DIPYRIDAMOLE TABLETS BP 100 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

DIPYRIDAMOLE TABLETS BP 100mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100mg Dipyridamole Ph.Eur.

3. PHARMACEUTICAL FORM

4.1.   Therapeutic Indications

4.2. Posology and Method of Administration

Dipyridamole should usually be taken before meals.

Adults: 300–600mg daily in three or four divided doses.

Children: The normal total oral daily dose is 5mg/kg bodyweight daily in divided doses.

Elderly: No specific information is available.

Route of administration

For oral administration.

4.3 Contraindications

Hypersensitivity to dipyridamole or 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).

Patients being treated with regular oral doses of Dipyridamole tablets 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 (up to 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.

This product contains lactose and sucrose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption; fructose intolerance 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 administration of antacids may reduce the efficacy of Dipyridamole tablets. It is possible that Dipyridamole tablets may enhance the effects of oral anti-coagulants.

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 (see Section 5.3).

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

No studies on the effect on human fertility have been conducted with dipyridamole. Non-clinical studies with dipyridamole did not indicate direct or indirect harmful effects with respect to fertility (see 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 effects at therapeutic doses are usually mild and transient.

The following adverse reactions have been reported in patients taking dipyridamole. The adverse reactions are classified according to frequencies determined from postmarketing experience and reference literature.

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

Not known, frequency cannot be estimated from the available data

Not known: Thrombocytopenia

Uncommon: Hypersensitivity reaction

Not known: Angioedema

Very common: Headache, dizziness

Common: Angina pectoris

Not known: Tachycardia

Common: Hypotension, hot flush

Not known: Bronchospasm

Very common: Nausea, diarrhoea

Common: Vomiting

Common: Rash

Not known: Urticaria

Common: Myalgia

Not known: Post procedural haemorrhage, operative haemorrhage.

Dipyridamole has been shown to be incorporated into gallstones (see Section 4.4).

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; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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. 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.

5.1 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 gg/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 |ig/mL (1.23 – 3.27 |ig/mL), and at trough were 0.13 |ig/mL (0.06 – 0.26 |ig/mL). With 75 mg q.i.d. corresponding peak concentrations were 1.54 |ig/mL (0.975 – 2.17 pg/mL), trough concentrations were 0.269 |ig/mL (0.168 – 0.547 |ig/mL). With 100 mg q.i.d. corresponding peak concentrations were 2.36 |ig/mL (1.13 – 3.81 |ig/mL), trough concentrations were 0.432 |ig/mL (0.186 – 1.38 |ig/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 halflife 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

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

Also contains: lactose, magnesium stearate, maize starch, polyvidone, propylene glycol, E171, E464, E553.

6.2. Incompatibilities

None known.

6.3. Shelf Life

Shelf-life

We propose a shelf-life of two years from the date of manufacture, to be extended when further stability testing becomes available.

Shelf-life after dilution/recon­stitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4. Special Precautions for Storage

Store below 25°C in a dry place. Protect from light.

6.5. Nature and Contents of Container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps and polyfoam wad or cotton wool. An alternative closure for polyethylene containers is a polypropylene, twist on, push down and twist off childresistant, tamper-evident lid.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 25Opm white rigid PVC. (ii) Surface printed 20pm hard temper aluminium foil with 5–8g/M2 PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 56s, 60s, 84s, 90s, l00s, 112s, l20s, l68s, l80s, 250s, 500s, l000s.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6. Instructions for Use/Handling

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Accord-UK Ltd

(Trading style: Accord)

Whiddon Valley

Barnstaple

Devon

EX32 8NS

8. MARKETING AUTHORISATION NUMBER(S)

PL 0142/0309

9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF AUTHORISATION

24.8.90