SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Dipyridamole 100mg/5ml Oral Suspension

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Dipyridamole 100mg/5ml Oral Suspension Excipients with known effect:

Each 5ml contains 6mg methyl hydroxybenzoate, 1.5mg propyl hydroxybenzoate, 2516mg liquid maltitol and 129. 75 mg propylene glycol.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Oral Suspension

Bright yellow suspension with odour of almond

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

An adjunct to oral anti-coagulation for prophylaxis of thrombo-embolism associated with prosthetic heart valves.

4.2    Posology and method of administration

Posologv

Dipyridamole suspension should usually be taken before meals. Adults: 300mg to a maximum of 600mg daily in three or four doses.

Paediatric population

Dipyridamole is not recommended for children.

Method of administration For oral use only.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Among other properties, dipyridamole acts as a vasodilator. It should be used with caution in patients with severe coronary artery disease, including unstable angina and/or recent myocardial infarction, left ventricular outflow obstruction or haemodynamic instability (e.g. decompensated heart failure).

Dipyridamole should be used with caution in patients with coagulation disorders.

In patients with myasthenia gravis, readjustment of therapy may be necessary after changes in dipyridamole dosage (see Drug Interactions).

Patients treated with regular oral doses of dipyridamole should not receive additional intravenous dipyridamole. If pharmacological stress testing with intravenous dipyridamole for coronary artery disease is considered necessary, then oral dipyridamole should be discontinued 24 hours prior to testing.

Excipients in the formulation

Dipyridamole suspension contains liquid maltitol. Patients with a rare hereditary problem of fructose intolerance should not take this medicine.

The medicine also contains parahydroxybenzoates which are known to cause urticaria, generally delayed type reactions such as contact dermatitis and rarely, immediate reaction with urticaria and bronchospasm.

4.5 Interaction with other medicinal products and other forms of interaction

Dipyridamole increases plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage should be considered if use with dipyridamole is unavoidable.

There is evidence that the effects of aspirin and dipyridamole on platelet behaviour are additive.

The administration of antacids may reduce the efficacy of dipyridamole. It is possible that dipyridamole may enhance the effects of oral anti-coagulants.

When dipyridamole is used in combination with anticoagulants and acetylsalicylic acid, the statements on intolerance and risks for these preparations must be observed. Addition of dipyridamole to acetylsalicylic acid does not increase the incidence of bleeding events. When dipyridamole was administered concomitantly with warfarin, bleeding was no greater in frequency or severity than that observed when warfarin was administered alone.

Dipyridamole may increase the hypotensive effect of drugs which reduce blood pressure and may counteract the anticholinesterase effect of cholinesterase inhibitors thereby potentially aggravating myasthenia gravis.

4.6 Pregnancy and lactation

Pregnancy

There is inadequate evidence of safety in human pregnancy, but dipyridamole has been used for many years without apparent ill-consequence. Animal studies have shown no hazard. Medicines should not be used in pregnancy, especially the first trimester unless the expected benefit is thought to outweigh the possible risk to the foetus.

Breast-feeding

Dipyridamole is excreted in breast milk at levels approximately 6% of the plasma concentration. Therefore dipyridamole should only be used during lactation if considered essential by the physician.

Fertility

There is no information on possible effects on fertility.

4.7 Effects on ability to drive and use machines

Dipyridamole has minor influence on the ability to drive and use machines due to the possibility of dizziness and faintness.

4.8 Undesirable effects

If undesirable effects do occur, it is usually during the early part of treatment.

Blood and the lymphatic system disorders

Isolated cases of thrombocytopenia have been reported in conjunction with treatment of dipyridamole.

Cardiac Disorders

In rare cases, worsening of symptoms of coronary heart disease has been observed.

Vascular Disorders

The vasodilating properties may occasionally produce a vascular headache which normally disappears with long-term use.

As a result of its vasodilator properties, dipyridamole may cause hypotension, hot flushes and tachycardia.

Hepatobiliary disorders

Dipyridamole has been shown to be incorporated into gallstones.

General Disorders and administration site conditions

Vomiting, diarrhoea and symptoms such as dizziness, faintness, nausea, dyspepsia, and myalgia have been observed.

Hypersensitivity reactions such as rash, urticaria, severe bronchospasm and angio-oedema have been reported.

Surgical and medical procedures

In very rare cases, increased bleeding during or after surgery has been observed.

4.9 Overdose

Symptoms

Due to the low number of observations, experience with dipyridamole overdose is limited. Symptoms such as a warm feeling, flushes, sweating, restlessness, feeling of weakness, dizziness and anginal complaints can be expected. A drop in blood pressure and tachycardia might be observed.

Management

Symptomatic therapy is recommended. Administration of xanthine derivatives (e.g. aminophylline) may reverse the haemodynamic effects of dipyridamole overdose. 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

Pharmacotherapeutic group: Antithrombotic, ATC code: B01AC07

Mechanism of action

Dipyridamole has an antithrombotic action based on its ability to modify various aspects of platelet function, such as platelet aggregation, adhesion and survival, which have been shown to be factors associated with the initiation of thrombus formation. Dipyridamole also has coronary vasodilator properties

5.2 Pharmacokinetic properties

Absorption

Dipyridamole is incompletely absorbed from the gastrointestinal tract.

Oral administration of dipyridamole gives a peak plasma level 1-2 hours after dosing.

Distribution

Owing to its high lipophilicity, log P 3.92 (n-octanol/0.1 N, NaOH), dipyridamole distributes to many organs.

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.

Biotransformation

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. In plasma about 80% of the total amount is parent compound, 20% of the total amount is monoglucuronide with oral administration.

Elimination

Renal excretion of parent compound is negligible (< 0.5%). Urinary excretion of the glucuronide metabolite is low (5%), the metabolites are mostly (about 95%) excreted via the bile into the faeces, with some evidence of entero-hepatic recirculation.

Hepatic impairment

Patients with hepatic insufficiency show no change in plasma concentrations of dipyridamole, but an increase of (pharmacodynamically inactive) 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.

5.3    Preclinical safety data

None

6    PHARMACEUTICAL    PARTICULARS

6.1    List of excipients

Methyl hydroxybenzoate (E218)

Propyl hydroxybenzoate (E216)

Propylene glycol (E1520)

Xanthan gum (E415)

Ammonium glycyrrhizinate Almond flavour (contains ethanol)

Liquid maltitol (E965)

Polysorbate 80 (E433)

Simethicone emulsion Magnesium Aluminum Silicate Disodium hydrogen phosphate (E339)

Citric acid (E330) (for pH-adjustment)

Purified water

6.2    Incompatibilities

Not applicable

6.3    Shelf life

1 year

26/09/2012