1.1 Central Nervous System

Magnevist injection is indicated for use with magnetic resonance imaging (MRI) in adults, and pediatric patients (2 years of age and older) to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues. Magnevist injection has been shown to facilitate visualization of intracranial lesions including but not limited to tumors.

1.2 Extracranial/Extraspinal Tissues

Magnevist injection is indicated for use with MRI in adults and pediatric patients (2 years of age and older) to facilitate the visualization of lesions with abnormal vascularity in the head and neck.

1.3 Body

Magnevist injection is indicated for use in MRI in adults and pediatric patients (2 years of age and older) to facilitate the visualization of lesions with abnormal vascularity in the body.

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 a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. When administering Gadopentetate dimeglumine, do not exceed the recommended dose and allow a 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 a 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 a facility that has immediate availability of resuscitative equipment. If a hypersensitivity reaction occurs, stop Magnevist injection and immediately begin appropriate therapy.

Observe closely patients with a history of drug reactions, allergy, or other hypersensitivity disorders, during and up to several hours after Magnevist injection.

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 3 to 4 hours. Elimination half-life in patients with severe renal impairment is about 11 hours. Magnevist is cleared by glomerular filtration and is dialyzable. After 3 dialysis sessions of 3 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 a companion non-contrast MRI scan.

6.1 Clinical Trial 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.

The mean age of the 1272 patients who received Magnevist injection in pre-market clinical trials was 46.4 years (range 2 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 Gadopentetate dimeglumine. 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.

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Anaphylactic shock, respiratory distress, and laryngeal edema [see Warnings and Precautions (5.2)]

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Cardiac/respiratory arrest, shock

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Nephrogenic systemic fibrosis [see Warnings and Precautions (5.1)]

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General Disorders and Administrations 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.

•

Skin: Gadolinium associated plaques

The 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 Gadopentetate dimeglumine.

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, parosmia, speech disorder.

Respiratory System: Respiratory arrest, pulmonary edema.

Skin: Erythema multiforme, pustules

7.1 Drug/Laboratory Test Interactions

There are no known drug interactions. Magnevist does not interfere with serum and plasma calcium measurements determined by colorimetric assays.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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 2 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 2 years have not been established. Magnevist is eliminated primarily by the kidney. In a study with pediatric patients aged 2 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.

12.1 Mechanism of Action

Magnevist is a paramagnetic agent and, as such, it develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a 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 a 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 a 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 6 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 Impairment

Magnevist 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 a single intravenous dose of gadopentetate dimeglumine (0.1 mmol/kg) were 2.6 ± 1.2 h, 4.2 ± 2.0 h 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 h in healthy subjects.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadopentetate dimeglumine.

A comprehensive battery of in vitro and in vivo studies in bacterial and mammalian systems suggest that gadopentetate dimeglumine is not mutagenic or clastogenic and does not induce unscheduled DNA repair in rat hepatocytes or cause cellular transformation of mouse embryo fibroblasts. However, the drug did show some evidence of mutagenic potential in vivo in the mouse dominant lethal assay at doses of 6 mmol/kg, but did not show any such potential in the mouse and dog micronucleus tests at intravenous doses of 9 mmol/kg and 2.5 mmol/kg, respectively.

When administered intra-peritoneally to male and female rats daily prior to mating, during mating, and during embryonic development for up to 74 days (males) or 35 days (females), gadopentetate caused a decrease in number of corpora lutea at the 0.1 mmol/kg dose level. After daily dosing with 2.5 mmol/kg suppression of food consumption and body weight gain (males and females) and a decrease in the weights of testes and epididymis were observed.

Intravenous injections of gadopentetate dimeglumine (16 to 18 doses over 23 to 25 days) caused spermatogenic cell atrophy and degeneration in male rats at a dose of 5 mmol per kg; 8 times (based on body surface area [BSA]) the recommended human dose.

Spermatogenesis was not affected in rats and dogs given repeatedly over 4 weeks at a dose of 2.5 mmol per kg or 4 times based on BSA (rats) and 14 times based on BSA (dogs) the recommended human dose.

16.1 How Supplied

Magnevist injection is a clear, colorless to slightly yellow solution containing 469.01 mg/mL of gadopentetate dimeglumine. Magnevist injection is supplied in the following sizes:

Single-Dose Vials

 

5 mL single-dose vials, rubber stoppered, in individual cartons of 10, 2 cartons per Box NDC 50419-188-81

 

10 mL single-dose vials, rubber stoppered, in individual cartons of 10, 2 cartons per Box NDC 50419-188-82

 

15 mL single-dose vials, rubber stoppered, in individual cartons of 10, 2 cartons per Box NDC 50419-188-83

 

20 mL single-dose vials, rubber stoppered, in individual cartons of 10, 2 cartons per Box NDC 50419-188-84

Single-Dose Pre-Filled Syringes

 

10 mL pre-filled disposable syringe, Boxes of 5 NDC 50419-188-36

 

15 mL pre-filled disposable syringe, Boxes of 5 NDC 50419-188-37

 

20 mL pre-filled disposable syringe, Boxes of 5 NDC 50419-188-38

16.2 Storage and Handling

Magnevist injection should be stored at controlled room temperature, between 15 - 30° C (59 - 86° F) and protected from light. DO NOT FREEZE. Should freezing occur in the vial, Magnevist injection should be brought to room temperature before use. If allowed to stand at room temperature for a minimum of 90 minutes, Magnevist injection should return to a clear, colorless to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and that the container and closure have not been damaged. Should solids persist, discard vial.