4.1. Therapeutic indications

Secondary prevention of ischaemic stroke and transient ischaemia attacks either alone or in conjunction with aspirin.

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

4.2. Posology and method of administration

Posology

The recommended dose is one capsule twice daily, usually one in the morning and one in the evening.

The capsules should be taken with or independently of food. The capsules should be swallowed whole without chewing.

Paediatric population

Dipyridamole 200mg Prolonged Release Capsules, Hard is not recommended for children, due to lack of data on safety and efficacy.

Elderly

No dosage adjustment is needed.

Patients with renal impairment

No dosage adjustment is needed.

Patients with hepatic impairment

No dosage adjustment is needed.

Method of administration

For oral administration.

Alternative dosage in case of intolerable headache

In case of intolerable headache at the start of treatment, 1 capsule can be provisionally dosed at bedtime and a low dose of acetylsalicylic acid in the morning.

As there are insufficient efficacy data on this alternative dosing and headache usually resolves with regular dosing, the patient should return to the normal dosing promptly (within one week).

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 potent vasodilator. It should therefore 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 adjustment of therapy may be necessary after changes in dipyridamole dosage (see section 4.5, Interactions).

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.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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

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

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

It is possible that dipyridamole 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 blood pressure lowering drugs and may counteract the anticholinesterase effect of cholinesterase inhibitors thereby potentially aggravating myasthenia gravis.

Co-administration of alcohol may increase the rate of absorption of Dipyridamole 200mg Prolonged Release Capsules. It is recommended that patients are advised to avoid alcohol.

Theophylline and other xanthines

Xanthines may reduce the effect of dipyridamole. This should be taken into account in particular with intravenous administration of theophylline.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is inadequate evidence of safety in human pregnancy, but Dipyridamole 200mg Prolonged Release Capsules has been used for many years without apparent ill-consequence. Dipyridamole 200mg Prolonged Release Capsules, Hard should only be administrated if clearly needed. Data from the use of dipyridamole in pregnancy are inadequate. Animal studies have shown no hazard of fetal harm. Nevertheless, 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 about 6% of plasma concentration), and therefore there is a risk of affecting the breast-feeding infant. 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 200 mg prolonged‑release capsules, hard. 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. 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.

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 1

Blood and lymphatic system disorders

Not known*

Thrombocytopenia

Immune system disorders

Not known

Hypersensitivity, angioedema

Nervous system disorders

Very common

Headache, dizziness

Cardiac disorders

Common

Angina pectoris

Not known

Tachycardia

Vascular disorders

Not known*

Hypotension, hot flush

Respiratory, thoracic and mediastinal disorders

Not known*

Bronchospasm

Gastrointestinal disorders

Very common

Diarrhoea, nausea

Common

Vomiting

Skin and subcutaneous tissue disorders

Common

Rash

Not known*

Urticaria

Musculoskeletal, connective tissue and bone disorders

Common

Myalgia

Injury, poisoning and procedural complications

Not known*

Post procedural haemorrhage, operative haemorrhage

Surgical and medical procedures

Not known*

Increased bleeding during or after surgery.

* This side effect has been seen after marketing. There is a 95% probability that the frequency does not exceed "not common" and it may be lower. It is not possible to determine the exact frequency as this side effect was not seen in a clinical trial database of 1654 patients.

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.

Toxicity

The toxicity is likely to be low. 37.5 mg in 2-year-olds caused mild intoxication, while 75-150 mg in 1- to 3-year-olds after administration of charcoal caused no symptoms. 1 g as a single dose and 2.8 g per 24 hours in adults did not cause any pronounced symptoms. However, 1.75 g in adults caused severe intoxication, and 5 g in adults may promote heart attacks.

Symptoms

Symptoms such as feeling warm, redness, flushes, sweating, restlessness, feeling of weakness, dizziness, headache and angina complaints can be expected. A drop in blood pressure and tachycardia might be observed.

Tachypnoea, tachycardia, angina pectoris, coma, bronchospasm, respiratory depression, gastrointestinal discomfort, prolonged bleeding time and yellowing of the skin.

Therapy:

Symptomatic therapy is recommended.

Ventricular emptying must be considered.

Administration of xanthine derivatives (e.g. aminophylline) may reverse the haemodynamic effects of dipyridamole overdose. ECG monitoring is advised in such a situation.

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