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PACKAGE LEAFLET: INFORMATION FOR THE USER

UROGRAFIN®

Sodium amidotrizoate (sodium diatrizoate) and meglumine amidotrizoate (meglumine

diatrizoate)

Read all of this leaflet carefully before you are given this medicine.

-    Keep this leaflet. You may need to read it again.

-    If you have any further questions, ask the doctor giving you Urografin (the radiologist) or the X-ray department staff.

-    If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or the X-ray department staff/radiologist.

In this leaflet:

1.    What Urografin is and what it is used for

2.    Before you are given Urografin

3.    How you will be given Urografin

4.    Possible side effects

5.    How to store Urografin

6.    Further information

1. What Urografin is and what it is used for

Urografin is an injectable contrast medium (a dye) which contains iodine. It is used to clearly show on X-rays the area of your body that your doctor wants to investigate.

X-rays, like radio waves, can pass through objects and can be focused to make a picture. When you have an X-ray, the beam of rays goes through your body where it is absorbed to differing degrees by different tissues such as bones, muscles and organs. When the rays come out on the other side they make a pattern of light and shade on a film. Urografin helps to make this pattern clearer. The film is then examined by a specialist who will make a diagnosis.

This medicine is for diagnostic use only.

2. Before you are given Urografin

Do not use Urografin if:

•    you are, or suspect you are, allergic (hypersensitive) to iodine or iodine-containing contrast media or any of the other ingredients of Urografin (see Section 6: Further Information)

•    you have a condition caused by too much thyroid hormone (uncontrolled thyrotoxicosis)

•    you have severe heart insufficiency (causing oedema (swelling of areas of your body e.g. ankles) or shortness of breath)

•    you are pregnant or have inflammation of the pelvic cavity (symptoms include stomach pain and tenderness, fever and irregular menstrual periods): you must not have your uterus (womb) investigated with Urografin.

Take special care with Urografin

You must tell the X-ray department staff if you have any of the following:

•    reduced liver or kidney function

•    epilepsy or a history of seizures

•    a disease of blood vessels in the brain (cerebral arteriosclerosis)

•    diabetes mellitus requiring treatment and/or associated with diabetic complications

•    damaged lungs (pulmonary emphysema)

•    poor general health

•    an overactive thyroid gland (hyperthyroidism) or a swollen neck due to an enlarged thyroid gland (benign nodular goitre)

•    a disease of the bone marrow (multiple myeloma)

•    a history of allergy or a tendency to develop hypersensitivity reactions (for example if you have hay fever, asthma or eczema), especially if you have taken a medicine like Urografin (a contrast medium) before

•    poor heart function or blood circulation

•    previously had a reaction to any contrast media.

If any of these apply to you, you may be at a higher risk of having an allergic reaction or becoming unconscious/fainting.

If you have a phaeochromocytoma (tumour of the adrenal gland) you may be given a medicine called an alpha-receptor blocker before the investigation to prevent your blood pressure from rising.

Urografin may affect the way the thyroid gland works for 6 weeks or more after being given it. If you are going to have an iodine test for thyroid disease, tell your doctor or the laboratory staff if you have been given Urografin recently.

Taking or using other medicines

Please tell the radiologist or X-ray department staff if you are taking or have recently taken any other medicines, including medicines obtained without prescription. This is particularly important for:

•    beta-blockers (drugs used to treat heart or blood pressure), because they can make allergic reactions worse

•    if you have been treated with a drug called interleukin, because there is a higher chance of getting delayed reactions (e.g. fever flu-like symptoms, joint pain and pruritus (itching))

•    if you have kidney disease due to diabetes (diabetic nephropathy) and are taking a type of medicine called biguanides (metformin). You should inform your doctor who will probably stop the biguanides 48 hours before the examination.

Ask the X-ray department staff if you are not sure.

Using with food and drink

If the procedure is to look at your abdomen, kidneys or bladder you may be asked to avoid foods that cause flatulence (wind) for two days beforehand. These foods include:

-    peas, beans, lentils, salads, fruit

-    brown or granary bread

-    all kinds of uncooked vegetables.

You will be told not to eat after 6pm on the day before the examination, but you can still drink. Babies and young children, however, must not fast. If you have a disorder of your body water and body salts balance this will be corrected before the examination.

Do not reduce the amount you normally drink before the investigation, especially if you have any of the following:

•    multiple myeloma (disease of the bone marrow)

•    diabetes mellitus

•    polyuria (production of large amounts of urine which is pale in colour)

•    oliguria (production of small amounts of urine)

•    gout.

Also, fluid intake must not be reduced in babies, young children, or in someone who is in a very poor general state of health where their body tissues are wasting away.

Pregnancy and breast-feeding

Tell the X-ray department staff if you are pregnant, think you may be pregnant, or are breast feeding.

Driving and using machines

You should not drive or operate machinery for 24 hours after the examination as you may have a delayed reaction to Urografin.

3. How you will be given Urografin

The X-ray department staff will decide how much Urografin is needed for your particular investigation. They will explain how everything works and what position you should lie in on the X-ray table.

The dose of Urografin varies depending on the investigation and your weight. The dose range is normally between 1 and 500ml.

Once you lie down the Urografin will be injected into a vein. Sometimes, Urografin will be injected into your muscles or anus (back passage). The staff in the X-ray department will observe you for 30 minutes after the injection just in case you have any side effects.

If you receive more Urografin than you should

Overdosing is unlikely. If it does happen the radiologist will treat any symptoms that follow.

4. Possible side effects

Like all medicines, Urografin can cause side effects, although not everybody gets them.

Side effects you may get after being given a contrast medium like Urografin are usually mild and do not last long.

However, as with similar contrast media, severe and life-threatening reactions, as well as deaths, have been reported.

If you notice:

•    itching of the skin, rash, wheals on the skin (urticaria)

•    difficulty breathing, gagging, feeling of suffocation

•    swelling of the face, neck or body

•    itchy or watery eyes, tickling in the throat or nose, hoarseness, coughing or sneezing

•    headache, dizziness, feeling faint

•    feeling particularly hot or cold, sweating

•    paleness or reddening of the skin

•    chest pain, cramp, tremor

•    feeling sick

Tell the radiologist or X-ray staff immediately as these may be the first signs of allergic reaction or shock. Your investigation will need to be stopped, and you may need further treatment.

Apart from the symptoms listed above the other possible side effects of Urografin are:

•    feeling sick or being sick

•    a sensation of pain and a general feeling of warmth

•    in rare cases your kidneys temporarily stop working

•    reddening or other reactions at the injection site if Urografin is not injected properly.

Very rarely severe or even life-threatening side-effects may occur and in some cases have been fatal. These include:

lowered blood pressure fainting (collapse) circulatory failure

an irregular, rapid heart beat which may cause the heart to suddenly stop beating altogether (cardiac arrest)

fits or other brain related symptoms a build-up of water in the air spaces of the lung

anaphylactic shock (a very severe allergic reaction).

If you are having a procedure where Urografin will reach the brain, you may have complications such as:

•    coma, temporary confusion and drowsiness

•    temporary weakness of the muscles

•    disturbed vision or weakness of the facial muscles

•    epileptic fits, especially in someone with epilepsy or brain damage.

Delayed reactions can occasionally occur, if you are concerned you should contact your doctor.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or the X-ray department staff/radiologist.

5. How to store Urografin

Keep out of the reach and sight of children.

Do not use Urografin after the expiry date which is stated on the label. The expiry date refers to the last day of that month.

Protect from light and secondary X-rays.

6. Further Information What Urografin contains

• The active substances are sodium amidotrizoate and meglumine amidotrizoate.

1ml Urografin 150 contains 40mg sodium amidotrizoate and 260mg meglumine amidotrizoate.

1ml Urografin 150 for infusion contains 40mg sodium amidotrizoate and 260mg meglumine amidotrizoate.

1ml Urografin 370 contains 100mg sodium amidotrizoate and 660 mg meglumine amidotrizoate.

• The other ingredients are sodium calcium edetate (E 385) and water for injections.

What Urografin looks like and contents of the pack

Urografin 150 is available in packs of ten 10ml ampoules or packs of ten 20ml ampoules. Urografin 150 for infusion is available in 250ml or 500ml bottles.

Urografin 370 is available in packs of ten 50 ml bottles or one 100ml bottle.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder: Bayer plc

Bayer House Strawberry Hill Newbury

Berkshire, RG14 1JA

Manufacturer:    BerliMed S.A

Madrid

Spain

This leaflet was last revised in March 2013

X'

Information for Healthcare Professionals

UROGRAFIN®

Composition, availability and viscosity

The Urografin range contains sodium and meglumine amidotrizoate in various ratios. The numerical suffix gives the approximate iodine concentration of each medium (see table 1).

1ml Urografin 150 contains 40mg sodium amidotrizoate and 260mg meglumine amidotrizoate.

1ml Urografin 370 contains 100mg sodium amidotrizoate and 660mg meglumine amidotrizoate.

Excipients: Sodium calcium edetate (E Number 385), water for injection.

Table 1

Medium	Ratio of	Exact Iodine	Availability	Iodine	Viscosity
	sodium:	concentration		content (g)	(cp)
	meglumine amidotrizoate	mg/ml		per container	20°C 37°C
Urografin	10:66	1 46	10ml	1 .46	2.2 1.4
150			ampoule

Package quantities

Urografin 150: Packs of 10x10ml ampoules and 10x20ml ampoules.

Urografin 150 for infusion: Packs of 1x250ml bottles and 1x500ml bottles.

Urografin 370: Packs of 10x20ml ampoules and 10x50ml bottles. In addition packs of 1x100ml bottles.

Urografin is a contrast medium.

The product licence is held by: Bayer plc

Bayer House Strawberry Hill Newbury

Berkshire, RG14 1JA

Product licence numbers Urografin 150 (30%)

Urografin 150 (30%) for infusion Urografin 370 (76%)

Urografin is manufactured by:    BerliMed S.A., Madrid, Spain.

Uses

X-ray contrast media for the delineation of the vascular and renal systems. Contra-indications

Proven or suspected hypersensitivity to iodine-containing contrast media, uncontrolled thyrotoxicosis and decompensated cardiac insufficiency.

Hysterosalpingography must not be carried out during pregnancy or in patients with acute inflammatory conditions in the pelvic cavity.

Warnings

For patients with severe impairment of hepatic or renal function, cerebral arteriosclerosis, epileptic conditions, diabetes mellitus requiring drug treatment and/or associated with diabetic complications, pulmonary emphysema, poor general health, latent hyperthyroidism, multiple myeloma or benign nodular goitre the need for examination with X-ray contrast media merits careful consideration.

This also applies to patients with a history of allergy, atopy, bronchial asthma, endogenous eczema, cardiac or circulatory insufficiency or a previous adverse

reaction with any contrast medium since experience shows that they may be at higher risk from developing anaphylaxis or cardiovascular collapse. Consideration should be given to the use of low osmolar radiocontrast media in such patients.

The patient should be recumbent during the administration of Urografin. Thereafter, the patient must be kept under close observation for at least 30 minutes, since about 90% of all severe incidents occur within that time. If the administration does not take place on the X-ray table, any patient with a labile circulation should be brought to the X-ray machine sitting or lying down.

Particular caution should be exercised in allergic persons who have previously tolerated an injectable iodine-containing contrast medium without any complication because they may have become sensitized to these substances in the meantime.

As with any contrast medium, the possibility of hypersensitivity must always be considered. If marked side-effects or suspected allergic reactions occur during injection and do not disappear, or even get worse, when the injection is briefly interrupted, it is probable that the patient is hypersensitive and the investigation must be abandoned. Even relatively minor symptoms such as itching of the skin, sneezing, violent yawns, tickling in the throat, hoarseness or attacks of coughing may be early signs of a severe reaction and, therefore, merit careful attention.

Ionic iodinated contrast media inhibit blood coagulation in vitro more than non-ionic contrast media. Nevertheless medical personnel performing vascular catheterisation procedures should pay meticulous attention to the angiographic technique and catheter flushing so as to minimise the risk of procedure-related thrombosis and embolisation.

In patients with multiple myeloma, diabetes mellitus requiring drug treatment, polyuria, oliguria or gout, and in infants, young children and marasmic patients the fluid supply should not be restricted. Existing disturbances of the balance of water and electrolytes must be corrected before the administration of a hypertonic contrast-medium solution.

Premedication with an alpha-blocker is recommended in patients with phaeochromocytoma, because of the risk of hypertensive crisis.

If iodine isotopes are to be administered for the diagnosis of thyroid disease, it should be borne in mind that after the administration of iodinated contrast media which are excreted via the kidneys, the capacity of the thyroid tissue to take up iodine will be reduced for 2 weeks, and sometimes up to 6 weeks.

Experience shows that pronounced states of excitement, anxiety and pain can be the cause of side effects or intensify contrast medium-related reactions. They can be counteracted by calm management of the patient and the use of suitable drugs.

Pregnancy and lactation

X-ray examinations should if possible be avoided during pregnancy. It has not yet been proved beyond question that Urografin may be used without hesitation in pregnant patients. Therefore, an examination with a contrast medium during pregnancy should be carried out only if considered absolutely necessary by the physician.

Renally eliminated contrast media such as Urografin enter the breast milk in only very small amounts.

Limited data suggest that the risk to the suckling infant of administering salts of diatrizoic acid to its mother is low.

Drug Interactions

Diabetic nephropathy may predispose to renal impairment following intravascular contrast medium administration. This may precipitate lactic acidosis in patients who are taking biguanides. As a precaution, biguanides should be stopped 48 hours prior to the contrast medium examination and reinstated only after adequate renal function has been regained.

Hypersensitivity reactions can be aggravated in patients on beta-blockers.

The prevalence of delayed reactions (e. g. fever, rash, flu-like symptoms, joint pain and pruritus) to contrast media is higher in patients who have received interleukin.

Incompatibilities

Some radiologists give an antihistamine or a corticoid prophylactically to patients with a history of allergy. However, because of the possibility of precipitation, X-ray contrast media and prophylactic agents must not be administered mixed together.

Effects on ability to drive and to use machines

Delayed reactions following intravascular administration of iodinated contrast media are rare. Nevertheless, driving or operating machinery is not advisable for the first 24 hours.

Dosage and administration

1. Adults only

Table 2 shows the medium/media that the license holder suggests for each investigation. These media may be used at the discretion of the radiologist for other established permutations of medium and examination which, for the sake of simplicity, have been omitted from the table.

Table 2

Examination	150	370
Intravenous urography		Up to 70mla
Drip-infusion urography	2-4ml/kg body wt up to 250ml
Retrograde urography	5-10ml
Cystography	Up to 500ml
Angiocardiography		30-50ml
Right heart catheterisation		40-80ml
Left heart catheterisation		40-60ml
Pulmonary angiography		30-40ml
Coronary arteriography		4-8ml per arteryb
Renal arteriography		5-8ml
Coeliac-axis arteriography		35-80ml
Thoracic aortography		30-60ml
Pelvic aortography		20-25ml
Translumbar abdominal aortography		20-30ml
Placentography		25ml
Splenoportography		40-50ml
Hysterosalpingo- graphy		4-7ml

^a If patients with cardiac insufficiency are given 100ml or more, an injection time of at least 20-30 minutes is recommended. ^b 100ml vials are available for coronary arteriography.

Other indications include: high dose urography, pelvic venography, venacavography, arthrography, selective visceral angiography, limb venography, jugular venography, vesiculography, sialography, sinusography, amniography, lymphangiography, intramuscular urography, operative and percutaneous cholangiography, fistulography, oesophageal and anal atresia.

Urografin media are not suitable for myelography.

Urodynamic studies

Urografin 150 (a 30% solution) can be diluted with normal saline to obtain the desired density.

The pH is not significantly affected by dilution.

• Retrograde urography

A 30% solution (Urografin 150) is generally sufficient for retrograde urography. It is advisable to warm the contrast medium to body temperature to avoid low-temperature stimulus and resultant ureteric spasms.

•    Infusion urography

The rapid infusion of large amounts of a contrast medium in low concentration produces increased urine formation while retaining a high concentration of the contrast medium in the urine.

This method can provide complete visualisation of the renal pelvis and calyces as well as the entire course of the ureters. The nephrographic effect is also intensified, and is prolonged for up to 15-30 minutes after the termination of the infusion.

•    Angiography

Urografin 370 is suitable for angiographic investigations. It is preferred for those angiographic investigations in which a high iodine concentration is of special significance, e.g. aortography, angiocardiography, coronary arteriography.

2. Children and neonates

•    Intravenous Urography

The fact that urograms of infants and young children generally show a lower contrast density than those of adults is explained by the physiologically less effective function of the immature nephron. Relatively high doses of media are therefore indicated.

Urografin 370
up to 1 year	7-10ml
1-2 years	10-12ml
2-6 years	12-15ml
6-12 years	15-20ml
over 12 years	adult dose

•    Drip infusion urography

Dosage of Urografin 150 should not exceed 4ml/kg body weight.

•    Angiocardiography

In neonates up to 5kg body weight, 8ml Urografin 370; Infants over 5kg body weight, 1ml/kg body weight up to 25ml per injection.

•    Right and left heart catheterisation

1-1.2ml/kg body weight of Urografin 370, with a maximum of 15ml per injection for right heart and 25ml per injection for left heart.

•    Pulmonary angiography

0.5-0.6ml/kg body weight up to 8ml Urografin 370 per injection.

3. General

In the case of abdominal angiography and urography, the diagnostic yield is increased if the bowels are emptied of faecal matter and gas. On the two days prior to the examination, patients should therefore avoid flatulent food, in particular peas, beans and lentils, salads, fruit, brown or granary bread and all kinds of uncooked vegetables. On the day before examination, patients should refrain from eating after 6pm. Moreover, it can be appropriate to administer a laxative in the evening.

The patient must attend for examination fasting but adequately hydrated. Disorders of the water and electrolyte balance must be corrected. This applies in particular to patients who are predisposed to such disturbances.

In babies and young children, however, prolonged fasting and the administration of a laxative before the examination are contraindicated.

Intravascular administration of contrast media should, if possible, be done with the patient lying down. After the administration, the patient should be kept under observation for at least 30 minutes, since experience shows that the majority of all severe incidents occur within this time. If the administration does not take place on the X-ray table, any patient with a labile circulation should be brought to the X-ray machine sitting or lying down.

Experience shows that contrast medium is tolerated better if it is warmed to body temperature.

The contrast medium solution should not be drawn into the syringe or the infusion bottle attached to the infusion set until immediately before the examination.

Vials containing contrast medium solutions are not intended for the withdrawal of multiple doses. The rubber stopper should never be pierced more than once. The use of cannulas with a long tip and a maximum diameter of 18G is recommended for piercing the stopper and drawing up the contrast medium (dedicated withdrawal cannulas with a side hole, e.g. Nocore-Admix cannulas, are particularly suitable).

Contrast media not used in one investigation must be discarded.

If diagnostic clarification necessitates several high single doses, the patient should be given the opportunity between injections to compensate for the increased serum osmolality by the influx of interstitial fluid.

To achieve this, a period of 10-15 minutes is necessary in adequately hydrated patients. The intravascular administration of water and electrolytes is indicated if more than 300ml contrast medium are required for a single examination.

• Filming times after injection

The renal parenchyma can be demonstrated best when the film is taken immediately after the end of the administration.

For visualisation of the renal pelvis and urinary tract, the first film is taken 3-5 and the second 10-12 minutes after the administration of the contrast medium. The earlier time should be chosen for younger patients and the later time for older patients.

In babies and young children it is advisable to take the first film as early as about 2 minutes after the administration of the contrast medium.

Insufficient contrast can necessitate later films.

Overdosage

Acute symptoms of poisoning are unlikely with intravascular administration. On inadvertent overdosage or in greatly impaired renal function, the contrast medium may be removed by dialysis, and the balance of water and electrolytes should be corrected.

Acute toxicity studies do not suggest a risk of acute intoxication.

Side effects

Mild subjective symptoms, such as a feeling of heat and nausea, occur very seldom and disappear rapidly when the injection is slowed down or briefly interrupted. Transient pain may occur, in particular during the examination of peripheral vascular regions.

Other symptoms which may occur are:

Chills, fever, sweating, headache, dizziness, blanching, weakness, gagging and a feeling of suffocation, gasping, a rise or fall of blood pressure, itching, urticaria, other kinds of skin eruption, oedema, cramp, tremor, sneezing and lacrimation. These reactions, which can occur irrespective of the amount administered and the mode of administration, may be the first signs of incipient shock. Administration of the contrast medium must be discontinued immediately and - if necessary - specific therapy instituted intravenously. It is therefore advisable to use a flexible indwelling cannula for intravenous contrast medium administration.

Very rarely, severe or even life-threatening side-effects such as severe hypotension and collapse, circulatory failure, ventricular fibrillation, cardiac arrest, pulmonary oedema, anaphylactic shock or other allergic manifestations, convulsions, or other cerebral symptoms may occur. In some cases these have proved fatal.

To permit immediate countermeasures to be taken in emergencies, appropriate drugs, an endotracheal tube and a ventilator should be ready to hand.

Experience shows that hypersensitivity reactions occur more frequently in patients with an allergic disposition.

Paravascular administration of the contrast medium rarely leads to severe tissue reactions.

Delayed reactions can occasionally occur.

Neurological complications such as coma, temporary states of confusion and somnolence, transient paresis, disturbed vision or facial muscle paresis and epileptic fits may occur after cerebral angiography and other procedures in which the contrast medium reaches the brain with the arterial blood. In very rare cases the induction of fits has been observed after intravenous administration of Urografin in epileptics and patients with focal brain damage. However, a causal relationship seems to be questionable.

Temporary renal failure may occur in rare cases.

Suggestions for the treatment of contrast medium incidents

It is very important in order to be able to take prompt action in the event of contrast medium incidents to have all drugs and instruments for emergency therapy readily available and to be familiar with the practice of emergency measures. Please refer to the Royal College of Radiologists guidelines “Advice on the management of reactions to intravenous contrast media”.

Expiry date: The expiry date is printed on the label. The contrast medium should not be used after this date.

Storage: Protect from light and X-rays.

Date of last revision of this leaflet: March 2013

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