SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Iopamidol 300mg Iodine/ml Injection.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains 612.4mg iopamidol, equivalent to 300mg iodine/ml.

3.    PHARMACEUTICAL FORM

Solution for injection.

4 CLINICAL PARTICULARS

4.1    Therapeutic indications

Iopamidol 300mg Iodine/ml injection, an X-ray contrast media is indicated for the following procedures:

•    lumbar myelography

•    thoraco-cervical myelography

•    cerebral angiography

•    peripheral arteriography

•    venography

•    computer tomography enhancement

•    intravenous urography

•    arthrography

4.2    Posology and Method of Administration

Dosage and administration:

Adult and children:

Procedure	Dosage (ml)
	Adults	Children
Lumbar myelography	5-10	Not recommended
Thoraco-cervical myelography	5-10	Not recommended
Cerebral angiography	5-10**	5-7*

Peripheral arteriography	20-50**	*
Venography	20-50	*
Computer tomography enhancement: Brain scanning Whole body scanning	50-100 40-100	Not recommended Not recommended
Intravenous urography	40-80***	1-2.5 ml/kg*
Arthrography	1-10	Not recommended

* Dose dependent on body size and age.

** Repeat as necessary.

*** For severe renal failure patients use up to 1.5ml/kg.

Elderly: No special dosage requirements. However, the lowest effective dose to be used.

Once the vial is opened use immediately and discard any remaining solution after use.

4.3 Contraindications

Known or suspected hypersensitivity to iodine containing preparations or to any of the excipients detailed under section 6.1.

4.4 Special Warnings and Precautions for Use

As with other contrast media there is the possibility that this product may provoke anaphylactoid reactions or other signs of allergy with nausea, vomiting, dyspnoea, erythema, urticaria and hypotension. Extra caution to be taken with patients known to have a positive history of allergy, asthma or have reacted during previous similar investigations, hence the benefits must be assessed against the risks. Appropriate resuscitation procedures must be available immediately. Patients must be kept under close observation for 15 minutes following the last injection as the majority of severe reactions occur during this time. Patients should remain in the hospital environment (but not necessarily the radiology department) for one hour after the last injection is administered. Patients should be advised to return to the radiology department if any symptoms develop.

Patients who have been administered the media intrathecally should rest with the head and thorax elevated for at least 1 hour followed by subsequent ambulation or bed rest with the head elevated to 6 hours post-procedure.

The dose of iopamidol must be adjusted in patients with moderate to severe impaired renal function or in patients known to be diabetic. In patients taking metformin for renal impairment the use of contrast media may precipitate lactic acidosis. Hence, this drug should be stopped 48 hours prior to the administration of the contrast media and restarted after control of renal function has been regained. Such patients must be maintained hydrated through the procedure and renal function monitored after the procedure.

In patients suffering from severe hepato-renal impairment no procedure should be conducted unless absolutely required, with re-examination delayed for 5-7 days.

Investigation of the right heart can be conducted, but in patients with pulmonary hypertension, the pulmonary artery examination should not be conducted unless absolutely required. During intracardiac and/or coronary arteriography, ventricular arrhythmia’s may infrequently occur.

Care to be taken when conducting the procedure in patients with severe functional impairment of the liver or myocardium and severe systemic disease, especially in myelomatosis where patients should be well hydrated. Abnormalities of fluid or electrolyte balance should be corrected prior to the administration of the contrast media.

In patients suffering from or with known history of epilepsy, anticonvulsant therapy should be maintained before and following myelographic procedures, with therapy increased for 48 hours before the procedure in some patients.

Caution must be taken in patients with hyperthyroidism and those previously suffering from Graves’ disease. Hyperthyroidism may recur in patients previously treated for Graves’ disease.

Rarely, serious thromboembolic complications have occurred after the use of contrast media. To minimise the risk of clotting, non-ionic media should not be permitted to remain in contact with blood in the syringe and intravascular catheters should be flushed frequently.

4.5 Interaction with Other Medicinal Products and other Forms of Interaction

No other drugs should be mixed with this contrast media. As a precautionary measure, metformin should be stopped 48 hours prior to administration of this contrast media and only restarted after renal control has been regained. Iopamidol may interfere with tests for thyroid function.

4.6 Pregnancy and Lactation

Limited data are available on the use of iopamidol during pregnancy and lactation. Caution should therefore be exercised because of the risk of X-rays associated with this product, by balancing the potential benefits of treatment against any possible hazard. Hence, administration and investigational procedures should be conducted in the pre-ovulation phase in women.

4.7    Effects on Ability to Drive and Use Machines

None known. However, because of the risk of early reactions driving or operating machinery is not advisable for 1 hour following the time of injection. Driving or operating machinery is not advisable for 6 hours following intrathecal administration of the media (see section 4.4).

4.8    Undesirable Effects

This medicine may cause headache, nausea, vomiting, dizziness, heat sensation, skin rashes (e.g. erythema), dyspnoea and hypotension as seen with other contrast media. Iopamidol will irritate the gastrointestinal tract to cause nausea, vomiting and diarrhoea with heartburn.

In addition, for myelography procedures rare cases of seizures, transient confusion or transient motor or sensory dysfunction may occur. Menigism or meningitis have also been reported, the possibility of an infective meningitis should be considered.

Renal impairment developing during treatment usually responds to rehydration of the patient, therefore the patient should not be exposed to dehydration.

During intracardiac and/or coronary arteriography, ventricular arrhythmia's may infrequently occur.

Anaphylactoid reactions and cardiac arrest may occur following use of contrast media including iopamidol. Fatalities have been reported. There have also been isolated reports of acute pulmonary oedema. Resuscitation procedures should be immediately available in order to overcome more severe reactions involving the cardiovascular system.

Delayed reactions may occur occasionally with pruritus and urticaria being the most common of these reactions.

Rarely, serious thromboembolic complications have occurred after the use of contrast media.

4.9 Overdose

Iopamidol undergoes minimal metabolism, deiodination or biotransformation in vivo. Majority of dose is excreted in the urine unchanged, therefore increase intake of fluid.

5.1 Pharmacodynamic properties

As contrast medias are administered for diagnostic purposes they have minimal pharmacodynamic effect.

In blood it may dehydrate erythrocytes resulting in a decreased ability for circulation, combined with an inhibiting effect on platelet aggregation and coagulation.

Adverse cardiac effects of contrast media are related to the osmolality of the product, the presence of calcium chelating compounds, and anionic and cationic composition. Iopamidol is a non-ionic contrast media, low osmolality, low sodium content and low calcium chelating activity, hence exhibits a reduced evidence of adverse effect to the cardiovascular system.

As the preparation contains iodine, there is a small amount of free iodide that has the potential to induce a clinically significant byperthyroidism in susceptible patients.

5.2 Pharmacokinetic properties

Peak iodine levels occur immediately following rapid intravascular injection of iopamidol. It is rapidly absorbed into the bloodstream from the cerebrospinal fluid following administration into the subarachnoid space, with appearance in plasma within one hour and virtually all reaching the systemic circulation within 24 hours.

There is minimum protein binding, it is distributed between the circulating blood volume and other extracellular fluid with no disposition in tissues. It does not appear to cross the blood brain barrier following intravascular administration. The volume of distribution at steady state is approximately 16.8 litres, equivalent to the extracellular fluid volume.

Iopamidol undergoes minimal metabolism, deiodination or biotransformation, and no metabolites have been detected in urine.

Excretion occurs primarily through the kidneys with minimum amount detected in the faeces. The elimination half-life has been determined as approximately 2.5 hours (T^) this would increase in renal impairment.

5.3 Preclinical safety data

Acute toxicity is very low in mice, rats, rabbits and dogs.

Subacute toxicity studies have been performed in rats, dogs and rabbits. In rats and dogs, intravenous studies for up to four weeks showed some histological

alterations of the thyroid gland only at high doses, though the weight of the thyroid gland increased at all dose levels.

No effect on fertility was observed in rats and no teratogenic potential in rats and mice. No mutagenic potential was detected in mice.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tromethamine Sodium calcium edetate Water for Injections Sodium hydroxide*

Hydrochloric acid*

* Added if required, to adjust pH of the solution.

6.2    Incompatibilities

Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other drugs; therefore, no other pharmaceuticals should be admixed with contrast agents.

6.3    Shelf life

36 months, unopened.

6.4    Special precautions for storage

Do not store above 25°C. Keep container in outer carton.

6.5    Nature and contents of container

Colourless glass Type I vial, closed with rubber stopper and aluminium flip cap.

Pack sizes: Single vial, x5 vials or x10 vials in 20ml, 50ml, 100ml or 200ml volumes.

6.6 Special precautions for disposal

See 4.2 Posology and Method of Administration. Discard the solution if particulate matter present. Discard any unused solution at the end of the procedure. For immediate and single patient use only.

7    MARKETING AUTHORISATION HOLDER

Genus Pharmaceuticals Limited

T/A Genus Pharmaceuticals

Park View House

65 London Road

Newbury

RG14 1JN, UK

8. MARKETING AUTHORISATION NUMBER

PL 06831/0064

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/11/1999

10    DATE OF REVISION OF THE TEXT

14/01/2008