Information for the Doctor

lopamidol 340mg lodine/ml Injection

Summary of Product Characteristics

1.    Trade Name of the Medicinal Product

lopamidol 340mg lodine/ml Injection.

2.    Qualitative and Quantitative Composition

Contains 694.0mg iopamidol, equivalent to 340mg iodine/ml.

3.    Pharmaceutical Form Solution for injection.

4.    Clinical Particulars

4.1    Therapeutic indications

Iopamidol 340mg Iodine/ml Injection, an X-ray contrast media is indicated for the following procedures:

•    peripheral arteriography

•    angiocardiography and left ventriculography

•    coronary arteriography

•    aortography

•    selective renal arteriography

•    selective visceral angiography

•    digital subtraction angiography

•    computer tomography enhancement

•    intravenous urography

•    arthrography.

4.2    Posology and method of administration

Dosage and administration:

Adults and children:

* 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    Contra-indications

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 in the radiology department) for 1 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 arrhythmias 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    Interactions with other medicaments 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 preovulation 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.

Information for the Patient

Iopamidol 340mg Iodine/ml Injection

Please read this leaflet carefully. This leaflet does not contain the complete information about your medicine. If you have any questions or are not sure about anything, ask your doctor.

About your medicine

•    Iopamidol 340mg Iodine/ml Injection is a clear, colourless to pale yellow solution which contains 694.0mg of the active ingredient iopamidol. The iopamidol is equivalent to 340mg iodine/ml.

•    Each vial also contains tromethamine, sodium calcium edetate, Water for Injections, sodium hydroxide or hydrochloric acid.

•    It comes in 20ml, 50ml, 100ml and 200ml vials.

•    Iopamidol is a non-ionic X-ray contrast media, allowing the different tissues of the body to be visible under X-ray inspection.

Marketing Authorisation holder

Genus Pharmaceuticals, Park View House, 65 London Road, Newbury, Berkshire RG14 1JN, UK.

Manufacturer

N.P.B.I., Runde ZZ41,7881 HM Emmer-Compascuum, The Netherlands.

Uses for your medicine

This medicine is used to help the doctor examine the following:

•    peripheral arteriography - the blood vessels situated away from the main body organs

•    angiocardiography and left ventriculography - the heart

•    coronary arteriography - the arteries around the heart

•    aortography - the main artery leaving the heart, the aorta

•    selective renal arteriography - the arteries in the kidney

•    selective visceral angiography - any large organ in the body cavity, especially the abdomen

•    digital subtraction angiography - blood vessels in the body

•    computer tomography enhancement - for brain and whole body scanning

•    intravenous urography - the urinary tract from the bladder

•    arthrography - joints in the body.

Before starting your treatment

If the answer to any of the following questions is yes, tell the doctor before your treatment begins.

•    Have you ever had an allergic reaction to iopamidol, iodine or any of the ingredients listed above?

•    Have you ever had an uncomfortable reaction during previous similar investigations?

•    Are you asthmatic or have a history of allergies?

•    Do you suffer from liver, heart or kidney disease?

•    Do you have any other disease affecting any part of your body?

•    Have you experienced dehydration, especially as a result of cancer?

•    Do you suffer from epilepsy, diabetes, problems with your thyroid or Graves' disease?

•    Are you pregnant, think that you may be pregnant or planning a family?

•    Are you taking metformin, blood thinning medicines (anticoagulants) or any other drugs?

No other drugs should be mixed with this contrast media.

Do not drive or operate any tools/machines for at least 6 hours following a procedure during which iopamidol was injected into the spinal cord area of your back. For other procedures the time you should allow before driving or operating any tools/machines should be at least 1 hour following the last injection of iopamidol.

How is Iopamidol Injection given?

The doctor will decide the most suitable dose for the procedure to be undertaken.

The dose administered to adults will differ for children, the dose for children is according to body size and age.

The Iopamidol Injection will be given by injecting the solution into an artery, vein or the back around the spinal cord depending on the diagnostic purpose.

If too much iopamidol is given it can be quickly removed from your body by increasing the amount of fluids into your body or if necessary by haemodialysis (artificial kidney).

At the end of the procedure the medical staff caring for you will observe you closely for 15 minutes. This is in case you develop side-effects to iopamidol that might require immediate treatment. The medical staff are also likely to request that you stay on the hospital premises for 1 hour after the last injection of iopamidol given to you. If during this time you develop any of the side-effects listed in the next section (‘What unwanted effects can this medicine have?') you should return to the department where you had your procedure (radiology department) and tell the medical staff your symptoms.

If the procedure involved you being given injections of iopamidol into the spinal cord area of your back, the medical staff will ensure that you rest with your head and upper body kept upright for at least 1 hour.You will then also be told to rest with your head supported for 6 hours after the last injection of iopamidol was given to you.

What unwanted effects can this medicine have?

This medicine, like most other medicines, may cause side-effects in some people.

Occasionally, kidney problems may occur which rarely may result in kidney failure. Your doctor will ensure that you have adequate fluids in order for this to be avoided.

The following side-effects may occur; headache, nausea, vomiting, dizziness, hot flush, skin rashes, difficulty breathing and low blood pressure. The side-effects will go away after treatment is stopped.

Examination of your heart may result in an abnormal or irregular heart beat.

Occasionally, reactions such as itching and rashes of the skin can occur some time after iopamidol has been given to you. Severe, life-threatening, allergic reactions (swelling of the

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 arrhythmias 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 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. Pharmacological Properties

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 hyperthyroidism 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 1 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

(T1_), this would increase in renal impairment.

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5.3 Pre-clinical 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 hydroxide¹

Hydrochloric acid¹

*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 Instructions for use/handling

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

Park View House

65 London Road

Newbury

Berkshire

RG14 1JN

UK

8.    Marketing Authorisation Number

PL 06831/0065

9.    Date of First Authorisation/Renewal of Authorisation

23 November 1999.

10.    Date of (Partial) Revision of Text

December 2007.

tongue, lips, face and extremities, breathlessness, fluid in the lungs, low blood pressure, fainting and possible collapse), heart attacks and, rarely, blood vessel obstructions have also been reported following the use of contrast media.

Rarely, other side-effects affect the nervous system, including seizures, temporary confusion or the “shakes”. Meningitis has also been reported.

If you experience any of the above effects or any other undesirable effects, tell your doctor immediately. Your doctor will give you advice.

How should this medicine be stored?

Do not use this medicine after the expiry date indicated on the vial and pack.

Normally, your doctor or the pharmacist will store this medicine. Do not store above 25°C. Keep the container in the outer carton to protect from light. Once the vial has been opened, the solution should be used immediately and any remaining solution discarded.

If the solution is cloudy do not use.

Keep all medicines out of the reach and sight of children Remember: This medicine has been prescribed for you. Do not give it to others. It may harm them even if their symptoms appear to be the same as yours.

Leaflet prepared: December 2007.

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Trademark    GHVUS PHARMACEUTICALS