NIOPAM 370

1. Name Of The Medicinal Product

NIOPAM 370, solution for injection.

2. Qualitative And Quantitative Composition

75.5% w/v Iopamidol equivalent to 370mg iodine/ml.

Each ml contains 755.3 mg Iopamidol.

For excipients, see 6.1.

3. Pharmaceutical Form

Solution for injection.

Clear aqueous solution filled into colourless glass ampoules or bottles.

4. Clinical Particulars

4.1 Therapeutic Indications

X-ray contrast medium for use in:

Peripheral arteriography

Angiocardiography and left ventriculography

Coronary arteriography

Aortography - retrograde

Selective renal arteriography

Selective visceral angiography

Digital subtraction angiography

Urography

4.2 Posology And Method Of Administration

Route of administration

Intra-arterial

Intra-venous

Intra-ventricular

Dosage

NIOPAM 370 : DOSAGE SCHEDULE

Procedure	Dosage
Peripheral Arteriography   Venography	Adults 20 - 50 ml * Children ** Adults 20 - 50 ml * Children **
Angiocardiography and Left Ventriculography	Adults 30 - 80 ml Children **
Coronary Arteriography	Adults 4 - 8 ml per artery *
Aortography - Retrograde	Adults 30 - 80 ml Children **
Selective Renal Arteriography	Adults 5 - 10 ml Children **
Selective Visceral Angiography: Hepatic Coeliac Superior mesenteric, inferior mesenteric	Adults 30 - 70 ml 40 - 70 ml 5 - 30 ml Children **
Digital Subtraction Angiography: Intravenous injection   Left ventriculography   Selective coronary arteriography by intra-arterial DSA	Adults 50 ml Children 0.5 - 0.75 ml/kg Adults 25 ml Children 1 - 1.5 ml/kg Adults 2 - 5 ml
Intravenous Urography	Adults 40 - 80 ml In severe renal failure the usual high dose methods should be employed. (up to 1.5 mg/kg or **) Children 1- 2.5 ml/Kg**

*repeat as necessary; ** according to body size and age;

Do not exceed 250 ml. Single injection volume depends on the vascular area to be examined

Elderly: dosage as for adults. The lowest effective dose should be used.

Method of administration

No other drugs should be mixed with the contrast medium.

Peripheral arteriography and phlebography (venography)

Percutaneous injection into the appropriate blood vessel is used for visualisation of peripheral arteries and veins.

Angiocardiography, left ventriculography, selective coronary arteriography

Niopam may be administered by rapid injection through a catheter into a suitable peripheral artery or vein. It can also be introduced under pressure through a cardiac catheter into any of the heart chambers, or injected into large vessels for immediate visualisation.The contrast medium may also be administered during selective catheterisation of the coronary arteries.

Aortography

The contrast medium may be introduced directly by intra-arterial injection (retro-grade method) for visualisation of the aorta and its main branches.

Selective visceral angiography

Visualisation can be achieved by selective catheterisation and injection into the hepatic, coeliac or mesenteric arteries.

Digital subtraction angiography

For cardiac imaging the contrast medium may be administered intra-arterially by selectivecatheterisation to provide subtracted images. Niopam 340 and 370 injected intravenously either centrally or peripherally is also recommended for use in this modality.

Urography

The contrast medium is injected intravenously and rapidly eliminated through the kidneys. In patients with severe renal failure, high dose urography should be used.

4.3 Contraindications

Use in patients with proven or suspected hypersensitivity to iodine containing preparations of this type.

4.4 Special Warnings And Precautions For Use

A positive history of allergy, asthma or untoward reaction during previous similar investigations indicates a need for extra caution; the benefit should clearly outweigh the risk in such patients. Appropriate resuscitative measures should be immediately available.

X-ray examination of women should if possible be conducted during the pre-ovulation phase of the menstrual cycle and should be avoided during pregnancy.

When examining small children or babies, do not limit fluid intake before administering a hypertonic contrast solution. Also, correct any existing water and electrolyte imbalance.

Care should be exercised in carrying out radiographic procedures with contrast media in patients with severe functional impairment of the liver or myocardium, severe systemic disease and in myelomatosis (including Waldenströms macroglobulinemia, multiple myeloma).

In the latter condition patients should not be exposed to dehydration; similarly abnormalities of fluid or electrolyte balance should be corrected prior to use.

Particular care should also be exercised in patients with moderate to severe impairment of renal function (as reflected by a raised blood urea) or in diabetes. Substantial deterioration in renal function is minimised if the patient is well hydrated. Renal function parameters should be monitored after the procedure in these patients.

Patients with severe hepato-renal insufficiency should not be examined unless absolutely indicated. Re-examination should be delayed for 5-7 days.

Special care should be exercised when this product is injected into the right heart or pulmonary artery in patients with pulmonary hypertension. Right heart angiography should be carried out only when absolutely indicated.

Niopam should be administered with caution in elderly patients and patients with increased intracranial pressure or suspicion of intracranial tumour, abscess or haematoma, and in those with a history of a previous reaction to contrast media, asthma, allergy, epilepsy, severe cardiovascular disease, renal impairment, chronic alcoholism or multiple sclerosis.

Patients with these conditions have an increased risk of neurological complications.

General anaesthesia may be indicated in selected patients. However, a higher incidence of adverse reactions has been reported in these patients, probably due to the hypotensive effect of the anaesthetic.

Contrast media may promote sickling in individuals who are homozygous for sickle cell disease when injected intravenously and intra-arterially.

Patients with phaeochromocytoma may develop severe hypertensive crisis following intravascular iopamidol. Pre-medication with α-receptor blockers is recommended. The administration of iodinated contrast media may aggravate the symptoms of myasthenia gravis.

Patients with congestive heart failure should be observed for several hours following the procedure to detect delayed haemodynamic disturbances, which may be associated with a transitory increase in the circulating osmotic load. All other patients should be observed for at least one hour after the procedure, as most of the adverse events occur in this period. The patient should also be informed that allergic reactions may develop up to several days after the procedure; in such case, a physician should be consulted immediately.

In neonates, and particularly in premature neonates, it is recommended that tests of thyroid function (typically TSH and T4), should be checked 7-10 days and 1 month after the administration of iodinated contrast media because of the risk of hypothyroidism due to iodine overload.

In patients scheduled for thyroid examination with a radioactive iodine tracer, one must take into consideration that iodine uptake in the thyroid gland will be reduced for several days (up to two weeks) after dosing with an iodinized contrast medium that is eliminated through the kidneys.

Local tissue irritation can occur as an event of perivascular infiltration.

Neuroradiology

In patients who are known epileptics or have a history of epilepsy, anticonvulsant therapy should be maintained before and following myelographic procedures. In some instances anticonvulsant therapy may be increased for 48 hours before the examination.

Neuroleptics must be absolutely avoided because they lower the seizure threshold. The same applies to analgesics, anti-emetics, antihistamines and sedatives of the phenothiazine group. Whenever possible, treatment with such drugs should be discontinued at least 48 hours before administration of the contrast medium and not be resumed less than 12 hours after completion of the procedure.

Angiography

In patients undergoing angiocardiographic procedures special attention should be paid to the status of the right heart and pulmonary circulation. Right heart insufficiency and pulmonary hypertension may precipitate bradycardia and systemic hypotension, when the organic iodine solution is injected. Right heart angiography should be carried out only when absolutely indicated.

In angiographic procedures, the possibility of dislodging plaque or damaging or perforating the vessel wall should be considered during catheter manipulation and contrast medium injection. Test injections to ensure proper catheter placements are recommended.

Angiography should be avoided whenever possible in patients with homocystinuria due to an increased risk of thrombosis and embolism.

In patients undergoing peripheral angiography, there should be pulsation in the artery into which the X-ray contrast medium will be injected. In patients with thromboangiitis obliterans or ascending infections in combination with serious ischemia the angiography should be performed, if at all, with special caution.

In patients undergoing venography, special caution should be exercised in patients with suspected phlebitis, serious ischaemia, local infections, or a complete venous occlusion.

Serious neurological events have been observed following direct injection of contrast media into cerebral arteries or vessels supplying the spinal cord or in angiocardiography due to inadvertent filling of the carotids.

In paediatric roentgenology, one should proceed with great caution when injecting the contrast medium into the right heart chambers of cyanotic neonates with pulmonary hypertension and impaired cardiac function.

In examinations of the aortic arch the tip of the catheter should be positioned carefully to avoid hypotension, bradycardia and CNS injury due to excess pressure transmitted from the injector pump to the brachiocephalic branches of the aorta.

Urography

Care should be exercised in patients with moderate to severe impairment of renal function (as reflected by a raised blood urea). Substantial deterioration in renal function is minimized if the patient is well hydrated. Renal function parameters, especially urinary output should be monitored after the examination in these patients.

Re-examination should be delayed 5-7 days.

Non-ionic contrast media have less anti-coagulant activity in-vitro than ionic media. Meticulous attention should therefore be paid to angiographic technique. Non-ionic media should not be allowed to remain in contact with blood in the syringe and intravascular catheters should be flushed frequently, to minimise the risk of clotting, which rarely has led to serious thromboembolic complications after procedures.

Niopam should be used with caution in patients with hyperthyroidism. It is possible that hyperthyroidism may recur in patients previously treated for Graves' disease.

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 metformin. As a precaution, metformin should be discontinued at the time of, or prior to, the procedure and withheld for 48 hours subsequent to the procedure and re-instituted only after renal function has been re-evaluated and found to be normal.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Thyroid function tests: use of iodinated contrast media may interfere with tests for thyroid function which depend on iodine estimations, such as Protein Binding Iodine and radioactive iodine uptake. As a consequence they will not accurately reflect thyroid function for up to 16 days following administration of iodinated contrast media. Thyroid function tests not depending on iodine estimations, e.g. T3 resin uptake and total or free thyroxine (T4) assays are not affected.

No other specific interference with physiological functions have been noted.

The administration of an X-ray contrast medium in diabetic patients with nephropathy who are taking biguanides may precipitate lactic acidosis.

Arterial thrombosis has been reported when iopamidol was given following papaverine. The administration of vasopressors strongly potentiate the neurological effect of the intra-arterial contrast media.

Contrast media may interfere with laboratory tests for bilirubin, proteins or inorganic substances (eg iron, copper, calcium, phosphate). These substances should not be assayed during the same day following the administration of contrast media

4.6 Pregnancy And Lactation

X-ray examination of women should if possible be conducted during the pre-ovulation phase of the menstrual cycle and should be avoided during pregnancy ; also, since it has not been demonstrated that Niopam is safe for use in pregnant women, it should be administered only if the procedure is considered essential by the physician.

Niopam is poorly excreted in human milk. From animal experience, Niopam is non toxic in animals after oral administration. Although, no serious adverse reactions have been reported in nursing infants, Niopam should be administered to lactating women only if considered essential by the physician

4.7 Effects On Ability To Drive And Use Machines

There is no known effect on the ability to drive and operate machines. However, because of the risk of early reactions, driving or operating machinery is not advisable for one hour following the last injection.

4.8 Undesirable Effects

The use of iodinated contrast media may cause untoward side effects. They are usually mild to moderate and transient in nature. However , severe and life threatening reactions sometimes leading to death have been reported.

Anaphylaxis (anaphylactoid reactions/hypersensitivity) may manifest with: mild localized or more diffuse angioneurotic oedema, tongue oedema, laryngospasm or laryngeal oedema, dysphagia, pharyngitis and throat tightness, pharyngolaryngeal pain, cough, conjunctivitis, rhinitis, sneezing, feeling hot, sweating increased, asthenia, dizziness, pallor, dyspnoea, wheezing, bronchospasm, and moderate hypotension. Skin reactions may occur in the form of various types of rash, diffuse erythema, diffuse blisters, urticaria, and pruritus. These reactions, which occur irrespective of the dose administered and the route of administration, may represent the first signs of incipient state of shock. Administration of the contrast medium must be discontinued immediately and – if necessary – specific treatment initiated via a venous access.

More severe reactions involving the cardiovascular system such as vasodilatation with pronounced hypotension, tachycardia, dyspnoea, agitation, cyanosis and loss of consciousness (syncope) may require emergency treatment.

Intravascular administration –Adults

The safety of Iopamidol injection through intravascular administration was evaluated in 2,548 adult patients involved in clinical trials.

The adverse reactions are classified by System Organ Class and frequency, using the following convention: Very common (

System Organ Class	Adverse Reactions
Clinical Trials	Post-marketing Surveillance
Common (	Uncommon (	Rare (	Frequency unknown
Blood and lymphatic system disorders				Thrombocytopenia
Immune system disorders				Anaphylaxis, Anaphylactoid reaction
Psychiatric disorders			Confusional state
Nervous system disorders	Headache	Dizziness, Taste alteration	Paraesthesia	Coma, Transient ischaemic attack, Syncope, Depressed level of consciousness or loss of consciousness, Convulsion,
Eye disorders				Transient blindness, Visual disturbance, Conjunctivitis, Photophobia
Cardiac disorders		Cardiac dysrhythmias such as extrasystoles, atrial fibrillation, ventricular tachycardia and ventricular fibrillation*	Bradycardia	Myocardial ischaemia or infarction, Cardiac failure, Cardio-respiratory arrest, Tachycardia
Vascular disorders		Hypotension, Hypertension, Flushing		Circulatory collapse or shock
Respiratory, thoracic and mediastinal disorders			Pulmonary oedema, Asthma, Bronchospasm	Respiratory arrest, Respiratory failure, Acute respiratory distress syndrome, Respiratory distress, Apnoea, Laryngeal oedema, Dyspnoea
Gastrointestinal disorders	Nausea	Vomiting, Diarrhea, Abdominal pain, Dry mouth		Salivary hypersecretion, Salivary gland enlargement
Skin and subcutaneous tissue disorders		Rash, Urticaria, Pruritus, Erythema, Sweating increased		Face oedema, muco-cutaneous syndromes **
Musculoskeletal and connective tissue disorders		Back pain	Muscle spasms	Musculoskeletal pain, Muscular weakness
Renal and urinary disorders		Acute renal failure
General disorders and administration site conditions	Feeling hot	Chest pain, Injection site pain***, Pyrexia, Feeling cold		Rigors, Pain, Malaise
Investigations		Blood creatinine increased		Electrocardiogram change including ST segment depression

*	Cardiac reactions may occur as consequences of the coronary catheterization procedural hazard: these complications include coronary artery thrombosis and coronary artery embolism.
**	As with other iodinated contrast media, very rare cases of muco-cutaneous syndromes, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome) and erythema multiforme, have been reported following the administration of Iopamidol
***	Injection site pain and swelling may occur. In the majority of cases it is due to extravasation of contrast medium. These reactions are usually transient and result in recovery without sequelae. However, inflammation and even skin necrosis have been seen on very rare occasions. In isolated reports extravasation led to the development of compartment syndrome

Intravascular administration – Pediatric Population

Frequency type and severity of adverse reactions in children are similar to those in adults.

4.9 Overdose

Treatment of overdosage is directed toward the support of all vital functions and the elimination of the contrast medium while maintaining the patient well hydrated.

If needed, hemodyalisis can be used to eliminate iopamidol from the body.

5. Pharmacological Properties

Pharmacotherapeutic group; ATC code: V08A B04

5.1 Pharmacodynamic Properties

Iopamidol is contrast medium belonging to the new generation of non-ionic compound whose solubility is due to the presence of hydrophilic substitutes in the molecule. This results in a solution of low osmolality when compared with ionic media.

Iopamidol has been shown to be effective as an X-ray contrast medium in neuroradiology, angiography, venography, arthrography, urography, cerebral angiography and left ventriculography and coronary arteriography. Its toxicity particularly cardiac and CNS toxicity are less than those of ionic contrast media.

5.2 Pharmacokinetic Properties

The pharmacokinetics of iopamidol conform to an open two compartment pharmacokinetic model with first order elimination.

Distribution volume is equivalent to extra-cellular fluid.

Elimination is almost completely through the kidneys. Less that 1% of the administered dose has been recovered in the faeces up to 72 hours after dosing. Elimination is rapid; up to half the administered dose may be recovered in the urine in the first two hours of dosing.

There is no evidence of biotransformation.

Serum protein binding is negligible.

5.3 Preclinical Safety Data

No adverse effects can be predicted from animal toxicology studies other than those documented from human use of iopamidol.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Excipients are: trometamol, hydrochloric acid and edetate calcium disodium.

6.2 Incompatibilities

No other drug should be mixed with the contrast medium.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Protect from light.

6.5 Nature And Contents Of Container

10, 20 ml clear, colourless Type I glass ampoules.

30ml clear, colourless Type I or Type II glass vials with rubber closures and aluminium caps.

50, 70, 100, 200 and 250ml clear, colourless Type I or Type II glass bottles with rubber closures and aluminium caps.

6.6 Special Precautions For Disposal And Other Handling

Discard if the solution is not clear of particulate matter.

Exceptionally, the event of crystallisation of Niopam could occur. It has been shown that such a phenomenon is caused by a damaged or defective container and therefore the product should not be used in this case.

The bottle, once opened, must be used immediately.

Any residue of contrast medium must be discarded.

Niopam, as other iodinated contrast media, can react with metallic surfaces containing copper (e.g. brass), therefore the use of equipment, in which the product comes into direct contact with such surfaces, should be avoided.

7. Marketing Authorisation Holder

Bracco U.K. Ltd,

Bracco House, Mercury Park,

Wycombe Lane, Wooburn Green,

Buckinghamshire HP10 OHH

8. Marketing Authorisation Number(S)

PL 18920/0011

9. Date Of First Authorisation/Renewal Of The Authorisation

22^nd March 1982 / 9^th January 2002

10. Date Of Revision Of The Text

15 November 2011