Magnograf

Overdose

No signs of intoxication secondary to an overdose have so far been observed or reported on clinical use.

Systemic consequences associated with overdosage of MAGNEVIST Injection have not been reported.

Contraindications

MAGNEVIST is contraindicated in patients with:

• Chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m²), or
• Acute kidney injury.

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Undesirable effects

Frequency of adverse reactions from clinical trial data

Based on experience in more than 4,900 patients, the undesirable effects listed below have been observed and classified by investigators as drug-related.

Adverse reactions with the use of Magnograf 2 mmol are usually of mild to moderate intensity.

The most frequently reported reactions were local injection site reactions, i.e. injection site pain and joint pressure sensations which are mainly related to the procedure itself.

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs).

The most appropriate MedDRA term is used to describe a reaction and its synonyms and related conditions.

- Immune system disorders/Hypersensitivity/Allergic reaction

Systemic hypersensitivity may occur rarely in the form of skin reactions. The possibility of a severe hypersensitivity reaction cannot be totally excluded.

- General disorders and administration site conditions

Injection of Magnograf 2 mmol/l into the joint is commonly associated with transient discomfort, e.g. pressure and pain due to the injected volume. Severe pain may often result from undue use of pressure or the injection of large volumes.

Other adverse reactions commonly known from intravenous injection of gadolinium chelates were so far not observed with Magnograf 2 mmol/l, due to the low dose and the topical administration.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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; 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. (See WARNINGS AND PRECAUTIONS.)

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.

The following additional adverse reactions have been identified during postmarketing use of Magnevist. 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.

The most serious reactions were nephrogenic systemic fibrosis (see BOXED WARNING) and acute reactions including cardiac or respiratory arrest, anaphylactic shock, shock, respiratory distress, and laryngeal edema. Life threatening and/or fatal adverse reactions have been reported. 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), body temperature decreased, tremor, shivering (chills).

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).

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), 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 impaired.

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 (rash pustular).

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of systemic toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and contact sensitising potential.

- Local tolerance

Experimental local tolerance studies with gadopentetic acid, dimeglumine (at a concentration of 500 mmol/l) following single subcutaneous and intramuscular administration in animals indicated that slight local intolerance reactions could occur at the injection site after inadvertent administration.

Therapeutic indications

For contrast enhancement in direct magnetic resonance arthrography.

This medicinal product is for diagnostic use by intraarticular administration only.

Magnograf 2 mmol/l should be used only when diagnostic information is essential and not available with unenhanced magnetic resonance imaging (MRI) and when another authorised product cannot be used.

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.

MAGNEVIST 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.

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 (excluding the heart).

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: paramagnetic contrast media, ATC code: V08CA01

Magnograf 2 mmol/l is a paramagnetic contrast agent for magnetic resonance imaging. The contrast-enhancing effect is mediated by the di-N-methylglucamine salt of gadopentetic acid, dimeglumine - the gadolinium complex of pentetic acid (diethylene triamine pentaacetic acid = DTPA). When a suitable scanning sequence (e.g. T1-weighted spin-echo technique) is used in proton magnetic resonance imaging, the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues.

Gadopentetic acid, dimeglumine is a highly paramagnetic compound which leads to distinct shortening of relaxation times, even in low concentrations. The paramagnetic efficacy, the relaxivity (determined from the influence on the spin-lattice relaxation time of protons) is 3.67 in water and about 4.95 l/mmol/sec in plasma, and displays only slight dependency on the strength of the magnetic field.

The concentration of Magnograf 2 mmol/l corresponds to 1/250 of the concentration used for i.v. administration. This concentration is sufficient to allow adequate imaging efficacy even after further dilution with joint effusion. If the joint cavity is filled with gadolinium-containing fluid, the signal in the cavity increases on use of T1-weighted sequences, i.e. it becomes bright and contrasts clearly with all structures with a weak or intermediate signal (i.e. all intraarticular structures: hyaline and fibrous cartilage, all ligaments, tendons and the joint capsule). While normal, or even increased, joint fluid does not differ in its signal behaviour in T1-weighted images from all the other anatomical structures apart from fibrocartilage, the intraarticular administration of Magnograf 2 mmol/l leads to distinctly improved contrast situations.

DTPA forms a firm complex with the paramagnetic gadolinium ion with extremely high in vivo and in vitro stability (log K = 22 - 23). The dimeglumine salt of gadopentetic acid, dimeglumine is a highly water-soluble, extremely hydrophilic compound with a distribution coefficient between n-butanol and buffer at pH 7.6 of about 0.0001. The substance does not display any particular protein binding or inhibitory interaction with enzymes (e.g. myocardial Na+ and K+ ATPase). Magnograf 2 mmol/l does not activate the complement system and, therefore, probably has a very low potential for inducing anaphylactoid reactions.

Based on clinical experience, impairment of hepatic, renal or cardiovascular function is not expected.

The physico-chemical properties of Magnograf 2 mmol/l listed below are:

Pharmacokinetic properties

The pharmacokinetic properties of gadopentetic acid, dimeglumine have been extensively studied after intravenous and oral administration in doses exceeding the amount injected intraarticularly.

After intraarticular injection the compound distributes in the synovial fluid and diffuses into the interstitial space. Marginal uptake into the cartilage is completely reversible.

After distribution in the extracellular space primarily through diffusion controlled processes, the gadopentetic acid, dimeglumine is eliminated unmetabolised via the kidneys by glomerular filtration.

Gadopentetic acid, dimeglumine salt is a linear GdCA. Studies have shown that after exposure to GdCAs given intravenously at significantly higher doses than intra-articular products gadolinium is retained in the body. This includes retention in the brain and in other tissues and organs. With the linear GdCAs this can cause dose-dependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Signal intensity increases and non-clinical data show that gadolinium is released from linear GdCAs.

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.

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.

Transitory changes in serum iron, bilirubin and transaminase levels were observed in clinical trials.

MAGNEVIST Injection does not interfere with serum and plasma calcium measurements determined by colorimetric assays.

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 also observed.

In a separate experiment in rats, daily injections of gadopentetate dimeglumine over 16 days caused spermatogenic cell atrophy at a dose level of 5 mmol/kg but not at a dose level of 2.5 mmol/kg. This atrophy was not reversed within a 16-day observation period following the discontinuation of the drug.

Gadopentetate dimeglumine retarded fetal development slightly when given intravenously for 10 consecutive days to pregnant rats at daily doses of 0.25, 0.75, and 1.25 mmol/kg (2.5, 7.5 and 12.5 times the human dose based on body weight) and when given intravenously for 13 consecutive days to pregnant rabbits at daily doses of 0.75 and 1.25 mmol/kg (7.5 and 12.5 times the human dose respectively, based on body weight) but not at daily doses of 0.25 mmol/kg. No congenital anomalies were noted in rats or rabbits.

Adequate and well controlled studies were not conducted in pregnant women. MAGNEVIST Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

MAGNEVIST is excreted in human milk. MAGNEVIST Injection was administered intravenously to 18 lactating women with normal renal function at a dose of 0.1 mmol/kg body weight. In these women, less than 0.04% of the administered gadolinium was excreted into the breast milk during the 24-hour period following dosing. Breast milk obtained during the 24 hours following dosing revealed the average cumulative amount of gadolinium excreted in breast milk was 0.57+/-0.71 micromoles. The amount transferred from a 70 kg woman (receiving 0.1 mmol/kg body weight) to an infant by breastfeeding over a period of 24 hrs translates into less than 3 micromoles of gadolinium.

The overall duration of excretion of gadolinium into breast milk is unknown. The extent of the absorption of MAGNEVIST Injection in infants and its effect on the breast-fed child remains unknown.

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 Trials for details.)

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. (See INDICATIONS and DOSAGE AND ADMINISTRATION.)

Systemic consequences associated with overdosage of MAGNEVIST Injection have not been reported.

MAGNEVIST is contraindicated in patients with:

• Chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m²), or
• Acute kidney injury.

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. There was no detectable biotransformation or decomposition of gadopentetate dimeglumine.

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.

In vitro laboratory results indicate that gadopentetate does not bind to human plasma protein. In vivo protein binding studies have not been done.

Gadopentetate 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 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.

Gadopentetate dimeglumine 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.

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.

Gadopentetate dimeglumine does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier, e.g., cysts, mature post-operative scars, etc. However, 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.

MAGNEVIST Injection was administered to 1272 patients in open label controlled clinical studies. The mean age of these patients 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. 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 a 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); 8 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 a higher contrast score than before injection; and 18% of the images had a higher contrast score before MAGNEVIST Injection than after MAGNEVIST Injection. MAGNEVIST MRI of the 8 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. A 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, a 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).

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Strict aseptic technique is required to prevent infection.

Fluoroscopic control should be used to ensure proper needle placement and prevent extracapsular injection. Undue pressure should not be exerted during injection.

Intraarticular injections of Magnograf 2 mmol/l should be avoided in infected joints.

- Hypersensitivity

Severe systemic hypersensitivity reactions cannot be totally excluded.

Mild angioedema, conjunctivitis, coughing, pruritus, rhinitis, sneezing and urticaria, which can occur irrespective of the amount administered and the mode of administration, may be the first signs of incipient state of shock.

As with other contrast agents, delayed reactions may occur (hours later or up to several days).

As with other contrast enhanced diagnostic procedures, post-procedure observation of the patient is recommended.

Medication for the treatment of hypersensitivity reactions as well as readiness for institution of emergency measures are necessary. Appropriate drugs and instruments (e.g. endotracheal tube and ventilator) must be readily available.

The risk of hypersensitivity reactions is higher in case of;

- previous reaction to contrast media,

- history of bronchial asthma,

- history of allergic disorders

The decision to use Magnograf 2 mmol/l must be made after particularly careful evaluation of the risk-benefit-ratio in patients with an allergic disposition.

After intravenous administration of gadopentetic acid, dimeglumine salt, gadolinium can be retained in the brain and in other tissues of the body (bones, liver, kidneys, skin) and can cause dose-dependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Clinical consequences are unknown. Retention of gadolinium in the brain has not been identified for intra-articular administration. The possible diagnostic advantages of using gadopentetic acid, dimeglumine salt in patients who will require repeated scans should be weighed against the potential for deposition of gadolinium in the brain and other tissues.

- Magnograf 2 mmol/l contains sodium

This medicinal product contains 3.4 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Included as part of the PRECAUTIONS section.

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 (1800-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 Magnevist, 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 and DOSAGE AND ADMINISTRATION).

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.

In patients with renal impairment, acute renal failure (acute kidney injury) requiring dialysis or worsening renal function has occurred, mostly within 48 hrs 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, Pharmacokinetics).

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.

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.

Transitory changes in serum iron, bilirubin and transaminase levels were observed in clinical trials.

MAGNEVIST Injection does not interfere with serum and plasma calcium measurements determined by colorimetric assays.

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 also observed.

In a separate experiment in rats, daily injections of gadopentetate dimeglumine over 16 days caused spermatogenic cell atrophy at a dose level of 5 mmol/kg but not at a dose level of 2.5 mmol/kg. This atrophy was not reversed within a 16-day observation period following the discontinuation of the drug.

Gadopentetate dimeglumine retarded fetal development slightly when given intravenously for 10 consecutive days to pregnant rats at daily doses of 0.25, 0.75, and 1.25 mmol/kg (2.5, 7.5 and 12.5 times the human dose based on body weight) and when given intravenously for 13 consecutive days to pregnant rabbits at daily doses of 0.75 and 1.25 mmol/kg (7.5 and 12.5 times the human dose respectively, based on body weight) but not at daily doses of 0.25 mmol/kg. No congenital anomalies were noted in rats or rabbits.

Adequate and well controlled studies were not conducted in pregnant women. MAGNEVIST Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

MAGNEVIST is excreted in human milk. MAGNEVIST Injection was administered intravenously to 18 lactating women with normal renal function at a dose of 0.1 mmol/kg body weight. In these women, less than 0.04% of the administered gadolinium was excreted into the breast milk during the 24-hour period following dosing. Breast milk obtained during the 24 hours following dosing revealed the average cumulative amount of gadolinium excreted in breast milk was 0.57+/-0.71 micromoles. The amount transferred from a 70 kg woman (receiving 0.1 mmol/kg body weight) to an infant by breastfeeding over a period of 24 hrs translates into less than 3 micromoles of gadolinium.

The overall duration of excretion of gadolinium into breast milk is unknown. The extent of the absorption of MAGNEVIST Injection in infants and its effect on the breast-fed child remains unknown.

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 Trials for details.)

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. (See INDICATIONS and DOSAGE AND ADMINISTRATION.)

Effects on ability to drive and use machines

No effects of Magnograf 2 mmol/l on driving ability and use of machinery can be expected. However, joint effusion may affect the ability to drive due to a limited joint mobility.

Dosage (Posology) and method of administration

The usual precautions for MRI (e.g. exclusion of cardiac pacemakers and other ferro-magnetic objects including vascular clips etc) must be observed.

Posology

The recommendations for the use of Magnograf 2 mmol/l apply to a field strength between 0.2 Tesla and 1.5 Tesla.

Intraarticular administrations of contrast agents are to be given with the patient lying or sitting. After the end of the injection, the patient should be kept under supervision for at least half an hour.

The lowest dose that provides sufficient enhancement for diagnostic purposes should be used.

Adults:

In general, for all joints the administration of up to 20 ml (knee joint up to 50 ml) Magnograf 2 mmol/l is sufficient for good opacification and to answer all the relevant clinical questions. A volume leading to a slight distension of the joint capsule should be injected. Only so much contrast medium should be injected until discrete resistance is felt and/or the patient experiences a mild feeling of pressure.

Guidelines on volumes to be administered:

Paediatric population:

The safety and efficacy of Magnograf 2 mmol/l in children aged up to 18 years has not yet been established. No data are available. Magnograf 2 mmol/l is not recommended in the paediatric age group until further data become available.

Method of administration

Contrast-enhanced MRI can be commenced immediately afterwards.

The recommended dosage of MAGNEVIST Injection is 0.2 mL/kg (0.1 mmol/kg) administered intravenously, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286 lbs has not been studied systematically.

DOSE AND DURATION OF MAGNEVIST INJECTION BY BODY WEIGHT

Drug Handling: To ensure complete injection of the contrast medium, the injection should be followed by a 5-mL normal saline flush. The imaging procedure should be completed within 1 hour of injection of MAGNEVIST Injection.

As with other gadolinium contrast agents, MAGNEVIST Injection has not been established for use in magnetic resonance angiography.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present.

Any unused portion must be discarded in accordance with regulations dealing with the disposal of such materials.

Special precautions for disposal and other handling

The prefilled syringe must be taken from the pack and prepared for the injection immediately before the examination and injected under sterile conditions.

The tip cap should be removed from the prefilled syringe immediately before use.

Any contrast medium solution not used in one examination must be discarded.

Mixture of Magnograf 2 mmol/l with X-ray contrast media before injection is not recommended as it may reduce efficacy. The minimal amount of X-ray contrast medium required for control of the needle position in the joint may be separately injected prior to the administration of Magnograf 2 mmol/l (0.5 ml to a maximum of 1.0 ml).