ULTRAVIST 370 mg/ml INJECTABLE SOLUTION AND PERFUSION SOLUTION IN VIAL

Introduction

Package Leaflet: Information for the User

Ultravist 370 mg/ml Solution for Injection and Infusion in Vial

Iopromide

Contents of the pack and other information:

1. What is Ultravist and what is it used for
2. What you need to know before you use Ultravist
3. How to use Ultravist
4. Possible side effects
5. Storage of Ultravist
6. Contents of the pack and other information

1. What is Ultravist and what is it used for

This medicinal product is for diagnostic use only.

Ultravist belongs to a group of medicines called low-osmolar, water-soluble, nephrotropic X-ray contrast media.

Ultravist is used to enhance contrast during the visualization of different body regions using certain radiological techniques:

• Computed Tomography (CT, production of images of slices or sections of a specific region of the body)
• Conventional arteriography (for the visualization of arteries), including cardiac angiography (visualization of the heart arteries)
• Extremity phlebography (for the visualization of veins in the extremities)
• Angiography (visualization of blood vessels) by digital subtraction (DSA) intra-arterial/intravenous
• Intravenous urography (for the visualization of the urinary tract)
• Mammography (for the visualization of the interior of the breasts) with contrast (CEM) in adult women to evaluate and detect known or suspected breast lesions, as a complement to mammography (with or without ultrasound) or as an alternative to magnetic resonance imaging (MRI) when MRI is contraindicated or not available.
• Arthrography (visualization of joints) and hysterosalpingography (visualization of the uterus and fallopian tubes).

2. What you need to know before you use Ultravist

Do not use Ultravist

• if you are allergic (hypersensitive) to the active substance or any of the other ingredients of this medicinal product (listed in section 6)
• if you have clinical hyperthyroidism (your thyroid gland produces too much thyroid hormone)
• if you are pregnant or have acute inflammation in the pelvic cavity and are going to undergo hysterosalpingography (visualization of the uterus and fallopian tubes)

Warnings and precautions

Consult your doctor or pharmacist before starting treatment with Ultravist:

• If you have ever suffered from a severe skin rash or skin peeling, blistering, and/or oral ulcers after using Ultravist.

Be careful with Ultravist

For all indications

• If you have ever had an allergic reactionto another iodinated contrast medium, as there is an increased risk of hypersensitivity reactions (allergic reactions).

The risk of allergic reactions is also higher in patients with a history of bronchial asthma or other allergic disorders and in patients with known hypersensitivity to Ultravist or any of its excipients.

Your doctor may consider premedication with corticosteroids to minimize allergic reactions.

Patients who experience these reactions while being treated with beta-blockers may exhibit resistance to treatment with beta-agonists (see taking other medicines).

In the event of a severe hypersensitivity reaction, patients with cardiovascular disease (heart disease) are more susceptible to severe and even fatal reactions.

Due to the possibility of severe hypersensitivity reactions after administration, it is recommended that patients be observed after the diagnostic procedure.

• Severe skin reactionssuch as Stevens-Johnson syndrome (SSJ), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of Ultravist. Seek medical attention immediately if you notice any of the signs described in section 4.

• If you have thyroid dysfunction(thyroid function disorder). Inform your doctor if you have hyperthyroidism (overactive thyroid) or goiter (enlargement of the thyroid gland), as iodine-containing contrast media may induce hyperthyroidism and thyrotoxic crisis (a serious complication of an overactive thyroid). You may undergo a thyroid function blood test and receive necessary medication. Your doctor will consider the need for thyroid function tests before administering Ultravist.

Tell your doctor if you have a history of thyroid disease, including hypothyroidism (underactive thyroid). Abnormal thyroid function blood tests have been reported after imaging with iodine-containing contrast media, which may suggest possible hypothyroidism or transient (temporary) reduction of thyroid function, which may require treatment.

Newborns may also be exposed to Ultravist through their mother during pregnancy.

If your child is under 3 years old:

Your doctor may monitor and check thyroid function, especially in newborns.

• If you have central nervous system (CNS) disorders:

Patients with CNS disorders may have a higher risk of neurological complications related to the administration of Ultravist. Neurological complications are more frequent with cerebral angiography (X-ray of the brain vessels) and related procedures.

During or shortly after the imaging procedure, you may experience a short-term brain disorder called encephalopathy. Inform your doctor immediately if you notice any of the signs and symptoms related to this disorder described in section 4.

Caution should be exercised in situations where the convulsive threshold is decreased, such as a history of previous seizures or use of certain concomitant medication.

• Ultravist should not be administered to you if you are dehydrated (have not taken enough fluids). To avoid this, your doctor will ensure that you have taken enough fluids before your examination (see section "Be careful with Ultravist"). Adequate hydration should be ensured in all patients before the administration of Ultravist via the intra-arterial or intravenous route. This is especially important if you have multiple myeloma (a type of blood cell cancer), diabetes mellitus, polyuria (excessive urine production), or oliguria (reduced urine production), hyperuricemia (elevated uric acid in the blood), as well as in newborns, infants, young children, and elderly patients.

Tell your doctor if you have kidney problems. Your doctor will ensure that you are well-hydrated before your examination. However, it is not recommended to administer fluids intravenously (into the veins) if you have kidney problems.

Tell your doctor if you have severe kidney problems accompanied by heart disease. Administering fluids intravenously (into the veins) can be dangerous for the heart.

• If you have anxiety

States of excitement, anxiety, and intense pain can increase the risk of adverse reactions or the intensity of reactions associated with contrast media. In these cases, inform your doctor, who will try to minimize your anxiety.

• If you are elderly, as vascular pathology and neurological disorders commonly seen in these patients increase the risk of adverse reactions.

• If you have a significant deterioration in your health status, your doctor will assess the need to perform the examination.

In addition, in the case of intra-arterial or intravenous injectionof Ultravist, you should also be careful in the following situations:

• If you receive Ultravist, there is a risk that you may develop acute kidney injury after injection(Contrast-Induced Acute Kidney Injury(CI-AKI)). As a result, your kidneys may not function properly for a short period. Some patients experience kidney failure. This is especially relevant if you have any of the following conditions:

• pre-existing kidney failure (your kidneys do not function properly). For more information, see section 3: "How to use Ultravist", subsection "Patients with renal impairment",
• diabetes mellitus,
• dehydration,
• multiple myeloma (a type of blood cell cancer),
• paraproteinemia (a disease in which an excessive amount of certain proteins is produced),
• patients receiving high or repeated doses of Ultravist.

• If you have severe kidney or liver dysfunction, combined kidney and liver disorders, or are going to undergo a liver transplant. Ultravist will only be administered if it is absolutely necessary. In these cases, adequate hydration before administration of the contrast medium is essential.

• If you have diabetes mellitus, as the administration of iodinated contrast media in diabetic patients with pre-existing kidney damage predisposes to kidney dysfunction.

• If you have any cardiovascular disease.

There is a higher risk of clinically relevant changes in the cardiovascular system and arrhythmias (abnormal heart rhythms) in patients with significant heart disease or severe coronary artery disease.

Intra-arterial or intravenous injection of the contrast medium can precipitate the onset of pulmonary edema in patients with heart failure. (See section 3: "How to use Ultravist", subsection "Patients with renal impairment").

• If you have been diagnosed with pheochromocytoma(a type of tumor), as you may have a higher risk of developing a hypertensive crisis.

• If you have any autoimmune disease(diseases of the immune system that recognize the body's own tissues as foreign and attack them), as severe cases of vasculitis (inflammation of blood vessels) and Stevens-Johnson syndrome (a disease characterized by polymorphic erythema and cutaneous, mucosal, and ocular manifestations) have been described.

• If you have myasthenia gravis(a disease in which muscles weaken and fatigue easily), as symptoms may worsen.

• Caution should be exercised if you have homocystinuria(a disease of protein metabolism) due to the risk of inducing thrombosis and embolism.

• If you have multiple myeloma(a type of blood cell cancer) or Waldenström's paraproteinemia(a disease in which an excessive amount of certain proteins is produced), as you are more likely to experience transient kidney function impairment after administration of the contrast medium.

• Contrast mammography exposes you to higher levels of ionizing radiation than traditional mammography, although they are still within the limits defined by international guidelines for mammography. The radiation dose depends on breast thickness and the type of mammography device used.

In addition, in the case of useof Ultravist for hysterosalpingography, the following considerations should be taken into account:

• It is necessary to rule out any possibility of pregnancy.

• Inflammation of the fallopian tubes may increase the risk of reactions after hysterosalpingography.

Consult your doctor, even if any of the above circumstances have occurred to you in the past.

Using Ultravist with other medicines

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines, including those obtained without a prescription.

Certain medicines may interact, in which case it may be necessary to change the dose or interrupt treatment with one of the medicines. It is especially important that you inform your doctor if you are using any of the following medicines:

• Metformin (biguanide: a medicine used to treat some forms of diabetes mellitus): in patients with kidney failure, the elimination of biguanides may be decreased, leading to accumulation and development of lactic acidosis (accumulation of lactic acid in the body). As the use of Ultravist may lead to kidney failure or worsening of existing kidney failure, patients treated with metformin may have a higher risk of developing lactic acidosis, especially those with pre-existing kidney failure. Based on measurements of kidney function, the need to interrupt metformin administration should be considered.

• Neuroleptics (medicines commonly used to treat psychosis), analgesics (medicines that relieve or eliminate pain), antiemetics (medicines that prevent vomiting or nausea), antihistamines (medicines for the treatment of allergic rhinitis or dermatitis), and sedatives (tranquilizers). With the use of these medicines, your susceptibility to seizures may be reduced, and you may have a higher risk of reactions related to the contrast medium. Therapy with these drugs should be discontinued 48 hours before administration of the contrast medium and not resumed before 12 hours after the procedure.

• Beta-blockers, as hypersensitivity reactions may be worsened, especially in cases of allergic predisposition, bronchial asthma, or history of allergy to other contrast media. Additionally, you may not respond to standard treatment with beta-agonists.

• Interleukin-2, as previous treatments (up to several weeks) with interleukin-2 have been associated with an increased risk of delayed reactions to Ultravist.

• Oral cholecystographic contrast media: There is no evidence of interaction with contrast media eliminated by the kidneys.

• Diuretics: Due to the risk of dehydration caused by diuretics, before administering the iodinated contrast medium, your doctor should administer rehydration salts to minimize the risk of acute kidney failure.

• Interference with laboratory tests: Iodinated contrast media may interfere with thyroid function tests, as the thyroid's ability to fix iodine may be reduced for several weeks.

• Radioactive drugs: If you are going to undergo tests for the diagnosis and treatment of thyroid diseases with radioisotopes, they should be delayed until several weeks after administration of Ultravist, due to a decrease in the uptake of the radioisotope.

Using Ultravist with food and drinks

You can maintain a normal diet until two hours before the examination. During the two hours prior to the study, you should abstain from eating.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

No well-controlled studies have been conducted in pregnant women.

After diagnostic application of Ultravist in humans, animal studies have not shown harmful effects on pregnancy, embryonic/fetal development, childbirth, or postnatal development.

The risk-benefit ratio should be assessed before administering an iodinated contrast medium, taking into account the sensitivity of the fetal thyroid to iodine, as acute iodine overload after administration of an iodinated contrast medium to the mother may cause fetal thyroid dysfunction.

The safety of Ultravist has not been investigated in breastfeeding women. Contrast media are excreted in breast milk in minimal amounts. No harm to the breastfed child is expected.

Driving and using machines

No studies have been conducted on the effects on the ability to drive and use machines.

Ultravist contains sodium

This medicine contains less than 23 mg of sodium (1 mmol) per dose (based on the average amount administered to a person weighing 70 kg); this is essentially "sodium-free".

3. How to use Ultravist

Follow the administration instructions for this medication exactly as indicated by your doctor. In case of doubt, consult your doctor or pharmacist again.

Ultravist is a contrast medium used for a diagnostic test, which should be performed in the presence of qualified personnel, preferably under the supervision of a doctor, who will indicate the instructions to follow at all times.

• Before administering the contrast medium by intra-arterial or intravenous route, your doctor should rule out possible renal dysfunction through medical history and/or laboratory tests.

Contrast mammography (CEM): Ultravist will be injected intravenously (in large quantities in the vein) if possible using an automatic injector.

Posology in adults

The recommended doses in adults are as follows:

Posology in special populations

Elderly patients (population over 65 years of age):

No dose adjustment is necessary.

Pediatric population (under 18 years of age):

Ultravist should not be used in the pediatric population under 18 years of age because its clinical safety and efficacy have not been established in this group, with the exception that it may be used only for Intravenous Urography.

Children's kidneys, still immature, require relatively high doses of the contrast medium as indicated in the table below:

Children under 1 year of age and especially newborns are susceptible to suffering from alterations in blood dynamics and electrolyte content in the body. Caution should be exercised with the dose of the contrast medium to be administered, the technical performance of the radiological procedure, and their general condition.

The recommended doses in neonates, infants, young children, and pediatric population from 11 to 18 years should not be exceeded.

Patients with hepatic insufficiency:

No dose adjustment is necessary (see section 2).

Patients with renal insufficiency:

Since Ultravist is almost exclusively excreted unchanged by the kidneys, the elimination of Ultravist is prolonged in patients with renal insufficiency. In order to reduce the risk of additional contrast-induced nephropathy, in patients with pre-existing renal insufficiency, the lowest diagnostic dose should be used (see section 2).

If you think that the action of Ultravist is too strong or too weak, inform your doctor or pharmacist.

Your doctor will inform you about all the characteristics related to the administration of Ultravist.

If you use more Ultravist than you should

Symptoms may include hydroelectrolytic imbalance (increase or decrease in total water and electrolyte volume in the body), renal failure, and cardiovascular and pulmonary complications.

In case of accidental intra-arterial or intravenous overdose, it is recommended to monitor the hydroelectrolytic balance and renal function. The treatment of the overdose should be aimed at ensuring the support of vital functions. The loss of water and electrolytes should be compensated by perfusion. Renal function should be monitored for at least 3 days after the test. If necessary, hemodialysis can be used to eliminate most of the contrast medium from the body.

Ultravist is dialyzable.

In case of overdose or accidental ingestion, consult the Toxicology Information Service; Telephone 91 562 04 20

If you have any other doubts about the use of this product, ask your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

The overall safety profile of Ultravist is based on data obtained from pre-marketing studies in more than 3,900 patients and post-marketing studies in more than 74,000 patients, as well as from spontaneous notification data and literature.

The most frequently observed adverse reactions in patients receiving Ultravist are headache, nausea, and vasodilation.

The most serious adverse reactions observed in patients receiving Ultravist are anaphylactic shock, respiratory arrest, bronchospasm, laryngeal or pharyngeal edema, asthma, coma, cerebral infarction, cerebrovascular accident, cerebral edema, convulsions, arrhythmias, cardiac arrest, myocardial ischemia, myocardial infarction, heart failure, bradycardia, cyanosis, hypotension, shock, dyspnea, pulmonary edema, and respiratory failure.

All indications

Common adverse effects(may affect between 1 and 10 out of 100 patients):

• dizziness, headache, taste alteration
  • blurred vision, vision disturbances
  • chest pain or discomfort
  • hypertension, vasodilation
  • vomiting, nausea
  • pain, reactions at the injection site (e.g., pain, and with unknown frequency, sensation of heat, edema, inflammation, and injury) and sensation of heat.

Uncommon adverse effects(may affect between 1 and 10 out of 1,000 patients):

• allergic reactions (hypersensitivity/anaphylactoid reactions, e.g., facial edema, sneezing, coughing, mucosal edema, rhinitis, itching, rapid swelling of the skin and mucous membranes; with unknown frequency and *: anaphylactic shock, respiratory arrest, and asthma; *: bronchospasm, laryngeal or pharyngeal edema; with unknown frequency: tongue edema, pharyngeal or laryngeal spasm, conjunctivitis, lacrimation, rhinitis, hoarseness, and throat irritation)
• syncope, confusion, nervousness, altered sensitivity, decreased sensitivity, somnolence
• arrhythmias (*)
• hypotension (*)
• dyspnea (*)
• abdominal pain
• edema

Rare adverse effects(may affect between 1 and 10 out of 10,000 patients):

• anxiety
• cardiac arrest (*), myocardial ischemia (*), palpitations

Adverse effects of unknown frequency(frequency cannot be estimated from available data)

• thyrotoxic crisis (acute worsening of thyroid function), thyroid disorder
• coma (*), cerebral hypoperfusion or cerebral infarction (*), cerebrovascular accident (*), cerebral edema (*, only with intra-arterial or intravenous administration), convulsions (*), total or partial loss of vision in one eye (only with intra-arterial or intravenous administration), loss of consciousness, agitation, memory loss, tremors, speech disorders, paresis/paralysis, contrast encephalopathy
• hearing disorders
• myocardial infarction (*), heart failure (*), bradycardia (*), tachycardia, cyanosis (*)
• shock (*), decreased perfusion due to arterial obstruction (only with intra-arterial or intravenous administration), arterial constriction (only with intra-arterial or intravenous administration)
• pulmonary edema (*), respiratory failure (*), aspiration (*)
• dyspnea, salivary gland enlargement, diarrhea
• bullous skin reactions (e.g., Stevens-Johnson syndrome or Lyell syndrome), alteration of skin color and appearance, skin rash, excessive sweating, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms
• compartment syndrome in case of extravasation (only with intra-arterial or intravenous administration)
• renal failure (only with intra-arterial or intravenous administration), acute renal failure (only with intra-arterial or intravenous administration)
  • general malaise, chills, pallor
  • fluctuations in body temperature

*There have been cases that have put life at risk.

If you think that any of the adverse effects you are suffering from is serious or if you notice any adverse effect not mentioned in this prospectus, inform your doctor or pharmacist.

Seek immediate medical attention if you notice any of the following signs and symptoms (whose frequency is unknown):

• Reddish plaques on the trunk, which are target-shaped or circular macules, often with central blisters, skin peeling, and ulcers in the mouth, throat, nose, genitals, and eyes. These severe skin rashes may be preceded by fever and pseudo-flu symptoms (Stevens-Johnson syndrome, toxic epidermal necrolysis).
• Generalized rash, elevated body temperature, and lymph node enlargement (DRESS or drug hypersensitivity syndrome).
• Generalized exanthematous pustular rash with subcutaneous nodules and blisters accompanied by fever after imaging (acute generalized exanthematous pustulosis).

Transient cerebral disorder (encephalopathy) that can cause memory loss, confusion, hallucinations, vision problems, loss of vision, convulsions, loss of coordination, loss of mobility on one side of the body, speech problems, and fainting.

Class effects

Exploration with the contrast medium is performed under general anesthesia in some selected patients. However, a high incidence of adverse reactions has been described in these patients, which is attributed to the lack of patient criteria to distinguish between actual adverse reactions and the effects of low tension anesthesia, which prolongs the circulation time and increases the duration of exposure to the contrast medium.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or radiologist, even if it is an adverse effect not mentioned in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Conservation of Ultravist

Keep this medicine out of the sight and reach of children.

Store in the original packaging to protect it from light and X-rays.

Do not store at a temperature above 30°C.

Do not use this medicine after the expiration date shown on the packaging after CAD.

Ultravist is supplied as a clear, colorless to pale yellow solution, ready for use. Do not use Ultravist if you observe significant changes in color, appearance of particles in suspension, or if the packaging is defective.

Medicines should not be thrown away through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines that are no longer needed. This will help protect the environment.

6. Container Contents and Additional Information

Composition of Ultravist 370

The active ingredient is iopromide. 1 ml of injectable solution contains 769 mg of iopromide, equivalent to 370 mg of iodine.

• 1 vial with 50 ml of injectable solution contains 38.45 g of iopromide, equivalent to 18.5 g of iodine.
• 1 vial with 100 ml of injectable solution contains 76.9 g of iopromide, equivalent to 37 g of iodine.
• 1 vial with 200 ml of injectable solution contains 153.8 g of iopromide, equivalent to 74 g of iodine.
• 1 vial with 500 ml of injectable solution contains 384.5 g of iopromide, equivalent to 185 g of iodine.

The other components are: calcium and sodium edetate, trometamol, hydrochloric acid (diluted to 10%) (for pH adjustment), sodium hydroxide (for pH adjustment) and

water for injectable preparations.

Appearance of the Product and Container Contents

Ultravist 370 is supplied as a clear, colorless to pale yellow injectable and infusion solution, ready for use. Each container contains: vials of 50, 100 ml (single-dose) or 200, 500 ml (multi-dose).

Container sizes: 1 vial.

Only some container sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing authorization holder:

Bayer Hispania, S.L.

Avda. Baix Llobregat, 3-5

08970 Sant Joan Despí (Barcelona)

Spain

Manufacturer

The manufacturer can be identified by the batch number printed on the box and on the label of each vial:

• If the first and second characters are MA, the manufacturer is:

Berlimed S.A.

Polígono Industrial Santa Rosa

C/ Francisco Alonso, s/n

28806 Alcalá de Henares (Madrid) – Spain

• If the first and second characters are KT, the manufacturer is:

Bayer AG

Müllerstrasse 178

13353 Berlin, Germany

Date of the Last Revision of this Leaflet: September 2023

Detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/.

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This information is intended only for doctors or healthcare professionals (see also section 3: How to use Ultravist)

Indications

This medicinal product is for diagnostic use only

Ultravist 370 mg/ml is indicated for contrast enhancement in computed tomography (CT), conventional angiography including angiocardiology, phlebography of limbs, digital subtraction angiography (DSA), intravenous urography, arthrography, hysterosalpingography, and mammography with contrast in adult women to evaluate and detect known or suspected breast lesions as a complement to mammography (with or without ultrasound) or as an alternative to magnetic resonance imaging (MRI) when MRI is contraindicated or not available.

Before Injection

Ultravist must be warmed to body temperature before administration.

The contrast medium should be visually inspected before use and should not be administered if there has been a change in its color, if particles are present in suspension (including crystals), or if the container is defective.

Handling

• Vials (≤ 100 ml)

The contrast medium solution should not be drawn into a syringe, nor should the vial be connected to the infusion equipment, until immediately before the examination.

The rubber stopper should not be punctured more than once to avoid transferring large amounts of microparticles from the stopper to the solution. The use of long-tipped cannulas with a maximum diameter of 18 G is recommended to puncture the stopper and extract the contrast medium (special extraction cannulas with a lateral opening are particularly suitable).

The contrast medium solution administered to a patient and not used in an examination should be discarded. The disposal of unused medicinal products and all materials that have come into contact with them should be carried out in accordance with local regulations.

• Large volume containers (≥ 200 ml, for intra-arterial or intravenous administration only)

Multiple extraction of the contrast medium should be performed with authorized equipment for multiple administration. Autoinjectors/pumps should not be used in small children.

The rubber stopper of the vial should not be punctured more than once to avoid transferring large amounts of microparticles from the stopper to the solution.

The contrast medium should be administered through an automatic injector or other approved means that ensures the sterility of the contrast medium.

The patient tube of the injector (patient tube) should be replaced with each patient to avoid any possible contamination.

The connection tubes and all disposable parts of the injection system should be discarded when the infusion vial is empty.

Any remaining contrast medium solution in the vial, connection tubes, or any other part of the disposable material of the injection system should be discarded 10 hours after the first opening of the container.

It is essential to follow the additional instructions provided by the manufacturers of the respective materials used.

The contrast medium remaining in the opened Ultravist container should be discarded ten hours after the container has been opened. The disposal of unused medicinal products and all materials that have come into contact with them should be carried out in accordance with local regulations.