed in magnetic field, gadopentetate dimeglumine decreases the T1 and T2 relaxation time in tissues where it accumulates. At usual doses, the effect is primarily on the T1 relaxation time.Disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadopentetate dimeglumine in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of Magnevist in various lesions are not known.. 12.3 Pharmacokinetics. The pharmacokinetics of intravenously administered gadopentetate dimeglumine in normal subjects conforms to two compartment open-model with mean distribution and elimination half-lives (reported as mean +- SD) of about 0.2 +- 0.13 hours and 1.6 +- 0.13 hours, respectively.Upon injection, the meglumine salt is completely dissociated from the gadopentetate dimeglumine complex. Gadopentetate is exclusively eliminated in the urine with 83 +- 14% (mean +- SD) of the dose excreted within hours and 91 +- 13% (mean +- SD) by 24 hours, post-injection.The renal and plasma clearance rates (1.76 +- 0.39 mL/min/kg and 1.94 +- 0.28 mL/min/kg, respectively) of gadopentetate are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (266 +- 43 mL/kg) is equal to that of extracellular water and clearance is similar to that of substances, which are subject to glomerular filtration. Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)] In vitro laboratory results indicate that gadopentetate does not bind to human plasma protein. In vivo protein binding studies have not been done.Renal ImpairmentGadopentetate dimeglumine is excreted via the kidneys, even in patients with impaired renal function. In patients with impaired renal function, the serum half-life of gadopentetate dimeglumine is prolonged. Mean serum elimination half-lives of single intravenous dose of gadopentetate dimeglumine (0.1 mmol/kg) were 2.6 +- 1.2 h, 4.2 +- 2.0 and 10.8 +- 6.9 h, for mildly (creatinine clearance, CLCR 60 to 90 mL/min), moderately (CLCR 30 to 60 mL/min) and severely (CLCR < 30 mL/min) impaired patients, respectively, as compared with 1.6 +- 0.1 in healthy subjects.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Magnevist injection was administered to 1272 patients in open label controlled clinical studies. The mean age of these patients was 46.4 years (range to 93 years). Of these patients, 55% (700) were male and 45% (572) were female. Of the 1271 patients who received Magnevist injection and for whom race was reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3% (67) were Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were other. Of the 1272 patients, 550 patients were evaluated in blinded reader studies. These evaluated the use of contrast enhancement in magnetic resonance imaging of lesions in the head and neck, brain, spine and associated tissues, and body (excluding the heart). Of the 550 patients, all patients had reason for an MRI and efficacy assessments were based on pre-and post- Magnevist injection film quality, film contrast, lesion configuration (border, size, and location), and the number of lesions. The protocols did not include systematic verification of specific diseases or histopathologic confirmation of findings.Of the above 550 patients, 97 patients received 0.1 mmol/kg Magnevist injection IV in two clinical trials of MAGNEVIST MRI contrast enhancement for body imaging. Of these 97, 68 had MRIs of the internal organs/structures of the abdomen or thorax (excluding the heart); had breast images and 22 had images of appendages. The results of MRIs before and after Magnevist use were compared blindly. Overall additional lesions were identified in 22/97 (23%) of the patients after Magnevist injection. The mean number of lesions identified before (1.49/patient) and after Magnevist (1.75/patient) were similar. Seven (8%) of the patients had lesions seen before Magnevist that were not seen after Magnevist. Overall, after Magnevist injection, 41% of the images had higher contrast score than before injection; and 18% of the images had higher contrast score before Magnevist injection than after Magnevist injection. Magnevist MRI of the patients with breast images were not systematically compared to the results to mammography, breast biopsy or other modalities. In the 22 patients with appendage images (e.g., muscle, bone and intraarticular structures), Magnevist MRI was not systematically evaluated to determine the effects of contrast biodistribution in these different areas.Of the above 550 patients, 66 patients received Magnevist 0.1 mmol/kg IV in clinical trials of Magnevist MRl contrast enhancement of lesions in the head and neck. total of 66 MRI images were evaluated blindly by comparing each pair of MRI images, before and after Magnevist injection. In these paired images, 56/66 (85%) had greater enhancement after Magnevist and 40/66 (61%) had better lesion configuration or border delineation after Magnevist. Overall, there was better contrast after Magnevist in 55% of the images, comparable enhancement in 44 (36%) before and after Magnevist, and better enhancement in 9% without Magnevist.In the studies of the brain and spinal cord, Magnevist 0.1 mmol/kg IV provided contrast enhancement in lesions with an abnormal blood brain barrier.In two studies, total of 108 patients were evaluated to compare the dose response effects of 0.1 mmol/kg and 0.3 mmol/kg of Magnevist in CNS MRI. Both dosing regimens had similar imaging and general safety profiles; however, the 0.3 mmol/kg dose did not provide additional benefit to the final diagnosis (defined as number of lesions, location, and characterization).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage of Magnevist injection is 0.2 mL/kg (0.1 mmol/kg) administered intravenously, at rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286 lbs has not been studied systematically.To ensure complete injection of Magnevist, administer 5-mL normal saline flush after the injection. The imaging procedure should be completed within hour of injection of Magnevist injection.Visually inspect 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. Discard any unused portion in accordance with regulations dealing with the disposal of such materials.DOSE AND DURATION OF MAGNEVIST INJECTION BY BODY WEIGHTBODY WEIGHTTotal Volume, mLlbkg221024420466306884081105010132601215470141768016198901822010020242110222641202428613026Rate of injection: 10 mL/15 secondsPharmacy Bulk Package Preparation: NOT FOR DIRECT INFUSIONThe Pharmacy Bulk Package contains multiple single doses and is used with an appropriate transfer device for filling empty sterile syringes.1.The transfer of Magnevist Injection from the Pharmacy Bulk Package must be performed in an aseptic work area, such as laminar flow hood, using aseptic technique.2.Once the Pharmacy Bulk Package is punctured, it should not be removed from the aseptic work area during the entire 24-hour period of use.3.The contents of the Pharmacy Bulk Package after initial puncture should be used within 24 hours.4.Any unused Magnevist Injection must be discarded 24 hours after the initial puncture of the bulk package.IV tubing and syringes used to administer Magnevist Injection must be discarded at the conclusion of the radiological examination.Any unused portion must be discarded in accordance with regulations dealing with the disposal of such material.. 1.The transfer of Magnevist Injection from the Pharmacy Bulk Package must be performed in an aseptic work area, such as laminar flow hood, using aseptic technique.. 2.Once the Pharmacy Bulk Package is punctured, it should not be removed from the aseptic work area during the entire 24-hour period of use.. 3.The contents of the Pharmacy Bulk Package after initial puncture should be used within 24 hours.. 4.Any unused Magnevist Injection must be discarded 24 hours after the initial puncture of the bulk package.. Magnevist is administered intravenously, 0.2 mL/kg (0.1 mmol/kg), at rate not to exceed 10 mL per 15 seconds. See the dosage table to determine the amount to be administered based on body weight. (2).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. oAdvise the patient to read the FDA-approved patient labeling (Medication Guide).Nephrogenic Systemic FibrosisGBCAs increase the risk of NSF among patients with impaired elimination of drugs. To counsel patients at risk of NSF:oDescribe the clinical manifestation of NSFoDescribe procedures to screen for the detection of renal impairmentInstruct the patients to contact their physician if they develop signs or symptoms of NSF following Magnevist administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness.Gadolinium RetentionoAdvise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs [see Warnings and Precautions (5.3)].(C)2000, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.Bayer HealthCare Pharmaceuticals Inc.Whippany, NJ 07981Manufactured in Germany. oAdvise the patient to read the FDA-approved patient labeling (Medication Guide).. oDescribe the clinical manifestation of NSF. oDescribe procedures to screen for the detection of renal impairment. oAdvise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs [see Warnings and Precautions (5.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of intravenously administered gadopentetate dimeglumine in normal subjects conforms to two compartment open-model with mean distribution and elimination half-lives (reported as mean +- SD) of about 0.2 +- 0.13 hours and 1.6 +- 0.13 hours, respectively.Upon injection, the meglumine salt is completely dissociated from the gadopentetate dimeglumine complex. Gadopentetate is exclusively eliminated in the urine with 83 +- 14% (mean +- SD) of the dose excreted within hours and 91 +- 13% (mean +- SD) by 24 hours, post-injection.The renal and plasma clearance rates (1.76 +- 0.39 mL/min/kg and 1.94 +- 0.28 mL/min/kg, respectively) of gadopentetate are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (266 +- 43 mL/kg) is equal to that of extracellular water and clearance is similar to that of substances, which are subject to glomerular filtration. Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)] In vitro laboratory results indicate that gadopentetate does not bind to human plasma protein. In vivo protein binding studies have not been done.Renal ImpairmentGadopentetate dimeglumine is excreted via the kidneys, even in patients with impaired renal function. In patients with impaired renal function, the serum half-life of gadopentetate dimeglumine is prolonged. Mean serum elimination half-lives of single intravenous dose of gadopentetate dimeglumine (0.1 mmol/kg) were 2.6 +- 1.2 h, 4.2 +- 2.0 and 10.8 +- 6.9 h, for mildly (creatinine clearance, CLCR 60 to 90 mL/min), moderately (CLCR 30 to 60 mL/min) and severely (CLCR < 30 mL/min) impaired patients, respectively, as compared with 1.6 +- 0.1 in healthy subjects.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryGBCAs 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, repeated intravenous dosing of gadopentetate dimeglumine during organogenesis resulted in delayed fetal development in pregnant rats and rabbits at dose times and 2.4 times, respectively, the recommended human dose (based on body surface area [BSA]). No teratogenic effects were observed in rats or rabbits at doses or 7.3 times (rats) and 9.7 times (rabbits) the recommended human dose, based on BSA(see Data). Because of the potential risks of gadolinium to the fetus, use Magnevist 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 is unknown. All pregnancies have 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 to 4% and is 15 to 20%, respectively.DataHuman DataContrast enhancement is visualized in the human placenta and fetal tissues after maternal GBCA administration.Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported clear association between GBCAs and adverse effects in the exposed neonates. However, retrospective cohort study, comparing pregnant women who had GBCA MRI to pregnant women who did not have an MRI, reported higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.Animal DataGadolinium RetentionGBCAs 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 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 Gadopentetate dimeglumine was administered intravenous during organogenesis at doses of at 0.25, 0.75, and 1.25 mmol/kg/day for 10 consecutive days in pregnant rats and for 13 consecutive days in pregnant rabbits. Gadopentetate dimeglumine caused retardation of fetal development at dose of 1.25 mmol per kg (rats) and 0.75 mmol per kg (rabbits); times and 2.4 times, respectively, the recommended human dose (based on BSA).Gadopentetate dimeglumine was not teratogenic in pregnant rats and rabbits when given repeatedly during organogenesis at dose of mmol per kg in rabbits and 4.5 mmol per kg in rats; 9.7 and 7.3 times, respectively, the recommended human dose (based on BSA).

SPL MEDGUIDE SECTION.

Medication GuideMEDICATION GUIDEMAGNEVIST (mag-na-vist)(gadopentetate dimeglumine) Injection for intravenous useWhat is MagnevistoMagnevist is prescription medicine called gadolinium-based contrast agent (GBCA). Magnevist, like other GBCAs, is injected into your vein and used with magnetic resonance imaging (MRI) scanner. oAn MRI exam with GBCA, including Magnevist, helps your doctor to see problems better than an MRI exam without GBCA.oYour doctor has reviewed your medical records and has determined that you would benefit from using GBCA with your MRI exam.What is the most important information should know about MagnevistoMagnevist contains metal called gadolinium. Small amounts of gadolinium can stay in your body including the brain, bones, skin and other parts of your body for long time (several months to years).oIt is not known how gadolinium may affect you, but so far, studies have not found harmful effects in patients with normal kidneys.oRarely, patients can feel pains, tiredness, and skin, muscle or bone ailments for long time, but these symptoms have not been directly linked to gadolinium.oThere are different GBCAs that can be used for your MRI exam. The amount of gadolinium that stays in the body is different for different gadolinium medicines. Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist, or MultiHance. Gadolinium stays in the body the least after Dotarem, Gadavist, or ProHance.oPeople who get many doses of gadolinium medicines, women who are pregnant and young children may be at increased risk from gadolinium staying in the body.oSome people with kidney problems who get gadolinium medicines can develop condition with severe thickening of the skin, muscles and other organs in the body (nephrogenic systemic fibrosis). Your healthcare provider should screen you to see how well your kidneys are working before you receive Magnevist.Do not receive Magnevist if you have had severe allergic reaction to Magnevist.Before receiving Magnevist, tell your healthcare provider about all your medical conditions, including if you:ohave had any MRI procedures in the past where you received GBCA. Your healthcare provider may ask you for more information including the dates of these MRI procedures.oare pregnant or plan to become pregnant. It is not known if Magnevist can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if GBCA such as Magnevist is received during pregnancy.ohave kidney problems, diabetes, or high blood pressure.ohave had an allergic reaction to dyes (contrast agents) including GBCAsWhat are the possible side effects of MagnevistoSee What is the most important information should know about MagnevistoAllergic reactions. Magnevist can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.The most common side effects of Magnevist include: headache, nausea, injection site coldness/localized coldness, and dizziness.These are not all the possible side effects of Magnevist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of MAGNEVIST.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your healthcare provider for information about MAGNEVIST that is written for health professionals.What are the ingredients in MagnevistActive ingredient: gadopentetate dimeglumineInactive ingredients: meglumine, meglumine pentetate, and water for injectionManufactured for Bayer HealthCare Pharmaceuticals Inc.Manufactured in Germany(C) 1988, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.For more information, go to www.magnevist.com or call 1-888-842-2937. This Medication Guide has been approved by the U.S. Food and Drug Administration. 4/2018. oMagnevist is prescription medicine called gadolinium-based contrast agent (GBCA). Magnevist, like other GBCAs, is injected into your vein and used with magnetic resonance imaging (MRI) scanner. oAn MRI exam with GBCA, including Magnevist, helps your doctor to see problems better than an MRI exam without GBCA.. oYour doctor has reviewed your medical records and has determined that you would benefit from using GBCA with your MRI exam.. oMagnevist contains metal called gadolinium. Small amounts of gadolinium can stay in your body including the brain, bones, skin and other parts of your body for long time (several months to years).. oIt is not known how gadolinium may affect you, but so far, studies have not found harmful effects in patients with normal kidneys.. oRarely, patients can feel pains, tiredness, and skin, muscle or bone ailments for long time, but these symptoms have not been directly linked to gadolinium.. oThere are different GBCAs that can be used for your MRI exam. The amount of gadolinium that stays in the body is different for different gadolinium medicines. Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist, or MultiHance. Gadolinium stays in the body the least after Dotarem, Gadavist, or ProHance.. oPeople who get many doses of gadolinium medicines, women who are pregnant and young children may be at increased risk from gadolinium staying in the body.. oSome people with kidney problems who get gadolinium medicines can develop condition with severe thickening of the skin, muscles and other organs in the body (nephrogenic systemic fibrosis). Your healthcare provider should screen you to see how well your kidneys are working before you receive Magnevist.. ohave had any MRI procedures in the past where you received GBCA. Your healthcare provider may ask you for more information including the dates of these MRI procedures.. oare pregnant or plan to become pregnant. It is not known if Magnevist can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if GBCA such as Magnevist is received during pregnancy.. ohave kidney problems, diabetes, or high blood pressure.. ohave had an allergic reaction to dyes (contrast agents) including GBCAs. oSee What is the most important information should know about Magnevist. oAllergic reactions. Magnevist can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.. This Medication Guide has been approved by the U.S. Food and Drug Administration. 4/2018.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Use only if imaging is essential during pregnancy and cannot be delayed. (8.1). 8.1 Pregnancy. Risk SummaryGBCAs 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, repeated intravenous dosing of gadopentetate dimeglumine during organogenesis resulted in delayed fetal development in pregnant rats and rabbits at dose times and 2.4 times, respectively, the recommended human dose (based on body surface area [BSA]). No teratogenic effects were observed in rats or rabbits at doses or 7.3 times (rats) and 9.7 times (rabbits) the recommended human dose, based on BSA(see Data). Because of the potential risks of gadolinium to the fetus, use Magnevist 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 is unknown. All pregnancies have 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 to 4% and is 15 to 20%, respectively.DataHuman DataContrast enhancement is visualized in the human placenta and fetal tissues after maternal GBCA administration.Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported clear association between GBCAs and adverse effects in the exposed neonates. However, retrospective cohort study, comparing pregnant women who had GBCA MRI to pregnant women who did not have an MRI, reported higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.Animal DataGadolinium RetentionGBCAs 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 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 Gadopentetate dimeglumine was administered intravenous during organogenesis at doses of at 0.25, 0.75, and 1.25 mmol/kg/day for 10 consecutive days in pregnant rats and for 13 consecutive days in pregnant rabbits. Gadopentetate dimeglumine caused retardation of fetal development at dose of 1.25 mmol per kg (rats) and 0.75 mmol per kg (rabbits); times and 2.4 times, respectively, the recommended human dose (based on BSA).Gadopentetate dimeglumine was not teratogenic in pregnant rats and rabbits when given repeatedly during organogenesis at dose of mmol per kg in rabbits and 4.5 mmol per kg in rats; 9.7 and 7.3 times, respectively, the recommended human dose (based on BSA).. 8.2 Lactation Risk SummaryLimited literature reports that breastfeeding after gadopentetate dimeglumine administration to the mother would result in the infant receiving an oral dose of 0.001 to 0.04% of the maternal dose. There is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Additionally, there is limited GBCA gastrointestinal absorption. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Magnevist and any potential adverse effects on the breastfed child from Magnevist or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential. InfertilityIntravenous injections of gadopentetate dimeglumine (16 to 18 doses over 23 to 25 days) caused spermatogenic cell atrophy and degeneration that was irreversible in male rats at dose of times (based on BSA) the recommended human dose [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. The use of Magnevist in imaging the central nervous system, extracranial/extraspinal tissues, and body have been established in the pediatric population from the ages of to 16 years on the basis of adequate and well controlled clinical trials in adults and safety studies in this pediatric population [see Clinical Studies (14)]. Safety and efficacy in the pediatric population under the age of years have not been established. Magnevist is eliminated primarily by the kidney. In study with pediatric patients aged months to 2 years the pharmacokinetics (body weight-normalized clearance, body weight-normalized distribution volume, and terminal half-life) of gadopentetate were similar to adults.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oNephrogenic Systemic Fibrosis (NSF) has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appears to increase the risk. (5.1)oHypersensitivity: Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory, and/or cutaneous manifestations rarely resulting in death have occurred. Monitor patients closely for need of emergency cardiorespiratory support. (5.2) oRenal Failure: In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred, mostly within 48 hours of Magnevist injection. (5.4)oGadolinium is retained for months or years in brain, bone, and other organs (5.3). oNephrogenic Systemic Fibrosis (NSF) has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appears to increase the risk. (5.1). oHypersensitivity: Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory, and/or cutaneous manifestations rarely resulting in death have occurred. Monitor patients closely for need of emergency cardiorespiratory support. (5.2) oRenal Failure: In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred, mostly within 48 hours of Magnevist injection. (5.4). oGadolinium is retained for months or years in brain, bone, and other organs (5.3). 5.1 Nephrogenic Systemic Fibrosis (NSF). Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR 30 mL/min/1.73m2) as well as patients with acute kidney injury. Do not administer Magnevist to these patients. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30- 59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60- 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle, and internal organs. Report any diagnosis of NSF following Magnevist 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 GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to patient. When administering Magnevist, do not exceed the recommended dose and allow sufficient period of time for elimination of the drug prior to re-administration [see Clinical Pharmacology (12.3) and Dosage and Administration (2)].. 5.2 Hypersensitivity Reactions. Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory, and/or cutaneous manifestations rarely resulting in death have occurred. The risk of hypersensitivity reactions is higher in patients with history of reaction to contrast media, bronchial asthma, or allergic disorders. Hypersensitivity reactions can occur with or without prior exposure to GBCAs.Have appropriately trained personnel administer Magnevist in facility that has immediate availability of resuscitative equipment. If hypersensitivity reaction occurs, stop Magnevist injection and immediately begin appropriate therapy.Observe closely patients with history of drug reactions, allergy, or other hypersensitivity disorders, during and up to several hours after Magnevist injection.. 5.3 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 Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention than other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)]. 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 (5.1)]. 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 GBCA for these patients. Minimize repetitive GBCA imaging studies particularly closely spaced studies, when possible.. 5.4 Renal Failure. In patients with renal impairment, acute renal failure (acute kidney injury) requiring dialysis or worsening renal function has occurred, mostly within 48 hours of Magnevist injection. The risk of acute renal failure is higher with increasing dose of contrast. Use the lowest possible dose, evaluate renal function in patients with renal impairment, and allow sufficient time for contrast elimination before re-administration. Elimination half-life in patients with mild or moderate renal impairment is to hours. Elimination half-life in patients with severe renal impairment is about 11 hours. Magnevist is cleared by glomerular filtration and is dialyzable. After dialysis sessions of hours each, about 97% of the administered dose is eliminated from the body; each dialysis session removes about 70% of the circulating drug [see Clinical Pharmacology (12.3)] 5.5 Injection Site Reactions. Skin and soft tissue necrosis, thrombosis, fasciitis, and compartment syndrome requiring surgical intervention (e.g. compartment release or amputation) have occurred very rarely at the site of contrast injection or the dosed limb. Total volume and rate of Magnevist injection, extravasation of contrast agent, and patient susceptibility might contribute to these reactions. Phlebitis and thrombophlebitis may be observed generally within 24 hours after Magnevist injection and resolve with supportive treatment. Determine the patency and integrity of the intravenous line before administration of Magnevist injection. Assessment of the dosed limb for the development of injection site reactions is recommended.. 5.6 Interference with Visualization of Lesions Visible with Non-Contrast MRI. As with any paramagnetic contrast agent, Magnevist injection might impair the visualization of lesions seen on non-contrast MRI. Therefore, caution should be exercised when Magnevist MRI scans are interpreted without companion non-contrast MRI scan.