Magnevist (Gadopentetate Dimeglumine)

MAGNEVIST®

Berlex Canada

Gadopentetate Dimeglumine

Contrast Enhancement Agent for Magnetic Resonance Imaging (MRI)

Action And Clinical Pharmacology: Gadopentetate dimeglumine was developed as a contrast agent for diagnostic use in magnetic resonance imaging (MRI). Gadolinium is a rare earth element. Its ion (Gd++ has 7 unpaired electrons and, therefore, shows paramagnetic properties. Gd++has a strong effect on the hydrogen-proton spin-lattice relaxation time (T1), which causes the observed contrast enhancement in MRI scans. By chelation of Gd++with diethylenetriamine pentaacetic acid (DTPA), a strongly paramagnetic, well-tolerated, stable complex (gadopentetate dimeglumine salt) is obtained.

The free gadolinium ion is unsuitable for clinical use due to high toxicity, however, the metal chelate is metabolically inert. The organic component of the chelate is not measurably metabolized and the metal does not dissociate. After i.v. injection of gadopentetate dimeglumine, the meglumine ion completely dissociates from the gadopentetate. The hydrophylic chelate is distributed only in the extracellular water and does not cross the intact blood-brain barrier. Gadopentetate is excreted unchanged in the urine. It is rapidly eliminated by the kidneys with a clearance identical to that of inulin (no tubular reabsorption).

Pharmacokinetics: The pharmacokinetic profile of i.v. administered gadopentetate dimeglumine in normal subjects conforms to a 2 compartment open model with a mean distribution half-life of about 0.2 hours and a mean elimination half-life of about 1.6 hours. Approximately 80% of the dose was excreted in the urine within 6 hours and 93% within 24 hours post injection of a 0.1 mmol/kg dose. Excretion in the feces amounted to
Gadopentetate dimeglumine has no pharmacodynamic effect when administered as indicated with the exception of slightly increased plasma osmolality.

Indications And Clinical Uses: By i.v. injection, for contrast enhancement during cranial and spinal MRI investigations in adults and children, to detect lesions associated with abnormal vascularity, or those thought to alter the blood-brain barrier.

Contra-Indications: Should not be administered to patients who are known or suspected of being hypersensitive to it.

Manufacturers’ Warnings In Clinical States: The decision to use gadopentetate dimeglumine must be made after careful evaluation of the risk-benefit in patients with a history of allergic disposition or bronchial asthma, since experience shows that these patients suffer more frequently than others from hypersensitivity reactions.

In very rare cases anaphylactoid reactions, including anaphylactic shock, may occur after i.v. injection of gadopentetate dimeglumine. It is important for prompt action in the event of such incidents to be familiar with the practice of emergency measures. To permit immediate countermeasures to be taken in emergencies, appropriate drugs and instruments (e.g., endotracheal tube and ventilator) should be readily available.

Deoxygenated sickle cell erythrocytes have been shown in in vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by gadopentetate dimeglumine may possibly potentiate sickle erythrocyte alignment. Gadopentetate dimeglumine in patients with sickle cell anemia and other hemoglobinopathies has not been studied.

No studies have been conducted in children with severe renal or hepatic dysfunction, clinically unstable or uncontrolled hypertension, or in premature infants.

MRI procedures which involve the use of gadopentetate dimeglumine by injection should be carried out by physicians who have the prerequisite training and a thorough knowledge of the particular procedure to be performed.

Precautions: General: Gadopentetate dimeglumine is to be administered strictly by i.v. injection. It will cause tissue irritation and pain if administered extravascularly or if it leaks interstitially.

A sweet taste may be experienced briefly by patients receiving a bolus injection of gadopentetate dimeglumine i.v.

Hemolytic States: Gadopentetate dimeglumine alters red blood cell morphology resulting in transient, slight, extravascular (splenic) hemolysis with increased serum iron and total bilirubin levels. Although this effect was of no clinical significance during clinical trials, caution is advised in patients with hepatic disease and/or hemolytic states.

Convulsive States: While there is no evidence suggesting that gadopentetate dimeglumine directly precipitates convulsion, the possibility that it may decrease the convulsive threshold in susceptible patients cannot be ruled out. Precautionary measures should be taken with patients predisposed to seizure, e.g., close monitoring and availability of injectable anticonvulsants (see Dosage).

Pregnancy: There are no studies on the use of gadopentetate dimeglumine in pregnant women. Gadopentetate dimeglumine should not be used during human pregnancy unless the potential benefit justifies the potential risk to the fetus.

Lactation: Transfer of gadopentetate dimeglumine into the milk of lactating mothers can occur. Thus breast-feeding should be interrupted for 24 hours postadministration of gadopentetate dimeglumine and the milk discarded during this period.

Geriatrics: No special precautions are required for elderly patients.

Adverse Reactions: General: Most adverse reactions develop soon after injection, however the possibility of delayed reactions cannot be ruled out. The most frequently reported adverse reactions following administration of gadopentetate dimeglumine are shown in Table I.

Adverse reactions occurred in 11 of 319 (3.4%) pediatric patients receiving gadopentetate dimeglumine in clinical trials (headache, vasodilatation, dizziness, diarrhea, ear pain, tachycardia, fever, edema, seizure, vomiting, nausea and urticaria). This adverse reaction profile is consistent with the adverse reaction profile observed in adults.

Gadopentetate dimeglumine will cause tissue irritation and pain if administered extravascularly.

Transient increases or decreases in blood pressure may occur after the administration of gadopentetate dimeglumine. These changes are generally of little consequence although 3 clinically significant cases of hypotension have occurred 2 to 6 hours after gadopentetate dimeglumine injection. A relationship to the contrast medium could not be determined, however caution should be exercised by the patient when driving or operating machinery.

Serious or severe adverse effects associated with gadopentetate dimeglumine have been rare in clinical experience. Postmarketing anaphylactic reactions have been reported, but are very rare. Convulsions were reported in 3 patients with a history of seizures.

Laboratory Changes: Reversible mild elevations over baseline in serum iron and total bilirubin occur in most patients after receiving gadopentetate dimeglumine. These changes do not appear to be clinically relevant. Other disturbances in laboratory values (transient increases in liver function tests) have not been associated with the use of gadopentetate dimeglumine.

Adverse Drug Reaction Profile: The following adverse reactions, listed according to body system, have been reported after administration of gadopentetate dimeglumine.

Cardiovascular: hypotension, vasodilatation, pallor, phlebitis, nonspecific ECG changes, substernal pain, angina.

CNS: headache, dizziness, agitation, paresthesia, tinnitus, visual field defect, convulsions, hyperesthesia.

Gastrointestinal: nausea, vomiting, gastrointestinal distress, stomach pain, thirst, increased salivation, taste abnormality.

Respiratory: dry mouth, throat irritation, rhinorrhea, wheezing, sneezing, laryngismus, cough, dyspnea/apnea.

Cutaneous/Mucous Membranes: rash, sweating, urticaria, pruritus.

Miscellaneous: injection site discomfort (coldness, burning, warmth, pain), teeth pain, generalized weakness, fever, localized edema, tiredness, anaphylactoid reactions (characterized by cardiovascular, respiratory and cutaneous symptoms), conjunctivitis.

Laboratory Tests: transient elevation of serum iron and bilirubin levels.

The following other adverse events were reported. A causal relationship has neither been established nor refuted.

Cardiovascular: hypertension, tachycardia, syncope, death related to myocardial infarction or other undetermined causes.

CNS: diplopia, migraine, anxiety, drowsiness, nystagmus, stupor.

Gastrointestinal: constipation, diarrhea, anorexia.

Cutaneous/Mucous Membranes: facial edema, erythema, epidermal necrolysis.

Miscellaneous: localized pain (back, ear, eye).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of inadvertent overdosage or in the case of severely impaired renal function, gadopentetate dimeglumine can be removed from the body by extracorporeal hemodialysis.

Dosage And Administration: Special preparation of the patient for examination with gadopentetate meglumine is not required; however, precautionary measures should be taken with patients predisposed to seizure, e.g., close monitoring and availability of injectable anticonvulsants (see Precautions). The usual safety rules for MRI (e.g., exclusion of ferromagnetic vascular clips) must be observed.

Young children, infants and neonates may require sedation prior to undergoing an MRI examination, in order to eliminate movement artifacts.

The following dosage guidelines apply to adults and children (including neonates and infants):

Recommended Dose: 0.2 mL/kg (0.1 mmol/kg).

Route of Administration: i.v. (into a large vein, if possible).

Rate of Administration: 10 mL/min or as a bolus injection at 10 mL/15 sec.

Maximum Total Dose: 20 mL.

To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush.

If strong clinical suspicion of an intracranial or intraspinal lesion persists, despite a normal MRI scan, the diagnostic yield of the examination may be increased by giving another injection of gadopentetate dimeglumine equivalent to the original total dose within 30 minutes and performing MRI again.

Gadopentetate dimeglumine should not be drawn into the syringe until immediately before use. Any unused portion must be discarded upon completion of the procedure.

T1-weighted scanning sequences are particularly suitable for contrast-enhanced examinations.

Gadopentetate dimeglumine has been shown to be effective in a wide range of field strengths (0.14 to 1.5 Tesla).

Important Note: The imaging procedure should be completed within 1 hour since optimal contrast is generally observed in cranial investigations within 27 minutes following injection of gadopentetate dimeglumine and in spinal investigations during the early postadministration phase (10 to 30 minutes).

In neonates and infants, optimal CNS contrast has been observed to persist for several hours after gadopentetate dimeglumine administration.

Supplied: Each mL of sterile, clear colorless to slightly yellow aqueous i.v. injection solution, contains: gadopentetic acid dimeglumine salt 469.01 mg (equivalent to 0.5 mmol/mL). Nonmedicinal ingredients: diethylenetriamine pentaacetic acid and meglumine. Osmolality: 1 960 mOsm/kg H2O at 37°C. Single dose vials of 10, 15 and 20 mL packaged in individual cartons. Store at 15 to 30°C and protect from light.

MAGNEVIST® Berlex Canada Gadopentetate Dimeglumine Contrast Enhancement Agent for Magnetic Resonance Imaging (MRI)

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