Omniscan (Gadodiamide)

OMNISCAN®

Nycomed Imaging A.S.

Gadodiamide

Contrast Enhancement Agent for Magnetic Resonance Imaging (MRI)

Action And Clinical Pharmacology: Gadodiamide was developed as a contrast agent for diagnostic use in Magnetic Resonance Imaging (MRI). Gadodiamide is a paramagnetic agent with unpaired electron spins which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent.

In magnetic resonance imaging, visualization of normal and pathological brain and spinal tissue depends in part on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration of the spin-lattice or longitudinal relaxation time (T1); and variation of the spin-spin or transverse relaxation time (T2).

By increasing the relaxation rate, gadodiamide decreases both the T1 and T2 relaxation times in tissues where it is distributed. At clinical doses, the effect is primarily on the T1 relaxation time, and produces an increase in signal intensity.

Gadodiamide 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 postoperative scars, etc. [Lack of enhancement need not indicate absence of pathology since some types of low grade malignancies or inactive MS-plaques fail to enhance; it can be used for differential diagnosis between different pathologies.] Disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadodiamide in lesions such as neoplasms, abscesses and subacute infarcts. The extended time for gadodiamide to be accumulated in the lesions is unknown.

Pharmacokinetics: The pharmacokinetics of i.v. administered gadodiamide in normal subjects conforms to an open, 2 compartment model with mean distribution and elimination half-lives (reported as mean±SD) of 3.7±2.7 minutes and 77.8±16 minutes, respectively.

Gadodiamide is eliminated primarily in the urine with 95.4±5.5% (mean±SD) of the administered dose eliminated by 24 hours. There is no detectable biotransformation or decomposition of gadodiamide. The renal and plasma clearance rates of gadodiamide are nearly identical (1.7 and 1.8 mL/min/kg, respectively), and are similar to that of substances excreted primarily by glomerular filtration. The volume of distribution of gadodiamide (200±61 mL/kg) is equivalent to that of extracellular water. No protein binding has been observed.

Plasma clearance and elimination half-life were independent of dose after injection of 0.1 and 0.3 mmol/kg. No metabolites have been detected.

Secondary Pharmacodynamics: There were no clinically significant deviations from preinjection values in hemodynamic, blood and urine laboratory parameters following i.v. injection of gadodiamide in healthy volunteers. However, a minimal transient increase in serum iron levels 8 to 48 hours after gadodiamide injection was observed.

Indications And Clinical Uses: In adults and the pediatric population for contrast enhancement of Magnetic Resonance Imaging (MRI) of lesions of the CNS with expected abnormal vascularity or those thought to cause abnormalities in the blood-brain barrier. Gadodiamide has been shown to facilitate visualization of CNS lesions including but not limited to tumors.

For i.v. administration for use in MRI in adults to facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities, breast, retroperitoneal space and musculoskeletal system.

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

Manufacturers’ Warnings In Clinical States: As with any contrast agent, the possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or other idiosyncratic reactions should always be considered (see Adverse Effects), especially in those patients with a known clinical hypersensitivity. In the event of hypersensitive reactions, it is essential that medical personnel be familiar with the practice of emergency measures and that adequate equipment and drugs utilized in these situations be readily available for emergency treatment.

Patients with history of allergy or drug reaction should be observed for several hours after drug administration.

Deoxygenated sickle 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 gadodiamide may possibly potentiate sickle erythrocyte alignment. Gadodiamide injection in patients with sickle cell anemia and other hemoglobinopathies has not been studied.

Patients with other hemolytic anemias have not been adequately evaluated following administration of gadodiamide to exclude the possibility of increased hemolysis.

Precautions: General: Diagnostic procedures involving the use of contrast agents should be conducted under supervision of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. Gadodiamide should be drawn into the syringe and used immediately. If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

Since gadodiamide is cleared from the body by glomerular filtration, caution should be exercised in patients with impaired renal function. Gadodiamide can be removed from circulation by hemodialysis.

Adequate time should elapse between administration of iodine containing contrast media and enhanced MRI examination, due to the possibility of inducing reversible renal failure. A single case of reversible renal failure occurred in a clinical study when a patient with previously reported normal kidney function, was administered a high dose of gadodiamide within 24 hours of prior examination with an iodine containing contrast agent.

If, in the clinical judgment of the physician, sequential or repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body.

Children: At this time, there is no data in the pediatric population regarding the minimum period of time before a repeat injection of gadodiamide; see Pharmacology for information on pharmacokinetics in adults.

Convulsive States: While there is no evidence suggesting that gadodiamide directly precipitates convulsion, the possibility that it may decrease the convulsive threshold in susceptible patients cannot be ruled out. Appropriate precautionary measures should be taken with patients predisposed to seizure.

Laboratory Test Findings: Asymptomatic transitory changes in serum iron have been observed. The clinical significance is unknown.

Gadodiamide interferes with serum calcium measurements with some colorimetric (complexometric) methods commonly used in hospitals. It may also interfere with determinations of other electrolytes (e.g., iron). Thus it is recommended not to use such methods for 12 to 24 hours after administration of gadodiamide.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Gadodiamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Gadodiamide had no effects on fertility or reproductive performance in rats or in teratology studies in rats and rabbits at doses that did not cause maternal toxicity (1 mmol/kg).

Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when gadodiamide is administered to a nursing woman.

Children: No studies have been conducted in pediatric patients with severe renal or hepatic dysfunction; clinically unstable hypertension or uncontrolled hypertension; and in premature infants (see Adverse Effects).

Geriatrics: No specific precautions other than those pertinent to MRI and gadodiamide in general are applicable for elderly patients.

Adverse Reactions: Adults: The most frequent adverse reactions observed in patients during gadodiamide clinical trials were nausea, headache and dizziness with an incidence of 3% or less. The majority of these adverse reactions were of mild to moderate intensity.

The following adverse reactions occurred in less than 1% of the adult patients:

Application Site Disorders: injection site reaction.

Autonomic Nervous System Disorders: vasodilation.

Body as a Whole – General Disorders: anaphylactoid reactions (characterized by cardiovascular, respiratory, and cutaneous symptoms), asthenia, chest pain, fatigue, fever, hot flushes, malaise, pain, rigors, syncope.

Cardiovascular Disorders: cardiac failure, rare arrhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, deep thrombophlebitis.

Central and Peripheral Nervous System Disorders: aggravated migraine, ataxia, convulsions (including grand mal), abnormal coordination, aggravated multiple sclerosis (characterized by sensory and motor disturbances) paresthesia, tremor.

Gastrointestinal System Disorders: abdominal pain, diarrhea, eructation, melena, dry mouth, vomiting.

Hearing and Vestibular Disorders: tinnitus.

Musculoskeletal System Disorders: arthralgia, myalgia.

Psychiatric Disorders: anorexia, anxiety, personality disorder, somnolence.

Respiratory System Disorders: rhinitis, dyspnea.

Skin and Appendage Disorders: pruritus, rash, erythematous rash, skin discoloration, sweating increased, urticaria.

Special Senses, Other Disorders: taste loss, taste perversion.

Urinary System Disorders: acute reversible renal failure.

Vision Disorders: abnormal vision.

Children: Three adverse events occurred in 3 of 91 (3%) patients during gadodiamide clinical trials in pediatric patients. This includes all adverse events regardless of attribution.

Body as a Whole – General Disorders: fever.

Liver and Biliary System Disorders: abnormal hepatic function.

Skin and Appendage Disorders: rash.

The fever and rash were of mild intensity and the abnormal hepatic function was of severe intensity (although of uncertain relationship to administration of gadodiamide).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Clinical consequences of overdosage have not been reported and acute symptoms of toxicity are unlikely in patients with normal renal function. Treatment is symptomatic. There is no antidote for this contrast medium. In patients with delayed elimination due to renal insufficiency and in patients who have received excessive doses, the contrast medium may theoretically be eliminated by hemodialysis.

Dosage And Administration: Gadodiamide should be drawn into the syringe and used immediately. If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

Contrast-enhanced MRI should start shortly after administration of the contrast medium. Optimal enhancement is generally observed within 45 minutes after injection of gadodiamide. T1-weighted scanning sequences are particularly suitable for contrast-enhanced examinations with gadodiamide. In the investigated range of field strengths, from 0.15 Tesla up to 1.5 Tesla, the relative image contrast was found to be independent of the applied field strength.

The recommended dosage of gadodiamide for imaging of the CNS is 0.2 mL/kg (0.1 mmol/kg), administered as a bolus i.v. injection (see Table I). If medically indicated, preprocedural medication (e.g., sedatives) may be administered according to the normal routine for MR examinations. Any unused portion must be discarded.

To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL flush of 0.9% sodium chloride. The imaging procedure should be completed within 1 hour of administration of gadodiamide.

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

Availability And Storage: Each mL of sterile, clear, colorless to slightly yellow, aqueous solution contains: gadodiamide 287 mg, caldiamide sodium 12 mg and water for injection. The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. Vials of 10 mL (5 mL fill); vials of 10 mL; vials of 20 mL (15 mL fill); vials of 20 mL. Boxes of 10 single dose vials.

All solutions are sterilized by autoclaving and contain no preservatives. Unused portions must be discarded. Protect from light. Do not freeze. If inadvertently frozen, do not use gadodiamide solutions, as freezing could cause small cracks in the vials which would compromise the sterility of the product.

Store at controlled room temperature 15 to 30°C.

OMNISCAN® Nycomed Imaging A.S. Gadodiamide Contrast Enhancement Agent for Magnetic Resonance Imaging (MRI)

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