Trazograph® 76 %

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRAZOGRAF® 76 % (TRAZOGRAF® 76 %)

Composition:

Active substances: meglumine salt of diatrizoic acid, sodium salt of diatrizoic acid;

1 ml of solution contains 660 mg meglumine salt of diatrizoic acid, 100 mg sodium salt of diatrizoic acid (corresponding to a total iodine content of 370 mg);

Excipients: disodium edetate calcium dihydrate; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellow, slightly viscous liquid.

Pharmacotherapeutic group.

Water-soluble, highly osmolar nephrotropic X-ray contrast agents.

ATC code V08A A01.

Pharmacological Properties.

Pharmacodynamics.

Trasograf® 76 % is a radiopaque agent and a salt of amidotrizoic acid containing bound iodine, which absorbs X-rays.

Pharmacokinetics.

Distribution

After intravenous administration, the amount of the drug bound to plasma proteins does not exceed 10 %.

Five minutes after intravenous bolus administration of a 60 % solution of diatrizoic acid at a dose of 1 ml/kg body weight, plasma concentrations corresponding to 2–3 g of iodine per liter are achieved. Within 3 hours after administration, a relatively rapid decline in concentration is observed during the first 30 minutes, followed by a gradual decline with a half-life of 1–2 hours.

Diatrizoic acid does not penetrate into erythrocytes. After intravascular administration, it rapidly distributes into the extracellular fluid but does not cross the intact blood-brain barrier. The agent passes into breast milk only in minimal amounts.

Metabolism and Elimination

When administered in diagnostic doses, diatrizoic acid undergoes glomerular filtration in the kidneys. Approximately 15 % of the administered dose is excreted unchanged in urine within 30 minutes after administration, and more than 50 % within 3 hours; no metabolites have been detected.

Kinetic properties regarding distribution and elimination of the drug are independent of dose within the clinically relevant range. This means that when a double or half dose is administered, the drug concentration in blood and the amount of contrast agent eliminated from the body, in grams per unit time, will respectively double or halve. However, due to increased osmotic diuresis with a double dose, the concentration of the contrast agent in urine does not increase to the same extent.

Characteristics in Patients

In patients with impaired renal function, amidotrizoate may also be eliminated via extrarenal pathways through the liver, although at a considerably reduced rate. Contrast agents eliminated by the kidneys can be readily removed from the body by extracorporeal hemodialysis. Regardless of the site of administration, complete elimination from tissues occurs within a short period of time.

Clinical characteristics.

Indications.

Intravenous and retrograde urography.

In addition, angiography, as well as arthrography, intraoperative cholangiography, endoscopic retrograde cholangiopancreatography (ERCP), sialography, fistulography, hysterosalpingography, and other procedures.

Contraindications.

Hypersensitivity to components of the drug or to iodine-containing contrast agents. Hyperthyroidism, decompensated heart failure, severe renal and hepatic insufficiency; active tuberculosis and pulmonary emphysema; myocardial lesions (arrhythmia, ventricular fibrillation); severe arterial hypertension; shock and collapse; acute forms of phlebitis; epilepsy; significant increase in prothrombin index.

Trazograf® 76% must not be used for myelography, ventriculography, or cisternography due to the risk of provoking neurotoxic reactions (pain, convulsions, and coma, often with fatal outcome) when performing these procedures.

During pregnancy. Hysterosalpingography must not be performed in the presence of acute inflammatory processes in the pelvic cavity.

Endoscopic retrograde cholangiopancreatography (ERCP) is contraindicated in acute pancreatitis.

Interaction with other medicinal products and other types of interactions.

In patients with diabetic nephropathy who are taking biguanides, administration of contrast agents may lead to lactic acidosis. To prevent this complication, biguanide therapy should be discontinued 48 hours before the procedure. Before resuming biguanide treatment, renal function must be confirmed as normal.

Hypersensitivity reactions may be more pronounced in patients taking beta-adrenergic blockers.

Delayed reactions (e.g., fever, rash, pruritus, joint pain) and influenza-like symptoms occur more frequently in patients taking neuroleptics.

In patients who have received interleukin, the incidence of delayed reactions (e.g., fever, rash, influenza-like symptoms, joint pain, and pruritus) is higher.

Interaction with diagnostic tests

After intravascular administration of iodine-containing contrast agents, the thyroid gland's ability to uptake radioisotopes for diagnostic evaluation of thyroid disorders may be reduced for up to 2 weeks, and in some cases, even longer.

Special precautions for use.

Two days prior to the examination, the patient should avoid foods that promote flatulence, especially legumes, salads, coarse dark or freshly baked bread, milk, and all vegetables. The night before the examination, the patient must not eat after 6 p.m. In the evening, the bowel should be thoroughly emptied; if necessary, a laxative should be taken during the last two days before the examination. On the day of the examination, the patient should fast. In bedridden patients, gases should be removed from the stomach and intestines.

Since anxiety, fear, and pain may cause adverse effects or intensify the reaction to the contrast agent, a calming conversation with the patient or appropriate sedative therapy is recommended before the examination.

Prior to administration of Trasograf® 76%, the patient's fluid and electrolyte balance should be normalized. This is particularly important for patients with multiple myeloma, decompensated diabetes mellitus, polyuria, oliguria, or gout, as well as elderly patients, for whom fluid intake should not be restricted before the examination.

If the thyroid gland is being examined, iodine should be taken for several days, sometimes up to 2 weeks.

The precautions and warnings listed below apply to any route of administration; however, the risk of the situations described below is higher with intravascular administration.

• Hypersensitivity

Occasionally, hypersensitivity reactions occur after administration of iodinated contrast agents such as Trasograf® 76% (see section "Adverse reactions"). These are usually mild respiratory or cutaneous symptoms, such as mild respiratory distress, skin redness (erythema), urticaria, pruritus, or facial swelling. Severe adverse reactions, including angioneurotic edema, subglottic edema, bronchospasm, and anaphylactic shock, may also occur. Such reactions usually occur within 1 hour after contrast agent administration. However, delayed reactions (several hours or days after administration) are possible in rare cases.

Patients with known hypersensitivity or prior reaction to iodinated contrast agents have an increased risk of developing severe complications.

Prior to administration of any contrast agent, the patient's history should be reviewed for allergic reactions (e.g., seafood allergy, hay fever, urticaria), iodine sensitivity, prior reactions to radiographic contrast agents, or bronchial asthma, as serious reactions to contrast agents have been reported more frequently in patients with these conditions. Premedication with antihistamines and/or glucocorticoids may be considered.

Patients with bronchial asthma are at increased risk of bronchospasm or hypersensitivity reactions.

Hypersensitivity reactions may be exacerbated in patients taking beta-blockers, especially those with bronchial asthma. Additionally, it should be noted that patients taking beta-blockers may be unresponsive to standard treatment of hypersensitivity reactions with beta-agonists.

If hypersensitivity reactions occur (see section "Adverse reactions"), administration of the contrast agent must be immediately discontinued, and specific intravenous therapy should be initiated if necessary. Therefore, flexible indwelling cannulas (catheters) are recommended for intravenous contrast administration. Emergency equipment (appropriate medications, endotracheal intubation tube, and ventilator) should always be readily available to initiate immediate emergency measures.

• Thyroid dysfunction

A small amount of free inorganic iodide from iodinated contrast agents may affect thyroid function. Therefore, special caution is required when performing examinations in patients with latent hyperthyroidism or goiter due to the potential risk.

• Cardiovascular diseases

There is an increased risk of serious reactions in individuals with severe cardiac disease, particularly in patients with heart failure or coronary artery disease.

• Elderly patients

Vascular and neurological disorders commonly observed in elderly patients increase the risk of adverse reactions to iodinated contrast agents.

• Poor general health condition

Special caution is required when performing examinations in patients with severely compromised general health due to potential risks.

Intravascular administration

• Renal impairment

Transient renal impairment may occur in isolated cases. Preventive measures to avoid acute renal failure after contrast agent administration include:

• identification of high-risk patients, such as those with a history of kidney disease, renal impairment, contrast-induced nephropathy, diabetes with nephropathy, reduced circulating blood volume, multiple myeloma, patients aged 60 years or older, advanced vascular disease, paraproteinemia, severe or chronic hypertension, gout, or those receiving large or repeated doses of the agent;
• ensuring adequate hydration in high-risk patients before contrast agent administration, preferably via intravenous infusion before and after the procedure, and until the contrast agent is excreted by the kidneys;
• avoiding additional nephrotoxic burden, such as nephrotoxic drugs, oral cholecystographic agents, arterial compression, renal angioplasty, or major surgical procedures, until the contrast agent is eliminated;
• postponing subsequent contrast examinations until renal function returns to baseline levels.

Patients on dialysis may receive contrast agents for radiological procedures, as iodinated agents are removed during dialysis.

• Metformin therapy

The use of intravenous iodinated contrast agents, which are excreted by the kidneys, may cause transient renal dysfunction. This may lead to lactic acidosis in patients taking biguanides.

To prevent complications, biguanide therapy should be discontinued 48 hours before contrast agent administration and not resumed for at least 48 hours afterward. Therapy may be restarted only after renal function has returned to normal.

• Cardiovascular diseases

In patients with cardiac valve disorders or pulmonary hypertension, contrast agent administration may cause significant hemodynamic changes. Reactions including ischemic ECG changes and severe arrhythmias are more common in elderly patients and those with a history of heart disease.

Intravenous administration of contrast agents may lead to pulmonary edema in patients with heart failure.

• Central nervous system (CNS) disorders

Special attention should be paid during intravenous contrast administration in patients with acute ischemic stroke, acute intracranial hemorrhage, or other conditions involving blood-brain barrier disruption, cerebral edema, or acute demyelination. Intracranial tumors or metastases and a history of epilepsy may increase the frequency of seizures after administration of iodinated contrast agents.

Neurological symptoms may worsen due to cerebrovascular disease, intracranial tumors or metastases, degenerative or inflammatory conditions. Vascular spasm and, consequently, cerebral ischemia may be induced by intra-arterial contrast administration. Patients with symptomatic cerebrovascular disease, recent stroke, or frequent transient ischemic attacks are at increased risk of neurological complications.

• Severe hepatic dysfunction

In cases of severe renal impairment, concomitant severe hepatic dysfunction may significantly delay contrast agent excretion, possibly requiring hemodialysis.

• Myeloma and paraproteinemia

Myeloma or paraproteinemia may predispose to renal failure after contrast agent administration. Adequate hydration is mandatory.

• Pheochromocytoma

Patients with pheochromocytoma may develop severe hypertensive crisis (sometimes uncontrollable) after intravenous contrast administration. Premedication with alpha-receptor blockers is recommended.

• Patients with autoimmune disorders

Cases of severe vasculitis or Stevens-Johnson-like syndromes have been reported in patients with a history of autoimmune disorders.

• Bulbospinal paralysis (myasthenia gravis)

Administration of iodinated contrast agents may exacerbate symptoms of bulbospinal paralysis.

• Alcoholism

Acute or chronic alcoholism may increase blood-brain barrier permeability, facilitating the passage of contrast agent into brain tissue and potentially causing CNS reactions. Special attention is required for patients with alcohol or drug dependence due to the possible lowered seizure threshold.

• Coagulation

Ionic iodinated contrast agents have greater in vitro anticoagulant activity than non-ionic contrast agents. However, medical personnel performing vascular catheterization should be aware that, apart from the contrast agent, numerous factors may contribute to thromboembolic events, including procedure duration, number of injections, catheter and syringe material, underlying disease, and concomitant medications. Therefore, during angiography, careful technique, frequent catheter flushing with saline (preferably with heparin, if possible), and minimizing procedure duration are essential to reduce the risk of procedure-related thrombosis and embolism.

It has been reported that using plastic syringes instead of glass syringes reduces, but does not eliminate, the risk of in vitro blood clotting.

Special attention is recommended for patients with homocystinuria due to increased risk of thrombosis and embolism.

Use with caution in patients with sickle cell anemia.

Administration into body cavities

Prior to hysterosalpingography, pregnancy must be excluded.

Inflammation of the biliary or fallopian ducts may increase the risk of reactions after cholangiography, ERCP, or hysterosalpingography.

The agent must not be used for myelography, ventriculography, or cisternography, as neurotoxic effects may occur during these procedures.

Instructions for use

Trasograf® 76% ready for use is a colorless or slightly yellow, clear solution. The product must not be used if the solution changes color, contains visible particles, or if the ampoule is damaged. The contrast agent should be drawn into the syringe immediately before the start of the examination.

Any unused contrast agent remaining after the examination must not be reused.

Use during pregnancy or breastfeeding

The safety of Trasograf® 76% in pregnant patients has not been established. Therefore, radiation exposure during pregnancy should be avoided, and the benefit-risk ratio of any radiographic examination (with or without contrast) should be carefully evaluated.

Breastfeeding

Iodinated contrast agents similar to Trasograf® 76%, which are excreted by the kidneys, pass into breast milk in very small amounts. The likelihood of harm to the infant is low; however, the potential risk to the infant should be considered before administering the agent during breastfeeding.

Ability to affect reaction speed when operating vehicles or machinery

Psychomotor reactions may be slowed in isolated cases after administration of the agent. Patients should avoid driving or operating machinery for 24 hours after administration.

Administration and Dosage.

Trazograf® 76% is administered intravascularly.

General Guidelines

• Dietary Recommendations

To facilitate diagnosis, angiography of the abdominal cavity and urography are recommended to be performed with an empty intestine. Therefore, for two days prior to the examination, avoid foods that cause meteorism, such as legumes, salads, fruits, dark and fresh bread, and any raw vegetables. The last meal should be no later than 6 PM the evening before the examination. It is also advisable to take a laxative in the evening. However, newborns and infants should not have prolonged fasting intervals, and laxatives should not be administered to them.

• Hydration

Adequate hydration is required before and after intravascular and intrathecal administration of contrast agents. This is particularly important for patients with multiple myeloma, diabetes mellitus associated with nephropathy, polyuria, oliguria, hyperuricemia, as well as newborns, infants, young children, and elderly patients. If imbalances are present prior to the examination, correction of the water-electrolyte balance is necessary.

Newborns and young children (from 1 month to 2 years of age).

Infants under 1 year of age, and especially newborns, are susceptible to electrolyte imbalances and hemodynamic changes. The dose of contrast agent to be administered, the technical performance of the radiological procedure, and the patient's condition should be carefully evaluated.

• Patient anxiety

Pronounced states of excitement, anxiety, and pain may increase the risk of adverse effects and intensify reactions associated with contrast agent administration. Such patients should be prescribed sedatives.

• Pre-administration sensitivity testing

Pre-testing for individual sensitivity using small doses of the drug is not recommended due to lack of predictive value and the risk of inducing severe hypersensitivity reactions.

• Warming prior to use

Contrast agents warmed to body temperature prior to administration are better tolerated and easier to inject due to reduced viscosity. Using a thermostat, warm the required number of ampoules—exclusively for examinations performed within one day—to 37°C. Provided protection from daylight, chemical purity remains unchanged. However, the warming period should not exceed three months.

Dosing for intravascular administration

Intravascular administration of the contrast agent should ideally be performed while the patient is lying down. After administration, the patient should be observed for at least 30 minutes, as most adverse reactions occur during this period.

Dosage may vary depending on age, body weight, cardiac output, and the patient's general condition.

For patients with severe renal or cardiac insufficiency and those in poor general condition, the lowest possible dose of contrast agent should be used. In such patients, renal function should be monitored for at least 3 days following administration.

Sufficient time should be allowed between individual injections to permit adequate drainage of interstitial fluid, compensating for increased plasma osmolality. In adequately hydrated patients, this interval should be 10–15 minutes. If exceeding the total dose of 300–350 mL of contrast agent per examination is necessary, additional water (and possibly electrolytes) should be administered to adults.

Recommended Doses

Intravenous urography

• Injection

The usual rate of intravascular administration is 20 mL/min. For patients with cardiac insufficiency receiving a dose of 100 mL or more, an administration time of at least 20–30 minutes is recommended.

Dosing.

For adults

The dose of Trazograf® 76% is 20 mL. Increasing the dose of Trazograf® 76% to 50 mL significantly improves the likelihood of an accurate diagnosis. Further dose increases are possible if clinically indicated.

For children

Due to the reduced physiological concentrating capacity of immature nephrons, children require relatively high doses of Trazograf® 76%:

Children under 1 year – 7–10 mL;

Aged 1 to 2 years – 10–12 mL;

Aged 2 to 6 years – 12–15 mL;

Aged 6 to 12 years – 15–20 mL;

Aged 12 years and older – as for adults.

Timing of imaging

Optimal contrast visualization of the renal parenchyma is achieved when imaging is performed immediately after completion of contrast agent administration.

For visualization of the renal pelvis and urinary tract, the first image should be taken 3–5 minutes and the second 10–12 minutes after contrast administration. For younger patients, the lower end of this time range should be used; for elderly patients, the upper end.

For newborns and infants, the first image is recommended as early as 2 minutes after contrast administration. If images appear poorly contrasted, later imaging may be necessary.

Angiography

The drug can also be used for angiographic examinations. The 76% solution is preferred when a particularly high iodine concentration is essential, such as in aortography, angiocardiography, or coronary angiography. The dose should be determined based on the diagnostic objective, examination technique, and the nature and extent of the vascular area being studied.

Administration into body cavities

Retrograde urography

A 60% solution may be used. Despite its high concentration, irritation symptoms are extremely rare. To avoid ureteral spasm caused by lower solution temperature, the contrast agent should be warmed to body temperature.

Other body cavities

During arthrography, hysterosalpingography, and especially ERCP (endoscopic retrograde cholangiopancreatography), contrast agent injections should be performed under fluoroscopic control.

Children.

Due to the reduced physiological concentrating capacity of immature nephrons, children require relatively high doses of the drug. Therefore, Trazograf® 76% is generally recommended for pediatric use.

Infants (under 1 year of age), and especially newborns, are sensitive to disturbances in water-electrolyte balance and hemodynamic changes. The dose of contrast agent to be administered should be carefully calculated, the radiological procedure performed cautiously, and the patient's condition closely monitored.

Overdose.

In case of overdose, symptoms of adverse reactions may be intensified.

In the event of accidental overdose during intravascular administration, fluid and electrolyte losses should be compensated by infusion. Renal function should be monitored for at least the following three days.

If necessary, hemodialysis may be used to remove the majority of the contrast agent from the patient's circulatory system.

Side effects.

Cardiac disorders: disturbances in heart rate; cardiac rhythm disorders; tachycardia, including reflex tachycardia; bradycardia; cyanosis; cardiac dysfunction; transient ECG changes; ventricular fibrillation; asystole; cardiac arrest; severe thromboembolic events leading to myocardial infarction.

Vascular disorders: circulatory disturbances associated with peripheral vasodilation and subsequent hypotension, collapse, sensation of flushing, possible increase in blood pressure, vasculitis.

Blood and lymphatic system disorders: inhibition of blood coagulation and platelet aggregation, disseminated intravascular coagulation, thrombocytopenia, hemolysis, thrombotic microangiopathy.

Endocrine disorders: hyperthyroidism.

Nervous system disorders: dizziness, headache, excitation, amnesia, subdural edema, exacerbation of symptoms of myasthenia gravis, speech disturbances, visual and hearing disturbances, photophobia, transient loss of vision, tremor/trembling, convulsions, epileptic seizures, coma, disorientation, drowsiness, paresis/paralysis, clouding of consciousness, loss of consciousness, severe thromboembolic events leading to stroke.

Renal and urinary disorders: renal function impairment, reversible renal failure (including acute).

Immune system disorders: anaphylactic reactions/hypersensitivity reactions, including anaphylactic shock, angioedema, conjunctivitis, increased lacrimation, cough, rhinitis, sneezing.

Skin and subcutaneous tissue disorders: skin rashes, pruritus, erythema/redness with vasodilation, pallor of the skin, urticaria, severe skin reactions, including Stevens-Johnson syndrome, Lyell's syndrome.

Respiratory system disorders: transient disturbances in respiratory rate, dyspnea, respiratory insufficiency, cough, bronchospasm, laryngeal spasm/edema, respiratory arrest, pulmonary edema.

Gastrointestinal disorders: nausea, vomiting, abdominal pain, metallic taste in the mouth.

General disorders: sensation of warmth, weakness, malaise, chills, vasovagal reactions, sweating, increased body temperature, swelling of salivary glands.

Local reactions: local site changes including pain, swelling, inflammation; possible development of phlebitis and thrombosis; in case of paravenous leakage of the drug, increased pain, swelling, and tissue necrosis.

Intravascular administration

Adverse effects associated with intravascular administration of iodine-containing contrast agents are usually mild or moderate in severity and transient in nature. However, severe and life-threatening reactions, as well as fatal outcomes, have been reported. The incidence of adverse reactions in patients receiving ionic contrast agents has been reported to be over 12%, compared to over 3% with non-ionic contrast agents.

The most commonly observed reactions during intravascular administration include nausea, vomiting, pain, and a general sensation of warmth.

Administration into other body cavities

After administration of contrast agents into body cavities, adverse reactions occur rarely. Most of them develop several hours after administration due to slow absorption from the site of injection and systemic distribution, primarily via a controlled diffusion process.

Following ERCP (endoscopic retrograde cholangiopancreatography), a slight increase in amylase levels is a common finding. It has been demonstrated that acinar contrast enhancement is associated with an increased risk of post-ERCP pancreatitis. Isolated cases of necrotizing pancreatitis have been reported.

Vasovagal reactions associated with hysterosalpingography are uncommon.

Anaphylactic reactions/hypersensitivity

Systemic hypersensitivity reactions are rare, mostly mild in severity, and usually manifest as skin reactions. However, the possibility of severe hypersensitivity reactions cannot be completely excluded. For a full description of anaphylactic reactions, refer to the relevant sections: "Immune system disorders", "Vascular disorders", "Respiratory system disorders".

Shelf life. 5 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Protect from light and secondary X-rays. Keep out of reach of children. Do not freeze.

Incompatibility.

Contrast agents should not be mixed with other medicinal products to avoid possible incompatibility.

Packaging.

20 ml of the drug in an ampoule, 5 ampoules packed on a polystyrene tray. One tray per cardboard box.

Prescription category. Prescription only.

Manufacturer.

"Unique Pharmaceutical Laboratories" (a division of "J.B. Chemicals and Pharmaceuticals Ltd.").

Manufacturer's name and address of the place of business.

Plot No. 4, Phase-IV, G.I.D.C. Industrial Estate, Panoli - 394 116, Bharuch District, India.