SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Dipyridamole 25mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Dipyridamole 25 mg per tablet

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Coated tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

As an adjunct to oral anti-coagulation for prophylaxis of thromboembolism

associated with prosthetic heart valves.

In combination with aspirin for:

a.    Prophylaxis of deep venous thrombosis as an alternative to subcutaneous heparin, other than in hip surgery.

b.    Prophylaxis of recurrent venous thrombosis resistant to oral anticoagulation.

c.    Prophylaxis of occlusion following prosthetic arterial grafts and coronary artery bypass grafts.

4.2    Posology and method of administration

Adults and the elderly:    300-600 mg daily in three or four doses.

Children:    Dipyridamole Tablets are not recommended for children

Route of administration:    Oral use (taken before meals).

4.3    Contraindications

Patients with a known hypersensitivity to Dipyridamole. Patients with known cardiac conduction difficulties or dysrhythmias.

4.4 Special warnings and precautions for use

Dipyridamole is a potent 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).

Patients being treated with regular oral doses of dipyridamole 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

In patients with myasthenia gravis readjustment of therapy may be necessary after changes in dipyridamole dosage (see Section 4.5).

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

A small number of cases have been reported in which unconjugated dipyridamole was shown to be incorporated into gallstones to a variable extent (upto 70% by dry weight of stone). These patients were all elderly, had evidence of ascending cholangitis and had been treated with oral dipyridamole for a number of years. There is no evidence that dipyridamole was the initiating factor in causing gallstones to form in these patients. It is possible that bacterial deglucuronidation of conjugated dipyridamole in the bile may be the mechanism responsible for the presence of dipyridamole in gallstones.

The tablets contain sunset yellow, E110 which can cause allergic- type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.

This product contains lactose and sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

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 concurrent use of antacids may reduce the efficacy of Dipyridamole Tablets. Dipyridamole Tablets may enhance the effects of oral anticoagulants.

When dipyridamole is used in combination with any substances impacting coagulation such as anticoagulants and antiplatelets, the safety profile for these medications -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 Fertility, 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 (please refer to section 5.3).

Lactation

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

Fertility

No studies on the effect on human fertility have been conducted with Dipyridamole Tablets. Non-clinical studies with dipyridamole did not indicate direct or indirect harmful effects with respect to fertility (please refer to section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

However, patients should be advised that they may experience undesirable effects such as dizziness during treatment with Dipyridamole Tablets. If patients experience dizziness they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Undesirable effects

Adverse reactions at therapeutic doses are usually mild and transient.

The following side effects have been reported, frequencies have been assigned based on a clinical trial (ESPS-2) in which 1654 patients received dipyridamole alone.

Frequencies

Very common ^ 1/10 Common ^ 1/100 and <1/10 Uncommon ^ 1/1000 and <1/100 Rare > 1/10,000 and <1/1000 Very rare < 1/10,000

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.

Therapy

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

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 therapeutic concentrations (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.

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

After dosing with the sugar-coated tablets there is a lag time of 10 - 15 min associated with disintegration of the tablet and gastric emptying. Thereafter the drug is rapidly absorbed and peak plasma concentrations are attained after 1 hour. Geometric mean (range) peak plasma concentrations at steady state conditions with 75 mg t.d.s. were 1.86 pg/mL (1.23 - 3.27 pg/mL), and at trough were 0.13 pg/mL (0.06 - 0.26 pg/mL). With 75 mg q.i.d. corresponding peak concentrations were 1.54 pg/mL (0.975 - 2.17 pg/mL), trough concentrations were 0.269 pg/mL (0.168 - 0.547 pg/mL). With 100 mg q.i.d. corresponding peak concentrations were 2.36 pg/mL (1.13 - 3.81 pg/mL), trough concentrations were 0.432 pg/mL (0.186 - 1.38 pg/mL). The dose linearity of dipyridamole after single dose administration was demonstrated in the range from 25 to 150 mg.

Pharmacokinetic evaluations as well as experimental results in steady state conditions indicate that t.d.s. or q.d.s. dosage regimens are suitable. Treatment with dipyridamole tablets at steady state provides absolute bioavailability of approx. 60% and relative bioavailability of approx. 95% compared to an orally administered solution. This is partly due to a first-pass-effect from the liver which removes approx. 1/3 of the dose administered and partly to incomplete absorption.

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.

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

Elimination

Dominant half-lives ranging from 2.2 to 3 hours have been calculated after the administration of dipyridamole tablets. A prolonged terminal elimination half-life of approximately 15 h is observed. This terminal elimination phase is of relatively minor importance in that it represents a small proportion of the total AUC, as evidenced by the fact that steady-state is achieved within 2 days with both t.d.s. and q.d.s., regimens. There is no significant accumulation of the drug with repeated dosing. 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.Total clearance is approx. 250 mL/min and mean residence time is approx. 8 h (resulting from an intrinsic MRT of approx. 6.4 h and a mean time of absorption of 1.4 h).

Elderly subjects

Plasma concentrations (determined as AUC) in elderly subjects (> 65 years) were about 50% higher for tablet treatment and about 30% higher with intake of dipyridamole 200 mg modified release capsules than in young (<55 years) subjects. The difference is caused mainly by reduced clearance; absorption appears to be similar. A similar increase in plasma concentrations in elderly patients was observed in the ESPS2 study.

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. 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

No additional data relevance to prescriber

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Core:

Lactose Maize starch Povidone

Pregelatinised starch Magnesium stearate

Coating:

Bleached shellac

Sucrose

Talc

Titanium dioxide E171 Beeswax Carnauba Wax Sunset yellow E110

6.2. Incompatibilities

Not applicable.

6.3    Shelf life

3 Years (all pack sizes)

6.4    Special precautions for storage

Do not store above 25°C

Keep container tightly closed (for containers)

Store in the original package (for blisters)

6.5    Nature and contents of container

Cylindrical polypropylene containers with polythene lids and polyurethane or

polythene inserts or PVC/Aluminium foil blister packs

Pack sizes: 28, 30, 50, 56, 60, 84, 100, 250, 500 & 1000 tablets

6.6 Special precautions for disposal

No special instructions

7    MARKETING AUTHORISATION HOLDER

Dr. Reddy’s Laboratories (UK) Ltd

6 Riverview Road

Beverley

East Yorkshire

HU 17 0LD

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 08553/0079

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/12/2003

10 DATE OF REVISION OF THE TEXT

05/06/2015