Dipyridamole

Registered South African indications: 

• Conditions where reduction in platelet aggregation and/or adhesiveness is considered to be of therapeutic benefit (tab)
• Prophylaxis of thromboembolism associated with mechanical prosthetic heart valves (SR cap)
• Secondary prevention of ischaemic stroke and transient ischaemic attacks (SR cap)
• An alternative to exercise stress in the evaluation of coronary artery disease (inj)

Contraindications

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Parenteral use in hypotensive patients (However, if deemed necessary, it can be injected at a very slow rate) (inj)
• Haemodynamic instability following myocardial infarction, or in states of shock or collapse (SR cap, inj)
• Uncontrolled cardiac failure (SR cap)
• Unstable angina pectoris (SR cap)
• Hypotension following myocardial infarction (tab)

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As IV use represents an alternative to exercise testing, the usual contraindications for exercise testing should be observed when used for this indication (inj)

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Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Severe coronary artery disease:
  - Unstable angina and/or recent myocardial infarction
  - Left ventricular outflow obstruction
  - Haemodynamic instability (e.g. decompensated heart failure)
• Myasthenia gravis
• Coagulation disorders
• Evidence of ascending cholangitis 
• Prolonged use
• Coadministration of regular oral doses of dipyridamole with additional IV dipyridamole (See Additional Prescribing Points)
• Galactose intolerance
• Total lactase deficiency (tab)
• Glucose-galactose malabsorption (tab)
• Fructose intolerance (tab)
• Sucrose-isomaltase insufficiency (tab)
• May impair ability to drive and operate machinery

South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• History of severe coronary heart disease (inj)
• Severe coronary artery disease (SR cap):
  - Recently sustained myocardial infarction
  - Subvalvular aortic stenosis
  - Left ventricular outflow obstruction
• History of asthma (inj)
• Coagulation disorders (SR cap)
• Evidence of ascending cholangitis (SR cap)
• Prolonged use (SR cap)
• Hypotension (tab)
• Myasthenia gravis
• Aspirin sensitivity (25mg tab)
• Coadministration of SR cap (or other oral medicines containing dipyridamole) and IV dipyridamole (See Additional Prescribing Points)
• Tartrazine (FD and C Yellow No.5) sensitivity (25mg tab)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: sustained-release cap (SR cap), tab, inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Prophylaxis of thromboembolism associated with prosthetic heart valves (Additional agents required)
- As an adjunct to oral anticoagulation

• Oral (tab):300-600mg, dly in 3-4 divided doses
• Oral (SR cap): 200mg, 12hrly

Secondary prevention of ischaemic stroke and transient ischaemic attacks (Additional agents may be required)
- As monotherapy or in conjunction with aspirin

• Oral (SR cap): 200mg, 12hrly

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Oral (tab): Immediate release tabs should be taken before meals

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Oral (SR cap): The recommended dose is usually taken as 1 cap in the morning and 1 cap in the evening, preferably with meals. SR caps should be swallowed whole without chewing

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Inj: There is no information available regarding adult dosages in international manufacturer recommendations 

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South African manufacturer recommendations

Conditions where reduction in platelet aggregation and/or adhesiveness is considered to be of therapeutic benefit 
(Additional agent may be required)
- As monotherapy or in conjunction with aspirin

• Oral (tab): 100mg, 6hrly

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The recommended dose is taken usually as 100mg, 3 times a day and 100mg taken at bedtime. Immediate release tabs should be taken before meals

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25mg tab: Where possible dosage should commence with 100mg (4x25mg tab) in the morning and evening for 5 days, 100mg, 3 times a day for 5 days and then 100mg, 4 times a day

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Aspirin potentiates the effect of dipyridamole and a reduction in dosage may be necessary

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Prophylaxis of thromboembolism associated with mechanical prosthetic heart valves (Additional agent required)
- As an adjunct to oral anticoagulation
Secondary prevention of ischaemic stroke and transient ischaemic attacks (Additional agent required)
- In conjunction with aspirin

• Oral (SR cap): 200mg, 12hrly

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The recommended dose is usually taken as 1 cap in the morning and 1 cap in the evening with meals. The capsules must be swallowed whole without chewing

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An alternative to exercise stress in the evaluation of coronary artery disease
- For use in the thallium scanning procedure in myocardial perfusion imaging in patients who cannot exercise adequately

• IV: 0.142mg/kg/min, as an infusion over 4min; Total dose: 0.57mg/kg/4min; Then: If necessary, 0.27mg/kg infused over an additional 6min; Max total dose: 0.84mg/kg

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The dose of IV dipyridamole should be adjusted according to the weight of the patient

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Inj: For administration instructions, see Additional Prescribing Points

Forms avail. in SA and covered in this monograph: sustained-release cap (SR cap), tab, inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Prophylaxis of thromboembolism associated with prosthetic heart valves (Additional agents required)
- As an adjunct to oral anticoagulation

• Oral (tab):5mg/kg, dly in divided doses

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Oral (tab): Immediate release tabs should be taken before meals

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Oral (SR cap): Not recommended for use in children

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Inj: There is no information available regarding paediatric dosages in international manufacturer recommendations 

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South African manufacturer recommendations

• Not recommended for use in children (SR cap, inj)

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Oral (tab): There is no information available regarding paediatric dosages in South African manufacturer recommendations

Pregnancy

International manufacturer recommendations

• Caution (SR cap, tab)
• 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 1^st trimester, unless the expected benefit is thought to outweigh the possible risk to the foetus
• In a non-blinded randomized controlled trial (RCT) to prevent preeclampsia, 52 high-risk patients treated from the 13th week of gestation through delivery with daily doses of 300mg of dipyridamole plus 150mg of aspirin were compared with 50 high-risk controls. The outcome of pregnancy was significantly better in treated patients in three areas: preeclampsia (0 vs. 6), foetal and neonatal loss (0 vs. 5), and severe intrauterine growth restriction (0 vs. 4). No foetal malformations were observed in either group
• Caution; no information available (inj) 

South African manufacturer recommendations

• Caution; not recommended (SR cap, inj)
• Safety of dipyridamole during pregnancy has not been established. Dipyridamole is not recommended during pregnancy
• Caution; no information available (tab) 

Breastfeeding

International manufacturer recommendations

• Caution (SR cap, tab)
• Dipyridamole is excreted in breast milk at levels approximately 6% of the plasma concentration. Therefore dipyridamole should only be used during breastfeeding if considered essential by the physician
• Caution; no information available (inj)

South African manufacturer recommendations

• Caution; not recommended (SR cap, inj) 
• Safety of dipyridamole during breastfeeding has not been established
• Dipyridamole is excreted in breast milk
• Dipyridamole is not recommended for mothers who are breastfeeding their infants. Mothers who are taking dipyridamole should not breastfeed their infants
• Caution; no information available (tab) 

Fertility

International manufacturer recommendations

• 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 (SR cap, tab) 
• No information available (inj) 

South African manufacturer recommendations

• No information available 

Renal Impairment

International manufacturer recommendations

• Caution; no dose adjustment recommended (SR cap, tab)
  Since renal excretion is very low (5%), no change in pharmacokinetics is to be expected in cases of renal insufficiency
• Caution; no information available (inj)

South African manufacturer recommendations

• Caution; no dose adjustment recommended (SR cap, inj)
  Since renal excretion is very low (5%), no change in pharmacokinetics is to be expected in cases of renal insufficiency
• Caution; no information available (tab)

Hepatic Impairment

International manufacturer recommendations

• Caution; no dose adjustment recommended (SR cap, tab)
  Patients with hepatic insufficiency show no change in plasma concentrations of dipyridamole, but an increase of (pharmacodynamically inactive) glucuronides
  It is recommended to dose dipyridamole without restriction as long as there is no clinical evidence of hepatic failure
• Caution; no information available (inj)

South African manufacturer recommendations

• Caution; no dose adjustment recommended d (SR cap, inj)
  Patients with hepatic insufficiency show no change in plasma concentrations of dipyridamole, but an increase of (pharmacodynamically inactive) glucuronides
  Patients with hepatic impairment on treatment with dipyridamole should be monitored for further deterioration of hepatic function
• Caution; no information available (tab) 

Elderly

International manufacturer recommendations

• Caution; no dose adjustment recommended (SR cap, inj)
• Caution; no information available (tab)
  Not recommended for use

South African manufacturer recommendations

• Caution; no information available 
  Plasma concentrations (determined as AUC) in elderly patients (>65 years) were about 30-50% higher with oral treatment than in young (<55 years) patients and the difference is caused mainly by reduced clearance; a slower decrease of plasma concentrations after IV treatment is to be expected

Porphyria

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Paraesthesia (inj)
• Transient ischaemic attack (inj)
• Cerebrovascular accident (inj)
• Seizures (inj)
• Syncope (inj)

Cardiovascular Disorders

• Angina pectoris
• Tachycardia
• Hypotension
• Hot flush
• Dysrhythmias (inj)
• Myocardial infarction (inj)
• Bradycardia (inj)
• Cardiac arrest (inj)
• Ventricular fibrillation (inj)
• Cardiac death (inj)
• Electrocardiogram ST-T change (inj)
• Sinus arrest (inj)
• Atrioventricular block (inj)

Respiratory Disorders

• Bronchospasm
• Laryngospasm (inj)

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Incorporation of dipyridamole into gallstones
• Abdominal pain (inj)

Musculoskeletal Disorders

• Myalgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Angioedema
• Hypersensitivity reaction
• Anaphylactoid reaction (inj)
• Thrombocytopaenia
• Post procedural haemorrhage
• Operative haemorrhage
• Oedema (inj)

• Adenosine
• Hypotensive agents
• Cholinesterase inhibitors
• Antacids 
• Oral anticoagulants (See Additional Prescribing Points)
• Aspirin (See Additional Prescribing Points)
• Xanthine derivatives (inj)
• Caffeine (inj)
• Theophylline (inj)

Other interactions

• Alcohol (SR cap)

None routine. Specific cases may require:

• Blood pressure
• Heart rate
• Electrocardiogram
• Respiration

Additional observations

• Signs of poor perfusion:
  - Pallor
  - Cyanosis
  - Cold skin

Administration instructions (inj)

• Prior to IV administration, IV dipyridamole 10mg/2ml should be diluted in at least a 1:2 ratio with sodium chloride 0.45% or 0.9%, or glucose 5% to a total volume of approximately 20 to 50ml
• Infusion of undiluted IV dipyridamole 10mg/2ml may cause local irritation. Thallium-201 should be injected within 5mins following the 4min infusion of IV dipyridamole
• IV dipyridamole should not be mixed with other medicines in the same syringe or infusion container

Coadministration with anticoagulants and aspirin

• There is evidence that the effects of aspirin and dipyridamole on platelet behaviour are additive
• It is possible that 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

Coadministration of regular oral doses of dipyridamole and additional IV dipyridamole

• Patients being treated with regular oral doses of dipyridamole tablets should not receive additional IV dipyridamole
• Clinical experience suggests that patients being treated with oral dipyridamole who also require pharmacological stress testing with IV dipyridamole should discontinue drugs containing oral dipyridamole for 24hrs prior to stress testing

Excipients 

• This medicinal product may contain lactose, magnesium, maize starch, polyvidone, propylene glycol, and other colourants [E171, E464, E553]

Dipyridamole inhibits the uptake of adenosine into erythrocytes, platelets and endothelial cells in vitro and in vivo. Consequently, there is an increased concentration of adenosine locally to act on the platelet A-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. Additionally, dipyridamole reduces the thrombogenicity of subendothelial structures by increasing the concentration of the protective mediator 13-HODE (13-hydroxyoctadecadienic acid).

Tablet 25mg

• Plato (Pharmacare)

Tablet 100mg

• Plato (Pharmacare)

Capsule 200mg

• Persantin 200 Retard (Ingelheim Pharmaceuticals) originator

Injection 10mg/2ml

• Persantin (Ingelheim Pharmaceuticals) originator (Discontinued: 31/08/2022)

COMBINATION PREPARATIONS

Dipyridamole/Aspirin

Capsule 200mg/25mg 

• Asasantin 200/25 Retard  (Ingelheim Pharmaceuticals) originator