Md-76r

MD-76R (Diatrizoate Meglumine and Diatrizoate Sodium Injection USP) is a radiopaque contrast agent supplied as a sterile, aqueous solution. Intended for intravascular administration, MD-76R contains 66% w/v 1-deoxy-1-(methylamino)-D-glucitol 3,5-diacetamido-2,4,6, triiodobenzoate (salt) and 10% w/v monosodium 3,5-diacetamido-2,4,6, triiodobenzoate. The two salts have the following structural formulae:

Each mL provides 660 mg diatrizoate meglumine and 100 mg diatrizoate sodium, 0.125 mg monobasic sodium phosphate as a buffer and 0.11 mg edetate calcium disodium as a sequestering agent. The pH has been adjusted between 6.5 to 7.7 with either a meglumine and sodium hydroxide combination, or diatrizoic acid. Each mL contains approximately 3.65 mg (0.16 mEq) sodium and 370 mg of organically bound iodine. The viscosity of the solution is 16.4 cps at 25°C and 10.5 cps at 37°C. It is hypertonic to blood with an osmolality of 1551 m0sm/Kg. At the time of manufacture, the air in the container is replaced by nitrogen.

MD-76R should not be used for myelography.

Refer to PRECAUTIONS, General concerning hypersensitivity.

SEVERE ADVERSE EVENTS - INADVERTENT INTRATHECAL ADMINISTRATION: Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to ensure that this drug product is not administered intrathecally.

Ionic iodinated contrast media inhibit blood coagulation, in vitro, more than nonionic contrast media. Nonetheless, it is prudent to avoid prolonged contact of blood with syringes containing ionic contrast media. Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state, and concomitant medications may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended, including close attention to guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions and minimizing the length of the procedure. The use of plastic syringes in place of glass syringes has been reported to decrease, but not eliminate, the likelihood of in vitro clotting.

Serious or fatal reactions have been associated with the administration of iodine containing radiopaque media. It is of utmost importance to be completely prepared to treat any contrast medium reaction.

Serious neurologic sequelae, including permanent paralysis, have been reported following injections of concentrated contrast media into arteries supplying the spinal cord. The injection of a contrast medium should never be made following the administration of vasopressors, since they strongly potentiate neurologic effects (see PRECAUTIONS pertaining to Aortography).

In patients with subarachnoid hemorrhage, a rare association between contrast administration and clinical deterioration, including convulsions and death, has been reported. Therefore, administration of intravascular iodinated ionic contrast media in these patients should be undertaken with caution.

A definite risk exists in the use of intravascular contrast agents in patients who are known to have multiple myeloma. In such instances, there has been anuria resulting in progressive uremia, renal failure and eventually death. Although neither the contrast agent nor dehydration has separately proved to be the cause of anuria in myeloma, it has been speculated that the combination of both may be the causative factor. The risk in myelomatous patients is not a contraindication to the procedures; however, partial dehydration in the preparation of these patients for the examination is not recommended, since this may predispose to the precipitation of myeloma protein in the renal tubules. No form of therapy, including dialysis, has been successful in reversing this effect. Myeloma, which occurs most commonly in persons over age 40, should be considered before intravascular administration of a contrast agent.

Administration of radiopaque materials to patients known or suspected to have pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure and measures for treatment of a hypertensive crisis should be available.

Contrast media have been shown to promote the phenomenon of sickling in individuals who are homozygous for sickle cell disease when the material is injected intravenously or intra-arterially.

In patients with advanced renal disease, iodinated contrast media should be used with caution, and only when the need for the examination dictates, since excretion of the medium may be impaired. Patients with combined renal and hepatic disease, those with severe hypertension or congestive heart failure, and recent renal transplant recipients may present an additional risk.

Renal failure has been reported in patients with liver dysfunction who were given an oral cholecystographic agent followed by an intravascular iodinated radiopaque agent, and also in patients with occult renal disease, notably diabetics and hypertensives. In these classes of patients, there should be no fluid restriction and every attempt should be made to maintain normal hydration, prior to contrast medium administration, since dehydration is the single most important factor influencing further renal impairment.

Acute renal failure has been reported in diabetic patients with diabetic nephropathy and in susceptible nondiabetic patients (often elderly with pre-existing renal disease) following the administration of iodinated contrast agents. Therefore, careful consideration of the potential risks should be given before performing this radiographic procedure in these patients.

Caution should be exercised in performing contrast medium studies in patients with endotoxemia and/or those with elevated body temperatures.

Reports of thyroid storm occurring following the intravascular use of iodinated radiopaque agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule suggest that this additional risk be evaluated in such patients before use of this drug.

Serious Cutaneous Adverse Reactions: Severe cutaneous adverse reactions (SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). Reaction severity may increase and time to onset may decrease with repeat administration of contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering MD-76R to patients with a history of a severe cutaneous adverse reaction to MD-76R.

Avoid accidental introduction of this preparation into the subarachnoid space, since even small amounts may produce convulsions and possible fatal reactions.

Convulsions have occurred in patients with primary or metastatic cerebral lesions following administration of contrast media for contrast enhancement of CT brain images.

General

Diagnostic procedures which involve the use of iodinated intravascular contrast agents should be carried out under the direction of personnel skilled and experienced in the particular procedure to be performed. All procedures utilizing contrast media carry a definite risk of producing adverse reactions. While most reactions may be minor, life threatening and fatal reactions may occur without warning. The risk-benefit factor should always be carefully evaluated before such a procedure is undertaken. A fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse reactions of all types should always be available. If a serious reaction should occur, immediately discontinue administration. Since severe delayed reactions have been known to occur, emergency facilities and competent personnel should be available for at least 30 to 60 minutes after administration (see ADVERSE REACTIONS).

Preparatory dehydration is dangerous and may contribute to acute renal failure in infants, young children, the elderly, patients with pre-existing renal insufficiency, patients with advanced vascular disease and diabetic patients.

Severe reactions to contrast media often resemble allergic responses. This has prompted the use of several provocative pretesting methods, none of which can be relied on to predict severe reactions. No conclusive relationship between severe reactions and antigen-antibody reactions or other manifestations of allergy has been established. The possibility of an idiosyncratic reaction in patients who have previously received a contrast medium without ill effect should always be considered. Prior to the injection of any contrast medium, the patient should be questioned to obtain a medical history with emphasis on allergy and hypersensitivity. A positive history of bronchial asthma or allergy (including food), a family history of allergy, or a previous reaction or hypersensitivity to a contrast agent may imply a greater than usual risk. Such a history, by suggesting histamine sensitivity and consequently proneness to reactions, may be more accurate than pretesting in predicting the potential for reactions, although not necessarily the severity or type of reaction in the individual case. A positive history of this type does not arbitrarily contraindicate the use of a contrast agent when a diagnostic procedure is thought essential, but does call for caution (see ADVERSE REACTIONS).

Prophylactic therapy including corticosteroids and antihistamines should be considered for patients who present with a strong allergic history, a previous reaction to a contrast medium, or a positive pretest, since the incidence of reaction in these patients is two to three times that of the general population. Adequate doses of corticosteroids should be started early enough prior to contrast medium injection, and for 24 hours after injection. Antihistamines should be administered within 30 minutes of the contrast medium injection. Recent reports indicate that such pretreatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity. A separate syringe should be used for these injections.

The possibility of thrombosis should be borne in mind when percutaneous techniques are employed.

Consideration must be given to the functional ability of the kidneys before injecting this preparation.

General anesthesia may be indicated in the performance of some procedures in young or uncooperative children and in selected adult patients; however, a higher incidence of adverse reactions has been reported in these patients. This may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensive effect of anesthesia, which can prolong the circulation time and increase the duration of contact of the contrast agent.

Angiography should be avoided whenever possible in patients with hemocystinuria, because of the risk of inducing thrombosis and embolism.

Information for Patients

Patients receiving iodinated intravascular contrast agents should be instructed to:

1. Inform your physician if you are pregnant.
2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or known thyroid disease (see WARNINGS).
3. Inform your physician if you are allergic to any drugs, food or if you had any reactions to previous injections of dyes used for x-ray procedures (see PRECAUTIONS, General).
4. Inform your physician about any other medications you are currently taking, including non-prescription drugs.
5. Advise patients to inform their physician if they develop a rash after receiving MD-76R.

Drug/Laboratory Test Interactions

Iodine-containing contrast agents may alter the results of thyroid function tests which depend on iodine estimation, e.g., PBI and radioactive iodine uptake studies. Such tests, if indicated, should be performed prior to the administration of this preparation or delayed for about two weeks following administration.

Contrast agents may interfere with some chemical determinations made on urine specimens; therefore, urine should be collected before administration of the contrast medium, or two or more days afterwards.

Following selective coronary arteriography, transient elevation of creatinine phosphokinase (CPK) has occurred in approximately 30% of patients tested.

Post-arteriographic changes in laboratory studies include transient elevations in BUN, serum creatinine and glucose.

Hypertonic solutions cause a decrease in hematocrit in vitro and in vivo, and shrinkage of red blood cells.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed to evaluate carcinogenic potential. However, animal studies suggest that this drug is not mutagenic and does not affect fertility in males or females.

Pregnancy Category B

Diatrizoate sodium and diatrizoate meglumine administered intravenously cross the placenta and are evenly distributed in fetal tissues. No teratogenic effects attributable to diatrizoate sodium or diatrizoate meglumine have been observed in teratology studies performed in animals. There are, however, no adequate and well-controlled studies in pregnant women. Because animal teratology studies are not always predictive of human response, this agent should be used during pregnancy only if clearly needed.

Nursing Mothers

Diatrizoate salts are excreted in human milk. Because of the potential for adverse effects in nursing infants, bottle feedings should be substituted for breast feedings for 24 hours following the administration of this drug.

(Precautions for specific procedures receive comment under that procedure.)

Overdosage may occur. The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular system. The symptoms may include cyanosis, bradycardia, acidosis, pulmonary hemorrhage, convulsions, coma and cardiac arrest. Treatment of an overdose is directed toward the support of all vital functions and prompt institution of symptomatic therapy.

Diatrizoate salts are dialyzable.

The intravenous LD50 value of diatrizoate meglumine and diatrizoate sodium (in grams of iodine/kilogram body weight) varied from 5.3 to 6.1 g/kg in mice. The LD50 values decrease as the rate of injection increases.

Following intravenous injection, MD-76R is rapidly excreted by the kidneys. MD-76R may be visualized in the renal parenchyma 30 seconds following bolus injection. Maximum radiographic density in the calyces and pelves occurs in most instances within 3 to 8 minutes after injection. In patients with severe renal impairment, contrast visualization may be substantially delayed.

Patient Preparation

Appropriate preparation of the patient is important for optimal visualization. A low residue diet is recommended for the day preceding the examination and a laxative is given the evening before the examination, unless contraindicated.

Precautions

In addition to the general precautions previously described, infants and young children should not have any fluid restrictions prior to excretory urography. Injection of MD-76R represents an osmotic load which, if superimposed on increased serum osmolality due to partial dehydration, may magnify hypertonic dehydration (see WARNINGS and PRECAUTIONS, General concerning preparatory dehydration).

Usual Dosage

The dose range for adults is 20 to 40 mL; the usual dose is 20 mL; children require proportionately less. Suggested dosages are as follows:

In adults, when the smaller dose has provided inadequate visualization, or when poor visualization is anticipated, the 40 mL dose may be given.

The preparation is given by intravenous injection. If flushing or nausea occur during administration, injection should be slowed or briefly interrupted until the side effects have disappeared.

MD-76R may be administered intravenously or intra-arterially by accepted techniques to visualize the aorta and its major branches.

Warnings

In addition to the warnings previously described, during aortography by the translumbar technique, extreme care is advised to avoid inadvertent intrathecal injection, since the injection of even small amounts (5 to 7 mL) of the contrast medium may cause convulsions, permanent sequelae, or fatality. Should the accident occur, the patient should be placed upright to confine the hyperbaric solution to a low level, anesthesia may be required to control convulsions, and if there is evidence of a large dose having been administered, a careful cerebrospinal fluid exchange-washout should be considered.

Precautions

In addition to the general precautions previously described, the hazards of aortography include those associated with the particular technique employed, the contrast medium and the underlying pathology which warrants the procedure.

In order to prevent the inadvertent injection of a large dose into a branch of the aorta or intramurally, the position of the catheter tip or needle should be carefully evaluated. A small dose of 1 to 2 mL should be administered to locate the exact site of the needle or catheter tip. Inadvertent direct injection of contrast medium into brachiocephalic vessels may result in significant slowing of heart rate, peripheral hypotension and severe CNS reactions, including convulsions. Toxic effects may also be produced if large quantities of contrast medium are injected directly into aortic branches, such as the renal artery, and repetitive injection of the recommended clinical dosage may be hazardous.

Occasional serious neurologic complications, including paraplegia and quadriplegia, have been reported and may be attributable to an excessive dose being injected into arterial trunks supplying the spinal arteries or to prolonged contact time of the concentrated contrast medium on the CNS tissue. Conditions which can contribute to prolonged contact time include decreased circulation, aortic occlusions distal to the site of injection, abdominal compression, hypotension, general anesthesia or the administration of vasopressors. When these conditions exist or occur, the necessity of performing or continuing the procedure should be carefully evaluated, and the dose and number of repeat injections should be maintained at a minimum, with appropriate intervals between injections.

Severe pain, paresthesia, or peripheral muscle spasm during injection may require discontinuance of the procedure and a reevaluation of the placement of the catheter tip or needle.

Following catheter procedure, gentle pressure hemostasis is advised, followed by observation and immobilization of the limb for several hours to prevent hemorrhage from the site of arterial puncture.

Usual Dosage

For adults and children over 16 years of age, the usual dose is 15 to 40 mL as a single injection, repeated if indicated. Children require less in proportion to weight. Doses up to a total of 160 mL have been given safely.

Since the medium is given by rapid injection in this procedure, patients should be watched for untoward reactions during the injection. Unless general anesthesia is employed, patients should be warned that they may feel some transient pain or burning during the injection, followed by a feeling of warmth immediately afterward.

Precautions

In addition to the general precautions previously described, it is recommended that this procedure should not be performed for approximately four weeks following the diagnosis of myocardial infarction. Mandatory prerequisites to the procedure are experienced personnel, ECG monitoring apparatus, and adequate facilities for resuscitation and cardioversion.

Patients should be monitored continuously by ECG throughout the procedure.

Usual Dosage

The usual dosage is 4 to 10 mL injected into either coronary artery and repeated as necessary; doses up to a total of 150 mL have been given. For left ventriculography, the usual dose is 35 to 50 mL injected into the left ventricles and repeated as necessary. The total dose for combined selective coronary arteriography and left ventriculography should not exceed 200 mL.

Tumors

MD-76R may be useful to enhance the demonstration of the presence and extent of certain malignancies, such as: gliomas including malignant gliomas, glioblastomas, astrocytomas, oligodendrogliomas and gangliomas; ependyomas; medulloblastomas, meningiomas; neuromas; pinealomas; pituitary adenomas; craniopharyngiomas; germinomas; and metastatic lesions.

The usefulness of contrast enhancement for the investigation of the retrobulbar space and in cases of low grade or infiltrative glioma has not been demonstrated.

In cases where lesions have calcified, there is less likelihood of enhancement. Following therapy, tumors may show decreased or no enhancement.

Non-Neoplastic Conditions

The use of MD-76R may be beneficial in the image enhancement of non-neoplastic lesions. Cerebral infarctions of recent onset may be better visualized with the contrast enhancement, while some infarctions are obscured if contrast media are used. The use of iodinated contrast media results in contrast enhancement in about 60% of cerebral infarctions studied from one to four weeks from the onset of symptoms.

Sites of active infection may also be enhanced following contrast medium administration.

Arteriovenous malformations and aneurysms will show contrast enhancement. In the case of these vascular lesions, the enhancement is probably dependent on the iodine content of the circulating blood pool.

The opacification of the inferior vermis following contrast medium administration has resulted in false positive diagnoses in a number of normal studies.

Patient Preparation

No special patient preparation is required for contrast enhancement of CT brain scanning. However, it is advisable to ensure that patients are well hydrated prior to examination.

Usual Dosage

The usual dose is 0.6 mL per pound of body weight (1.3 mL/kg), not to exceed 125 mL, by intravenous administration. In most cases, scanning may be performed immediately after completion of administration. However, when fast scanning equipment (less than 1 minute) is used, consideration should be given to waiting approximately five minutes to allow for maximum contrast enhancement.