SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Persantin Ampoules 10mg / 2ml Solution for Infusion

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Dipyridamole 5 mg/ml. Each 2 ml ampoule contains 10 mg dipyridamole. For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Solution for infusion.

2ml glass ampoules containing a clear, yellow-coloured solution.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Adults:

As an alternative to exercise stress in thallium-201 myocardial imaging, particularly in patients unable to exercise or in those for whom exercise may be contraindicated.

Children:

As an alternative to exercise stress in myocardial perfusion imaging, particularly in children unable to exercise or in those for whom exercise may be contraindicated. More specifically, this may include children with Kawasaki disease complicated by coronary artery involvement, or those with congenitally abnormal coronary circulation.

4.2. Posology and method of administration

The dose of intravenous PERSANTIN as an adjunct to thallium myocardial perfusion imaging should be adjusted according to the weight of the patient.

The recommended dose is 0.142 mg/kg/minute (0.567 mg/kg total) infused over 4 minutes.

Thallium-201 should be injected within 3-5 minutes following the 4-minute infusion of PERSANTIN.

4.3. Contraindications

Hypersensitivity to any of the components of the product.

Patients with dysrhythmias, second- or third degree atrioventricular block or with sick sinus syndrome should not receive intravenous PERSANTIN (unless they have a functioning pacemaker). Patients with baseline hypotension (systolic blood pressure < 90 mmHg), recent unexplained syncope (within 4 weeks) or with recent transient ischaemic attacks are not suitable candidates for dipyridamole testing.

Patients with severe coronary artery disease, including unstable angina and recent myocardial infarction (within 4 weeks), left ventricular outflow obstruction or haemodynamic instability (e.g. decompensated heart failure).

Patients with bronchial asthma or a tendency to bronchospasm.

Patients with myasthenia gravis. (See Interactions).

Pregnancy and lactation.

4.4. Special warnings and precautions for use

The potential clinical information to be gained through use of intravenous PERSANTIN as an adjunct in myocardial imaging must be weighed against the risk to the patient. Comparable reactions to exercise-induced stress may occur. Therefore dipyridamole-thallium scanning should be performed with continuous ECG monitoring of the patient.

When myocardial imaging is performed with intravenous PERSANTIN, parenteral aminophylline should be readily available for relieving adverse effects such as bronchospasm or chest pain. Vital signs should be monitored during and for 10 - 15 minutes following the intravenous infusion of PERSANTIN and an electrocardiographic tracing should be obtained using at least one chest lead.

Sedation may be necessary in young children.

Use with caution in young infants with immature hepatic metabolism.

Should severe chest pain or bronchospasm occur, parenteral aminophylline may be administered by slow intravenous injection; for adults doses ranging from 75 mg to 100 mg aminophylline, repeated if necessary, are appropriate; for children, doses of 3-5mg/kg aminophylline have been used.

In the case of severe hypotension, the patient should be placed in a supine position with the head tilted down if necessary, before administration of parenteral aminophylline. If aminophylline does not relieve chest pain symptoms within a few minutes, sublingual nitroglycerin may be administered. If chest pain continues despite use of aminophylline and nitroglycerin, the possibility of myocardial infarction should be considered.

If the clinical condition of a patient with an adverse effect permits a one minute delay in the administration of parenteral aminophylline, thallium-201 may be injected and allowed to circulate for one minute before the injection of aminophylline. This will allow initial thallium perfusion imaging to be performed before reversal of the pharmacologic effects of PERSANTIN on the coronary circulation.

Patients being treated with regular oral doses of PERSANTIN should not receive additional intravenous dipyridamole. Clinical experience suggests that patients being treated with oral    dipyridamole who also require

pharmacological stress testing with intravenous dipyridamole, should discontinue drugs containing oral dipyridamole for twenty-four hours prior to stress testing.

Caution should be exercised in patients with known pre-existing first-degree heart block.

4.5. Interactions with other medicinal products and other forms of interaction

Xanthine derivatives (e.g. caffeine and theophylline) can potentially reduce the vasodilating effect of dipyridamole and should therefore be avoided 24 hours before myocardial imaging with_PERSANTIN. For discontinuation of oral dipyridamole see section 4.4.

Dipyridamole increases plasma levels and cardiovascular effects of adenosine.

Dipyridamole may increase the hypotensive effect of drugs which reduce blood pressure.

Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors thereby potentially aggravating myasthenia gravis.

Cardiac disorders

Chest pain/angina pectoris

Arrhythmia

Tachycardia

Myocardial infarction

Bradycardia

Cardiac arrest

Ventricular fibrillation

Syncope

Sinus arrest

Atrioventricular block

Vascular disorders

Hypotension    common

Hot flush    common

Respiratory, thoracic and mediastinal disorders Bronchospasm    uncommon

Laryngospasm    not known

Gastrointestinal disorders Nausea

Abdominal pain

Diarrhoea

Vomiting

Skin and subcutaneous tissue disorders Urticaria    not known

Rash    not known

Musculoskeletal, connective tissue and bone disorders Myalgia    not    known

General disorders and administration site conditions Cardiac death    rare

Oedema    not    known

Investigations

Electrocardiogram ST-T change common Electrocardiogram change not known

At high doses of intravenous dipryridamole as used in cardiac imaging, more frequent and severe side effects have been reported than those reported during either intravenous or oral administration of dipyridamole at the recommended doses. Nevertheless, all available data suggest that the benefit risk ratio is at least as favourable as the benefit-risk ratio of conventional exercise testing.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9. Overdose

Symptoms:

Although there is no experience of overdose, the signs and symptoms that might be expected to occur include cardiac death, cardiac arrest, myocardial infarction, chest pain, angina pectoris, electrocardiographic changes, syncope, cerebrovascular events, hypotension, hot flushes, hypersensitivity reactions, anaphylactoid reactions, gastrointestinal symptoms, dizziness, headache, paraesthesia, myalgia, bitter taste and blood pressure lability.

Therapy:

Symptomatic therapy is recommended.

Should severe chest pain or brochospasm occur, parenteral aminophylline may be administered by slow intravenous injection; for adults doses ranging from 75 to 100 mg aminophylline, repeated if necessary, are appropriate; for children, doses of 3-5mg/kg aminophylline have been used. If aminophylline does not relieve chest pain symptoms within a few minutes, sublingual nitroglycerin may be administered. If chest pain continues despite use of aminophylline and nitroglycerin, the possibility of myocardial infarction should be considered.

Due to its wide distribution to tissues and its predominantly hepatic elimination, dipyridamole is not likely to be accessible to enhanced removal procedures.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Dipyridamole inhibits the uptake of adenosine into erythrocytes, platelets and endothelial cells in vitro and in vivo; the inhibition amounts to 80% at its maximum and occurs dose-dependently at concentrations of 0.5 - 2 pg/mL. Consequently, there is an increased concentration of adenosine locally to act on the platelet A2-receptor, stimulating platelet adenylate cyclase, thereby increasing platelet cAMP levels. Thus, platelet aggregation in response to various stimuli such as PAF, collagen and ADP is inhibited. Reduced platelet aggregation reduces platelet consumption towards normal levels. In addition, adenosine has a vasodilator effect and this is one of the mechanisms by which dipyridamole produces vasodilation.

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Presumably via a 'steal effect' the vasodilation induced by PERSANTIN administered i.v. in doses used for cardiac imaging techniques leads to regional redistribution of coronary blood flow and may lead to abnormalities in thallium distribution and ventricular function in patients with coronary artery disease. The normal vessels dilate with enhanced flow, leaving relatively reduced pressure and flow across areas of haemodynamically important coronary stenoses.

Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. Whilst the inhibition of cAMP-PDE is weak, therapeutic levels inhibit cGMP-PDE, thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, identified as NO).

Dipyridamole also stimulates the biosynthesis and release of prostacyclin by the endothelium.

Dipyridamole reduces the thrombogenicity of subendothelial structures by increasing the concentration of the protective mediator 13-HODE (13-hydroxyoctadecadienic acid).

5.2 Pharmacokinetic Properties

Distribution

Owing to its high lipophilicity, log P 3.92 (n-octanol/0.1N, NaOH), dipyridamole distributes to many organs. After i.v. administration (60 mg/75 min) fitted by a 3-compartment model a rapid alpha phase, with a half-life of about 3 min presumably reflecting distribution of the drug from the central compartment to peripheral compartments, is observed. The apparent volume of distribution of the central compartment (Vc) is about 5 L (similar to plasma volume). The apparent volume of distribution at steady state is about 100 L, reflecting distribution to various compartments.

Non-clinical studies indicate that dipyridamole is distributed preferentially to the liver, then to the lungs, kidneys, spleen and heart, it does not cross the blood-brain barrier to a significant extent and shows a very low placental transfer . Non-clinical data have also shown that dipyridamole can be excreted in breast milk.

Protein binding of dipyridamole is about 97 - 99%, primarily it is bound to alpha 1-acid glycoprotein and albumin.

Metabolism

Metabolism of dipyridamole occurs in the liver. Dipyridamole is metabolized by conjugation with glucuronic acid to form mainly a monoglucuronide and only small amounts of diglucuronide.

After i.v. treatment, glucuronide concentrations are approx. 10% of total drug. Elimination

After i.v. administration (60 mg/75 min) fitted by a 3-compartment model, a beta phase, with a half-life of about 40 min (dominant half-life) and a prolonged terminal elimination phase (^_z) with a half-life of about 15 hours are observed. According to this model, the beta phase represents the elimination of most of the administered drug and accounting for about 70% (together with the alpha phase) of the total AUC, whereas the terminal elimination phase (about 30% of the total AUC) probably represents the rediffusion of a smaller proportion of the administered dose from remotely accessible tissues of low capacity back into the central compartment. Renal excretion of parent compound is negligible (< 0.5%). Urinary excretion of the glucuronide metabolite is low (< 8%), the metabolites are mostly (about 95 %) excreted via the bile into the faeces, with some evidence of entero-hepatic recirculation. Total clearance is approximately 200 mL/min and mean residence time is 6.4 hours.

Elderly subjects

Plasma concentrations (determined as AUC) in elderly subjects (> 65 years) were about

30 - 50% higher with oral treatment than in young (< 55 years) subjects and the difference is caused mainly by reduced clearance; a slower decrease of plasma concentrations after i.v. treatment is to be expected.

Hepatic impairment

Patients with hepatic insufficiency show no change in plasma concentrations of dipyridamole, but an increase of (pharmacodynamically low active) glucuronides. It is suggested to dose dipyridamole without restriction as long as there is no clinical evidence of liver failure.

Renal impairment

Since renal excretion is very low (5%), no change in pharmacokinetics is to be expected in cases of renal insufficiency. In the ESPS2 trial, in patients with creatinine clearances ranging from about 15 mL/min to >100 mL/min, no changes were observed in the pharmacokinetics of dipyridamole or its glucuronide metabolite if data were corrected for differences in age.

5.3 Preclinical Safety Data

Dipyridamole has been extensively investigated in animal models and no clinically significant findings have been observed at doses equivalent to therapeutic doses in humans.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Tartaric acid Macrogol 600 Hydrochloric acid Water for injections

6.2. Incompatibilities

None stated.

Shelf life

3 years.

6.4.    Special precautions for storage

Keep container in the outer carton.

6.5.    Nature and content of container

Carton containing 5 x 2 ml clear Type I glass ampoules.

6.6.    Instructions for use, handling and disposal

None stated.

7    MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

UK

8.    MARKETING AUTHORISATION NUMBER

PL 00015/0119

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/05/2007

10    DATE OF REVISION OF THE TEXT

26/02/2015