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UROGRAFIN 30%

SCHEDULING STATUS:
S2

PROPRIETARY NAME
(and dosage form):

UROGRAFIN 30%
Solution for infusion

COMPOSITION
Urografin 30% contains a mixture of sodium amidotrizoate and meglumine amidotrizoate in a proportion of 10:66 in aqueous solution (formed from amidotrizoic acid or diatrizoic acid:3,5-bis-acetamido-2,4,6-triiodobenzoic acid).
1 mL Urografin 30% contains sodium amidotrizoate 0,04 g and meglumine amidotrizoate 0,26 g. Each 250 mL bottle contains sodium amidotrizoate 9,85 g and meglumine amidotrizoate 65,15 g (146 mg I/mL).

PHARMACOLOGICAL CLASSIFICATION
A. 28 Contrast media.

PHARMACOLOGICAL ACTION
Pharmacodynamic properties
The contrast-giving substances of Urografin are salts of the amido(dia-)trizoic acid in which the X-ray absorbing iodine is present in stable chemical bond. The physico-chemical characteristics of Urografin 30% are:

Iodine concentration (mg/mL)	146
Osmolality (osm/kg H2O)         At 37°C	0,71
Viscosity (mPa.s)         At 20°C         At 37°C	2,2         1,4
Density (g/mL)         At 20°C         At 37°C	1,164         1,158
pH-value	6,0-7,0

Pharmacokinetic properties
Distribution
Plasma protein binding following intravenous injection amounts to less than 10%.
A concentration corresponding to 2 to 3 g iodine/litre plasma can be expected 5 minutes after an intravenous bolus injection of 1 mL Urografin 60%/kg body weight. Over a period of 3 hours, the blood level falls relatively quickly in the first 30 minutes, then with a half-life of 1 to 2 hours.
Amidotrizoic acid does not penetrate the erythrocytes, it is very quickly distributed in the extracellular space following intravascular administration, but is not able to overcome an intact blood-brain barrier and is transmitted in only minimal amounts into breast milk.
Metabolism and elimination
At diagnostic doses, amidotrizoic acid undergoes glomerular filtration. About 15% of the dose is eliminated in chemically unchanged form with the urine within 30 minutes after the injection, and more than 50% within 3 hours; no metabolites could be demonstrated.
The kinetics observed on distribution and elimination of Urografin are unrelated to the dose within the clinically relevant range. This means that doubling or halving the dose results in blood levels and an eliminated amount of contrast medium in grams per time unit which are twice or half as high. Because of increased osmotic diuresis at twice the dose however, the urinary concentration of contrast medium does not increase to the same extent.
Characteristics in patients
In impaired renal function amidotrizoate can also be eliminated extrarenally via the liver, although at a distinctly reduced rate. Renal contrast media can easily be removed from the body by extracorporeal haemodialysis. Regardless of the site of application, complete elimination within a short period of time is ensured even from tissues.

INDICATIONS
Infusion urography.

CONTRA-INDICATIONS
Hypersensitivity to iodinated contrast media, thyrotoxicosis, decompensated cardiac insufficiency.

WARNINGS
For all indications
The following warnings and precautions apply to any mode of administration however, the risks mentioned are higher in intravascular administration.
Hypersensitivity
Patients with hypersensitivity or a previous reaction to iodinated contrast media are at increased risk of having a severe reaction. However, such reactions are irregular and unpredictable in nature.
Before any contrast medium is injected, the patient should be questioned for a history of allergy (eg seafood allergy, hay fever, hives), sensitivity to iodine or to radiographic media and bronchial asthma as the reported incidence of adverse reactions to contrast media is higher in patients with these conditions. Patients with bronchial asthma are at special risk of having bronchospasms or a hypersensitivity reaction.
In patients with an allergic disposition, known hypersensitivity to iodinated contrast media or a history of asthma, premedication with antihistamines and/or glucocorticoids may be considered.
Occasionally, allergy-like hypersensitivity reactions have been observed after use of X-ray contrast media such as Urografin (see “Side effects and special precautions”). These reactions are usually manifest as non-serious respiratory or cutaneous symptoms, as mild respiratory distress, reddening of the skin (erythema), urticaria, itching or facial oedema. Serious events such as angioedema, subglottic oedema, bronchospasm and allergic shock are possible.

Fatal reactions have been associated with the administration of water-soluble contrast media. It is therefore of the utmost importance that a course of action be carefully planned in advance for the treatment of serious reactions, and that adequate and appropriate facilities and personnel be readily available in case of a severe reaction. Patients should be observed for a possible severe reaction during and for at least 30 to 60 minutes after administration. In rare cases delayed reactions may occur (after hours to days).

Generally these reactions occur within one hour after administration of contrast media. However, in rare cases delayed reactions may occur (after hours to days).
If hypersensitivity reactions occur (see “Side effects and special precautions”), administration of the contrast medium must be discontinued immediately and –if necessary – specific therapy instituted via a venous access. It is therefore advisable to use a flexible indwelling cannula for intravenous contrast medium administration. To permit immediate countermeasures to be taken in emergencies, appropriate drugs, an endotracheal tube and a respirator should be ready at hand.
Thyroid dysfunction
The small amount of free inorganic iodide from iodinated contrast media might interfere with thyroid function. Therefore, the need for examination merits particularly careful consideration in patients with latent hyperthyroidism or goitre.
Cardiovascular disease
There is an increased risk of severe reactions in individuals with severe cardiac disease and particularly in those with heart failure and coronary artery disease.
The elderly
Underlying vascular pathology and neurological disorders often seen in the elderly constitute an increased risk of adverse reactions to iodinated contrast media.
Very poor state of health
The need for examination merits particularly careful consideration in patients with a very poor general state of health.
Intravascular use
Renal failure
Temporary renal failure may occur in rare cases. Preventative measures against acute renal failure following contrast medium administration include:
Identification of high-risk patients, eg patients with: a history of renal disease, pre-existing renal insufficiency, previous renal failure after contrast medium administration, diabetes mellitus with nephropathy, volume depletion, multiple myeloma, age greater than 60 years, advanced vascular disease, paraproteinaemia, severe and chronic hypertension, gout, receiving large or repeated doses.
Ensuring adequate hydration in risk patients before contrast medium administration, preferably by maintaining intravascular infusion before and after the procedure and until the contrast medium has been cleared by the kidneys.
Avoiding additional strain on the kidneys in the form of nephrotoxic drugs, oral cholecystographic agents, arterial clamping, renal arterial angioplasty, major surgery, etc, until the contrast medium has been cleared.
Postponing a new contrast medium examination until renal function returns to pre-examination levels.
In patients with severely restricted renal function, 24 hours are recommended to elapse between two iodinated contrast medium examination sessions.
Patients on dialysis may receive contrast media for radiological procedures as iodinated contrast media are cleared by the dialysis process.
Cardiovascular disease.
In patients with valvular disease and pulmonary hypertension contrast medium administration may lead to pronounced haemodynamic changes. Reactions involving ischaemic ECG changes and major arrhythmia are more common in older patients and in those with preexisting cardiac disease.
The intravascular injection of contrast media may precipitate pulmonary oedema in patients with heart failure.
CNS disorders
Particular care should be paid to the intravascular administration of contrast media in patients with acute cerebral infarction, acute intracranial haemorrhage, and other conditions involving blood-brain barrier damage, cerebral oedema or acute demyelination. Intracranial tumours or metastases and a history of epilepsy may increase the incidence of convulsive seizures after administration of iodinated contrast media. Neurological symptoms due to cerebrovascular diseases, intracranial tumours or metastases, degenerative or inflammatory pathologies may be exacerbated by contrast medium administration. Vasospasm and subsequent cerebral ischaemic phenomena may be caused by intraarterial injections of contrast media. Patients with symptomatic cerebrovascular disease, recent stroke or frequent transient ischaemic attacks have an increased risk of neurological complications.
Severe liver dysfunction
In the case of severe renal insufficiency the coexistence of severe hepatic dysfunction can seriously delay contrast medium excretion, possibly necessitating haemodialysis.
Myeloma and paraproteinaemia
Myeloma or paraproteinaemia may predispose to renal impairment following contrast medium administration. Adequate hydration is mandatory.
Phaeochromocytoma
Patients with phaeochromocytoma may develop a severe (occasionally uncontrollable) hypertensive crisis following intravascular contrast medium use. Premedication with alpha-receptor blockers is recommended.
Patients with autoimmune disorders
Cases of severe vasculitis or Stevens-Johnson like syndrome have been reported in patients with preexisting autoimmune disorders.
Myasthenia gravis
The administration of iodinated contrast media may aggravate the symptoms of myasthenia gravis and/or precipitate a myasthenic crisis.
Alcoholism
Acute or chronic alcoholism may increase blood-brain barrier permeability. This facilitates the passage of the contrast medium into cerebral tissue, possibly leading to CNS reactions. Caution must also be exercised in alcoholics and drug addicts because of the possibility of a reduced seizure threshold.
Coagulation
Ionic iodinated contrast media inhibit blood coagulation in vitro, more than non-ionic contrast media. Nevertheless medical personnel performing vascular catheterisation procedures should consider that numerous factors in addition to the contrast medium, including length of procedure, number of injections, catheter and syringe material, underlying disease state, and concomitant medication may contribute to the development of thromboembolic events. Therefore, when performing a vascular catheterisation procedure one should be aware of this and pay meticulous attention to the angiographic technique and flush the catheter frequently with physiological saline (if possible with the addition of heparin) and minimise the length of the procedure so as to minimise the risk of procedure-related thrombosis and embolism.
The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.
Caution is advised in patients with homocystinuria because of the risk of inducing thrombosis and embolism.

DOSAGE AND DIRECTIONS FOR USE
General information
Dietary suggestions
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, dark and fresh bread and all kinds of uncooked vegetables. On the day before the examination, patients should refrain from eating after 6 pm. Moreover, it can be appropriate to administer a laxative in the evening. In neonates, infants and young children however, prolonged fasting and the administration of a laxative before the examination are contra-indicated.
Hydration
Adequate hydration must be assured before and after contrast medium administration. This applies especially to patients with multiple myeloma, diabetes mellitus with nephropathy, polyuria, oliguria, hyperuricaemia, as well as to neonates, infants, small children and elderly patients. Disorders of the water and electrolyte balance must be corrected before the examination.
Neonates (< 1 month), infants (1 month to 2 years) and children (2 to 11 years)
Young infants (age < 1 year) and especially neonates are susceptible to electrolyte imbalance and haemodynamic alterations. Care should be taken regarding: the dose of contrast medium to be given, the technical performance of the radiological procedure and the patient status.
Anxiety
Pronounced states of excitement, anxiety and pain may increase the risk of side effects or intensify contrast medium-related reactions. These patients may be given a sedative.
Warming prior to use
Contrast media which are warmed to body temperature before administration are better tolerated and can be injected more easily because of reduced viscosity. Using an incubator, only the calculated number of bottles needed for the same examination day should be warmed up to 37°C.
Pretesting
Sensitivity testing using a small test dose of contrast medium is not recommended as it has no predictive value. Furthermore, sensitivity testing itself has occasionally led to serious and even fatal hypersensitivity reactions.
Dosage for intravascular use
Intravascular administration of contrast media should, if possible, be done with the patient lying down. After the administration, the patient should be observed for at least 30 minutes, since the majority of reactions occur within this time.
The dosage may vary depending on the age, weight, cardiac output and general condition of the patient.
In patients suffering form marked renal or cardiovascular insufficiency, and in patients in a poor general condition, the contrast medium dose must be kept as low as possible. In these patients it is advisable to monitor renal function for at least 3 days following the examination.
Between separate injections the body should be given enough time for the influx of interstitial fluid to normalise the increased serum osmolality. To achieve this, a period of 10 to 15 minutes is necessary in adequately hydrated patients. If it is necessary in particular instances to exceed a total dose of 300 to 350 mL in the adult, additional water and possibly electrolytes should be given.
Recommended dosage for intravenous urography for infusion
Adults and adolescents
1 bottle of Urografin 30% 250 mL.
In general, the infusion time should not be less than 5 minutes nor much more than 10 minutes. Infusion times of 20 to 30 minutes are indicated in patients with cardiac insufficiency.
Children
1 bottle of Urografin 30% 250 mL.

3 to 12 months	6 mL/kg body weight.
1 to 8 years	4 mL/kg body weight.
over 8 years	3 mL/kg body weight.

Infusion time: 8 to 10 minutes.
Compression is contra-indicated in neonates and infants and is also inadvisable during the infusion of large amounts of contrast medium in children, adolescents and adults since, if drainage is obstructed, the increased diuresis can lead to rupture of the fornix as a result of the high pressure. Compression may however, be applied about 10 minutes after the end of the infusion to demarcate organic from functional filling defects.
Filming times
The first film should be taken towards the end of the infusion. Further films may be taken within the next 20 minutes, or later in case of excretory disturbances.
Handling
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.
The rubber stopper should never be pierced more than once to prevent large amounts of microparticles from the stopper getting into the solution. The use of cannulas with a long tip and a maximum diameter of 18 G is recommended for piercing the stopper and drawing up the contrast medium (dedicated withdrawal cannulas with a lateral aperture, eg Nocore-Admix cannulas, are particularly suitable).
Urografin 30% does not contain any preservatives and therefore any solution remaining in the container after a single procedure should be discarded.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
In order to give an approximate indication of incidence the following definitions apply when the words common, uncommon and rare appear in the text:

Common:	incidence > 1:100.
Uncommon:	incidence < 1:100 but > 1:1000.
Rare:	incidence < 1:1000.

Intravascular use
Side effects in association with the use of iodinated contrast media are usually mild to moderate and transient in nature. However, severe and life-threatening reactions as well as deaths have been reported. The prevalence of adverse drug reactions in patients receiving ionic contrast media is reported to be over 12% compared to over 3% for non-ionics.
Nausea, vomiting, a sensation of pain and a general feeling of warmth are the most frequently recorded reactions.
Anaphylactoid reactions/hypersensitivity
Angioedema, conjunctivitis, coughing, pruritus, rhinitis, sneezing and urticaria have been reported commonly. These reactions which can occur irrespective of the amount administered and the mode of administration, may be the first signs of an incipient state of shock. Administration of the contrast medium must be discontinued immediately and –if necessary –specific therapy instituted via a venous access (see “Warnings”).
Severe reactions requiring emergency treatment can occur in the form of a circulatory reaction accompanied by peripheral vasodilatation and subsequent hypotension, reflex tachycardia, dyspnoea, agitation, confusion and cyanosis possibly leading to unconsciousness.
Hypotension, bronchospasm and laryngeal spasm or oedema occur uncommonly.
Delayed contrast medium reactions are rare (see “Warnings”).
Body as a whole
Heat sensations and headache have been reported as being common. Malaise, chills or sweating and vasovagal reactions are uncommon.
In rare cases alterations in body temperature and swelling of salivary glands are possible.
Respiratory
Transient disturbance in respiratory rate, dyspnoea and respiratory distress and coughing are common.
Respiratory arrest and pulmonary oedema are rare reactions.
Cardiovascular
Clinically relevant transient disturbance in heart rate, blood pressure, disturbance in cardiac rhythm or function and cardiac arrest are uncommon.
Severe reactions requiring emergency treatment can occur in the form of a circulatory reaction accompanied by peripheral vasodilatation and subsequent hypotension, reflex tachycardia, dyspnoea, agitation, confusion and cyanosis possibly leading to unconsciousness.
Serious thromboembolic events causing myocardial infarction have been reported in rare cases.
Gastrointestinal
Nausea and vomiting are common reactions. Abdominal pain has been reported as being uncommon.
Cerebrovascular
Cerebral angiography and other procedures in which the contrast medium reaches the brain in high concentrations with the arterial blood can be accompanied by transient neurological complications such as: dizziness, headache, agitation or confusion, amnesia, disturbed speech, vision, hearing, convulsions, tremor, paresis/paralysis, photophobia, temporary blindness, coma, and somnolence are uncommon.
Serious, in isolated cases fatal, thromboembolic events causing stroke have been reported on rare occasions.
Renal
In rare cases renal impairment or failure have been reported.
Skin
Mild angioedema, flush reaction with vasodilatation, urticaria, pruritus and erythema have been commonly observed.
Toxic skin reactions such as the mucocutaneous syndrome (eg Stevens-Johnson’s or Lyell syndrome) may develop in rare cases.
Local irritation
Local pain occurs commonly mainly in peripheral angiography. Extravasation of contrast media gives rise to local pain and oedema, but usually recedes without sequela. However, inflammation and even tissue necrosis have been seen on very rare occasions. Thrombophlebitis and venous thrombosis are uncommon.
Interaction with other medicines and other forms of interaction
Hypersensitivity reactions can be aggravated in patients on beta-blockers, particularly in people with bronchial asthma. Moreover, it should be considered that patients on beta-blockers may be refractory to standard treatment of hypersensitivity reactions with beta-agonists.
The prevalence of delayed reactions (eg fever, rash, flu-like symptoms, joint pain and pruritus) to contrast media is higher in patients who have received interleukin.
The presence of renal damage in diabetic patients is one of the factors predisposing to renal impairment following contrast media 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 agent examination and reinstated only after control of renal function has been regained.
Interference with diagnostic tests
Following the administration of iodinated contrast media, the capacity of the thyroid tissue to take up radioisotopes for diagnosing disorders of the thyroid is reduced for up to two weeks, and even longer in individual cases.
Pregnancy and lactation
Reproduction-toxicological studies with meglumine- or sodium amidotrizoate gave no indication of a teratogenic or other embryotoxic potential following an inadvertent administration of Urografin during pregnancy.
It has not been sufficiently demonstrated that contrast media are safe for use in pregnant patients. Since, wherever possible, radiation exposure should be avoided during pregnancy, the benefits of any X-ray examination, with or without contrast media, should be carefully weighed against the possible risk.
Renally eliminated contrast media like 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. Breastfeeding is probably safe.
Effects on ability to drive and use machines
As with all iodinated contrast media, there is a possibility of delayed reactions following administration in rare cases.
As a precaution, driving or operating machinery should be avoided for the first 24 hours after administration of contrast media.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
In the event of accidental intravascular overdose in humans, the water and electrolyte losses must be compensated by infusion. Renal function needs monitoring for at least the next 3 days.
If needed, haemodialysis can be used to eliminate the bulk of the contrast medium from the patient’s system.

IDENTIFICATION
Clear colourless solution, free of particles.

PRESENTATION
Colourless glass bottles with a black rubber stopper each containing 250 mL.

STORAGE INSTRUCTIONS
To be stored in original packs at room temperature (below 30°C). Protect from light, heat and secondary X-rays and discard any unused solution after the completion of a single procedure. Keep out of reach of children.

REFERENCE NUMBER
F0606 (Act 101 of 1965)

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Schering (Pty) Ltd
(Reg No: 1964/009072/07)
106 Sixteenth Road
Randjespark
Midrand        1685
P O Box 5278
Halfway House        1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
23 September 2003

SCHERING (PTY) LTD
(Reg No: 1964/009072/07)
Subsidiary of
Schering AG        Germany

Updated on this site: March 2004
Current: January 2005
Source: Pharmaceutical Industry
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