Summary of Product Characteristics (SmPC) - Dipyridamole tablets 100 mg
1 NAME OF THE MEDICINAL PRODUCT
Dipyridamole Tablets 100mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Dipyridamole 100 mg
Also contains 96.0 mg of lactose and 107.20 mg of sucrose. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Sugar-coated tablet
White biconvex sugar-coated tablets with 9.5 mm in diameter approximately and plain on both sides.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
As an adjunct to oral anti-coagulation for prophylaxis of thromboembolism associated with prosthetic heart valves.
4.2 Posology and method of administration
Posology
Adults:
300-600 mg daily in three or four doses.
Paediatric population:
Dipyridamole is not recommended for children.
Elderly:
As for adults.
Method of administration
Dipyridamole is taken by mouth, and should usually be taken before meals.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In case of rare hereditary conditions that may be incompatible with an excipient of the product (please refer to Special warnings and precautions for use) the use of the product is contraindicated.
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 disease, including unstable angina and/or 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 tablets 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.
Dipyridamole contains lactose and sucrose. Patients with rare hereditary conditions of fructose intolerance, galactose intolerance, the Lapp lactase deficiency, glucose/galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Among other properties, Dipyridamole acts as a vasodilator. It should be used with caution in patients with severe coronary disease, including unstable angina and/or 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 tablets 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.
Dipyridamole contains lactose and sucrose. Patients with rare hereditary conditions of fructose intolerance, galactose intolerance, the Lapp lactase deficiency, glucose/galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
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. Dipyridamole should not be used in pregnancy, especially for the first trimester, unless the expected benefit is thought to outweigh any possible risk to the foetus (please refer to 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 breast-feeding 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 (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 of machines have been performed.
However, patients should be advised that they may experience undesirable effects such as dizziness during treatment with Dipyridamole. 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 side effects have been reported frequencies have been assigned based on a clinical trial (ESPS-2) in which 1654 patients received dipyridamole alone.
Very common (≥10),
Common (≥ 1/100 < 1/10),
Uncommon (≥1/1,000 < 1/100),
Rare (≥1/10,000 < 1/1,000),
Very rare (<1/10,000)
Not Known – cannot be estimated from the available data.
Blood and lymphatic system disorders
Thrombocytopenia: Not known
Immune system disorders
Hypersensitivity: Not known
Angioedema: Not known
Nervous system disorders
Headache: Very common
Dizziness: Very common
Cardiac disorders
angina pectoris: Common
Tachycardia: Not know
Vascular disorders
Hypotension: Not known
Hot flush: Not known
Respiratory, thoracic and mediastinal disorders
Bronchospasm: Not known
Gastrointestinal disorders
Diarrhoea: Very common
Nausea: Very common
Vomiting: Common
Skin and subcutaneous tissue disorders
Rash: Common
Urticaria: Not known
Musculoskeletal and connective tissue disorders:
Myalgia: Common
Injury, poisoning and medical procedures:
Post procedural haemorrhage: Not known
Operative haemorrhage: Not known
Dipyridamole has been shown to be incorporated into gallstones (please refer to section 4.4 Special warnings and precautions for use).
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 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 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 heaptic elimination, dipyridamole is not likely to be accessible to enhanced removal procedures.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B 01 AC 07
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 μg/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
Absorption
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 μg/mL (1.23 - 3.27 μg/mL), and at trough were 0.13 μg/mL (0.06 - 0.26 μg/mL). With 75 mg q.i.d. corresponding peak concentrations were 1.54 μg/mL (0.975 - 2.17 μg/mL), trough concentrations were 0.269 μg/mL (0.168 - 0.547 μg/mL). With 100 mg q.i.d. corresponding peak concentrations were 2.36 μg/mL (1.13 - 3.81 μg/mL), trough concentrations were 0.432 μg/mL (0.186 - 1.38 μg/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 PERSANTIN. 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
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
Lactose
Maize starch
Povidone
Pregelatinised starch
Magnesium stearate
Bleached shellac
Sucrose
Talc
Titanium dioxide E171
Beeswax
Carnauba wax
6.2 Incompatibilities
Not applicable
6.3 Shelf life
Containers: 36 months
Blister packs: 36 months
6.4 Special precautions for storage
Containers: Do not store above 25°C. Keep the container tightly closed. Blister packs: Do not store above 25°C. Store in the original package.
6.5 Nature and contents of container
Polypropylene or high density polystyrene with polythene closure and polyurethane wads or polythene inserts.
Packs of 28, 30, 50, 56, 60, 84, 100, 250, 500 and 1000.
PVC/Aluminium foil blister packs 250 micron PVC glass-clear bluish rigid PVC (Pharmaceutical grade). 20 micron hard-tempered aluminium foil coated on the dull side with 6-7 gsm heat-seal lacquer and printed on the bright side.
Packs of 28, 30, 50, 56, 60, 84, 100, 250, 500 and 1000.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Genesis Pharmaceuticals Limited
1st Floor, 16/17 College Green
Dublin, D02 V078
Ireland
8 MARKETING AUTHORISATION NUMBER(S)
PL 62354/0014
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
08/12/2005
10 DATE OF REVISION OF THE TEXT
01/09/2026