Consumer medicine information

APO-DIPYRIDAMOLE}ASPIRIN

Dipyridamole; Aspirin

BRAND INFORMATION

Brand name

APO-Dipyridamole/Aspirin Modified release capsules

Active ingredient

Dipyridamole; Aspirin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-DIPYRIDAMOLE}ASPIRIN.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up-to-date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is APO- Dipyridamole/Aspirin Modified Release Capsules.

It contains the active ingredients dipyridamole and aspirin.

This medicine helps prevent recurrence of stroke in people who have had a previous stroke or transient ischaemic attack (TIA).

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

How it works

This medicine works by preventing blood clots from forming. The ability of this medicine to prevent blood clots is due to its effect on blood cells known as platelets.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

There is limited information about the use of Dipyridamole/Aspirin SR in children.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You have or have had any of the following:
    - fructose intolerance. Each capsule contains 4.56 mg sucrose resulting in 9.12 mg sucrose per maximum recommended daily dose.
    - severe kidney disease
    - taking the medicine ketorolac
    - more than 6 months pregnant
    - an ulcer of the stomach or intestine, or
    - any condition that increases your risk of bleeding
  • You are pregnant.
    Dipyridamole/Aspirin may affect your developing baby if you take it during pregnancy.
  • You are breastfeeding.
    The active ingredient in Dipyridamole/Aspirin SR passes into breast milk.
  • You are hypersensitive to, or have had an allergic reaction to:
    - dipyridamole
    - aspirin, or NSAIDs, non-steroidal anti-inflammatory medicines
    - or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • Do not give Dipyridamole/Aspirin SR to children or adolescents with a fever or a viral infection (with or without a fever) except on doctor's advice.
    The aspirin component of this medicine can cause a very rare disease called 'Reye's Syndrome' if given to children or adolescents who have a fever or a viral infection (with or without a fever).
  • The expiry date (EXP) printed on the pack has passed.

The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes.
  2. You have or have had any medical conditions, especially the following:
    - an ulcer of the stomach or intestine
    - any condition that increases your risk of bleeding
    - any heart condition (e.g. angina, heart attack or failure, heart valve problems)
    - severe muscle disease (myasthenia gravis)
    - gallstones
    - asthma
    - hay fever
    - any unusual growth or tumour inside the nose (e.g. nasal polyps)
    - long-term stomach and intestinal problems
    - kidney or liver disease
    - deficiency of the enzyme glucose- 6-phosphate dehydrogenase, which may lead to a condition known as haemolytic anaemia (reduced red blood cells and iron stores)
    If you are uncertain as to whether you have, or have had, any of these conditions you should tell your doctor.
  3. You are currently pregnant or you plan to become pregnant.
    Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  4. You are currently breastfeeding or you plan to breast-feed.
    Do not take this medicine whilst breastfeeding.
  5. You are taking or are planning to take any other medicines.
    This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop

Taking other medicines

Some medicines may interact with Dipyridamole/Aspirin.

In particular you must tell your doctor if you are taking:

  • medicines used to thin your blood such as warfarin.
  • medicines used to treat high blood pressure
  • neostigmine, distigmine and related medicines (used, for example, to treat myasthenia gravis)
  • medicines used to control blood sugar levels
  • alcohol
  • alendronate
  • antacids
  • methotrexate
  • phenytoin
  • spironolactone
  • corticosteroids (steroid hormones)
  • corticotropin (substances which control the actions of corticosteroids)
  • quinidine
  • sodium valproate
  • diltiazem
  • verapamil
  • nicotinic acid
  • fluoxetine or any other medicines known as selective serotonin reuptake inhibitors or SSRIs (used in the treatment of depression)
  • zafirlukast
  • aspirin or other NSAIDs (e.g. diclofenac, ibuprofen)
  • any medicine that promotes the excretion of uric acid in the urine (eg. probenecid, sulphinpyrazone)
  • any medicine which prevents blood cells from clotting (eg. eptifibatide, ticlopidine, clopidogrel, tirofiban)

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with dipyridamole and aspirin.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

The recommended dose for adults is one capsule twice a day.

In some cases you may experience headache when you first start this medicine at the recommended dose.

See your doctor if this occurs.

Your doctor may then change your dose for about one week. The changed dose will be one capsule at bedtime and low dose aspirin (for example, aspirin 75 mg, 100 mg or 150 mg) in the morning. After this time, your doctor will put you back onto your normal dose.

How to take it

Swallow the capsule whole without chewing.

When to take it

Take this medicine at the same time each day, usually one in the morning and one in the evening, and preferably with meals.

Taking it at the same time each day will have the best effect and will also help you remember when to take it.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

This medicine helps control your condition, but does not cure it. Therefore you must take this medicine every day.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses.

This may increase the chance of you experiencing side effects.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Signs of overdose may include feeling warm, flushing, sweating, restlessness, dizziness, weakness, rapid breathing, ringing in the ears, nausea, vomiting, vision and hearing disturbances and confusion. There may be effects on the heart and circulation causing chest pain, an increase in heart rate and a drop in blood pressure. In severe overdose, symptoms may include severe mental confusion, shaking, difficulty in breathing, sweating, bleeding, dehydration, reduced body temperature and coma.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are taking any other medicines or are about to be started on a new medicine
    This applies to all medicines obtained with or without a doctor's prescription.
  • If you experience a headache or migraine-like headache, especially when you start taking this medicine. Do not treat the headache or migraine-like headache with analgesic doses of aspirin.
  • you plan to have 'pharmacological stress testing', surgery or other treatment (even at the dentist).

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

This medicine may cause dizziness and confusion in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking this medicine or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor if you notice any of the following:

  • headache or migraine-like headache, especially when you start taking this medicine
  • dizziness
  • indigestion
  • diarrhoea
  • nausea
  • stomach pain
  • vomiting
  • inflammation of and wearing of stomach lining
  • ulcer of the stomach or intestine
  • vomiting blood or material that looks like coffee grounds or bleeding from the back passage (rectum), black sticky bowel motions (stools) or bloody diarrhoea
  • muscle aches and pains
  • hot flushes
  • symptoms of low blood pressure (eg. lightheadedness)
  • fast heart beat
  • skin bruising and blood clots
  • bleeding (including nose bleeds, bleeding within the head, bleeding in the eyes or increased bleeding during or after surgery)
  • prolonged bleeding time
  • anaemia, a condition in which there is a decrease in the number of red blood cells or haemoglobin levels (signs of anaemia include tiredness, being short of breath, dizziness and looking pale)
  • iron deficiency anaemia may result from prolonged bleeding
  • reduction in blood platelet count (thrombocytopenia), which may result in bruising or bleeding more easily than normal, reddish or purplish blotches under the skin
  • worsening of symptoms of heart disease
  • fainting

Tell your doctor as soon as possible if you experience any side effect during or after using this medicine, so that these may be properly treated

Allergic reactions

If you think you are having an allergic reaction to this medicine, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

You may require urgent medical attention.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

In addition, other side effects not listed above may also occur in some patients.

Tell your doctor or pharmacist if you notice anything unusual, during or after taking this medicine.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Dipyridamole/Aspirin Modified Release Capsules looks like

The gelatin shell of the capsule consists of a red opaque cap and an ivory opaque body.

Available in blister packs of 60 capsules.

Ingredients

Each capsule contains:

  • 200 mg of dipyridamole in a sustained-release form and
  • 25 mg of aspirin in a standard (immediate) release form.

It also contains the following inactive ingredients:

  • tartaric acid
  • povidone
  • methacrylic acid copolymer (Eudragit S 100)
  • talc
  • acacia
  • hypromellose
  • hypromellose phthalate
  • simethicone
  • cetostearyl alcohol ethoxylate
  • sodium benzoate
  • triacetin
  • stearic acid
  • microcrystalline cellulose
  • starch pregelatinised
  • sucrose
  • gelatin
  • and the colouring agents:
  • titanium dioxide
  • iron oxide red (E172) and
  • iron oxide yellow (E172).

This medicine is gluten-free, contains sucrose.

Australian Registration Numbers

APO-Dipyridamole/Aspirin SR (HDPE bottle with CR cap):
AUST R 210813.

Sponsor

Apotex Pty Ltd
16 Giffnock Ave
Macquarie Park
NSW 2113
Australia

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in: March 2015

BRAND INFORMATION

Brand name

APO-Dipyridamole/Aspirin Modified release capsules

Active ingredient

Dipyridamole; Aspirin

Schedule

S4

 

Name of the medicine

Dipyridamole 200 mg, aspirin 25 mg.

Excipients.

Tartaric acid, povidone, methacrylic acid copolymer (Eudragit S 100), purified talc, acacia, hypromellose, hypromellose phthalate, glyceryl triacetate, simethicone, cetostearyl alcohol ethoxylate, sodium benzoate, microcrystalline cellulose, pregelatinised maize starch, stearic acid, sucrose, gelatin, titanium dioxide, iron oxide red and iron oxide yellow.

Description

Dipyridamole.

Chemical name: 2,6-bis(diethanolamino)-4,8-dipiperidino-pyrimido[5,4-d]pyrimidine. Molecular formula: C24H40N8O4. MW: 504.6. CAS: 58-32-2.

Aspirin.

Chemical name: 2-acetoxybenzoic acid. Molecular formula: C9H8O4. MW: 180.2. CAS: 50-78-2.

Pharmacology

Pharmacological actions.

Dipyridamole has an antithrombotic action based on its ability to modify various aspects of platelet function. It causes inhibition of platelet adhesion and aggregation, particularly in diseased states where platelet stickiness is above normal, and lengthens abnormally shortened platelet survival time. These actions are useful in limiting the initiation of thrombus formation. The mechanism of antiplatelet action is believed to be related to inhibition of the uptake of adenosine by red blood cells and platelets; weak inhibition of cAMP phosphodiesterase which potentiates the aggregation inhibiting effects of adenosine on platelets; and inhibition of cGMP phosphodiesterase which potentiates the antiaggregating effects of EDRF (endothelium derived relaxing factor, identified as nitric oxide (NO)). Dipyridamole is also a coronary vasodilator.
Dipyridamole has also been shown in stroke patients to reduce the density of prothrombotic surface proteins (PAR-1: thrombin receptor) on platelets as well as to reduce levels of C-reactive protein (CRP) and von Willebrand Factor (vWF). In vitro investigations have shown that dipyridamole inhibits inflammatory cytokines (MCP-1 and MMP-9) arising from platelet-monocyte interaction.
Dipyridamole increases the release of tissue plasminogen activator (t-PA) from microvascular endothelial cells (human brain, in vitro, concentration dependent) and is likely to lead to increased fibrinolytic/ antithrombotic activity. Dipyridamole is a potent scavenger of oxyradicals and peroxyradicals.
Aspirin inhibits platelet aggregation by its irreversible acetylation of cyclooxygenase, which effectively blocks the activity of this enzyme in platelets.
The antithrombotic effects of dipyridamole and aspirin are additive.

Pharmacokinetics.

Absorption.

Plasma concentrations of dipyridamole from the dipyridamole/ aspirin sustained release capsules formulation rise after a lag time of about 30 minutes. Steady state conditions are generally reached within 3 days. Peak plasma concentrations at steady state conditions are reached at about 2-3 hours, and then decline slowly. Peak concentrations of dipyridamole from the dipyridamole/ aspirin sustained release capsules formulation administered twice daily are about 1.76 (1.22-2.71) g/mL. There is no cumulation with repetitive dosing. The decline in plasma concentration after oral administration fits a two compartment model. The alpha half-life (the initial decline following peak plasma concentration), which represents elimination of the majority of administered drug, has been reported to be about 30-60 minutes and the beta half-life (the terminal decline in plasma concentration) is approximately 10-12 hours. Total plasma clearance has been reported to be about 12 L/hr. Dipyridamole may undergo enterohepatic recirculation. The absolute bioavailability is limited by first pass hepatic metabolism and incomplete oral absorption and is about 70%.

Distribution.

Animal studies have shown that dipyridamole is widely distributed, preferentially to the liver, lungs, kidney, spleen and heart. In man, the apparent volume of distribution is about 140 litres, and 97-99% of the drug is bound to plasma protein. Dipyridamole does not cross the blood brain barrier. Placental transfer of dipyridamole is very low. It is known to be excreted into breast milk.

Metabolism.

Dipyridamole is metabolised in the liver predominantly to form a monoglucuronide which is excreted in the bile. In plasma about 70-80% of the total amount is present as parent compound and 20-30% as the monoglucuronide. Renal excretion is about 5%.
Aspirin is absorbed rapidly from the gastrointestinal tract following oral administration. Approximately 30% of the dose of aspirin is hydrolysed presystemically to salicylate. Peak plasma concentrations at steady state conditions of aspirin are reached at 0.5 (0.5-1) hours after administration. Peak concentrations with 25 mg twice daily are about 200 (133-300) nanogram/mL. Plasma aspirin concentrations decline rapidly with a half-life of approximately 15 minutes. After absorption aspirin is rapidly converted to salicylate, but during the first 20 minutes following oral administration, aspirin is the predominant form of the drug in the plasma. Peak plasma concentrations at steady state conditions of salicylic acid are reached at 1-1.5 hours after administration. Peak concentrations with 25 mg twice daily are about 1330 (990-1900) nanogram/mL. Salicylic acid is 80-90% bound to plasma proteins and is widely distributed. The volume of distribution of salicylates is reported to be approximately 10 L bodyweight in adults. Although both aspirin and salicylate have pharmacological activity, only aspirin has an antiplatelet effect. Salicylate is extensively bound to plasma proteins and is rapidly distributed to all body tissues. Salicylate appears in breast milk and crosses the placenta.

Excretion.

Salicylate is mainly eliminated by hepatic metabolism; the major metabolites include salicyluric acid, salicyl phenolic glucuronide and salicylic acyl glucuronide, and the minor metabolites are gentisic acid and gentisuric acid. The formation of the major metabolites salicyluric acid and salicyl phenolic glucuronide is easily saturated and, as a result, steady-state plasma salicylate concentrations increase disproportionately with dose; the other metabolic routes are first-order process. Salicylate is also excreted unchanged in the urine; the amount excreted by this route increases with increasing dose and also depends on urinary pH, about 30% of a dose being excreted in alkaline urine compared with 2% of a dose in acidic urine. Aspirin has an elimination half-life of 15-20 minutes in plasma; the major metabolite salicylic acid has a half-life of elimination of 2-3 hours at low doses, which may rise to 30 hours at higher doses because of nonlinearity in metabolism and plasma protein binding.

Clinical Trials

The second European Stroke Prevention Study (ESPS2) was conducted to investigate the effect of sustained release dipyridamole 200 mg twice daily and low dose aspirin 25 mg twice daily, alone or in combination, for the indications prevention of secondary stroke and transient ischaemic attacks (TIAs). This was a multicentre, multinational, randomised, double blind, placebo controlled trial in patients (n = 6602) who had experienced a recent ischaemic stroke or TIA. There were 4 parallel treatment groups organised in a 2 x 2 factorial design with each treatment given for 2 years. Treatments were: placebo; aspirin 25 mg twice daily; dipyridamole 200 mg sustained release capsule twice daily; and dipyridamole/ aspirin sustained release capsules (dipyridamole 200 mg with aspirin 25 mg) twice daily. The mean age of the patients was 66.7 years. The qualifying event was TIA in 23.7% of patients and stroke in 73.6% of patients.
The three primary endpoints were: stroke (fatal or not); death from any cause; and stroke and/or death occurring within 2 years of inclusion in the study. Secondary endpoints were myocardial infarction, ischaemic events, other vascular events, vascular deaths, vascular events and TIA. Endpoint data were analysed by calculating for each endpoint the survival curves of the four treatment groups. The Cox model was used to identify covariates with significant negative or positive impact upon survival.
In terms of stroke prevention, the results showed highly significant differences between the four survival curves (p < 0.001). Factorial analysis showed that both drugs were effective (p < 0.001), without interaction of one treatment upon the other, and that both given together were additive. Pairwise comparisons demonstrated that the combined therapy with dipyridamole and aspirin resulted in more effective stroke prevention (risk reduction = 37%, p < 0.001, 157/1650) than treatment with either aspirin alone (risk reduction = 18%, p < 0.01, 206/1649) or dipyridamole alone (risk reduction = 16%, p < 0.01, 211/1654), compared to placebo (250/1649). Combined therapy with dipyridamole and aspirin reduced the risk of stroke by 23.1% (p = 0.006) when compared to aspirin therapy alone, and reduced the risk of stroke by 24.7% (p = 0.002) when compared to dipyridamole alone therapy. Subgroup analysis based upon demographic criteria, the type of qualifying event or associated risk factors, corroborated the significant treatment effects observed in the total trial population. Subjects who already had a history of cerebrovascular accidents before the qualifying event, had a greater risk reduction of further stroke with combined therapy (48% [p < 0.001 compared to placebo]) than subjects in which the qualifying event was the first cerebrovascular accident (29% [p < 0.01 compared to placebo]). Subgroup analysis also showed that aspirin and/or dipyridamole were only effective in preventing nonfatal stroke, in contrast to fatal stroke which was not influenced by the treatment. Cox analysis of the survival data identified history of a previous cerebrovascular accident before the qualifying event as the most important risk factor predisposing to stroke recurrence, followed by daily alcohol consumption of > 5 units/day, diabetes and atrial fibrillation. The same analysis showed that receiving dipyridamole or receiving aspirin were strongly protecting against stroke.
Neither aspirin nor dipyridamole influenced mortality significantly. Effects of dipyridamole and/or aspirin on protection from endpoint stroke and/or death were similar to the effects on stroke. In addition to the prevention of stroke, dipyridamole and/or aspirin were effective in preventing subsequent TIAs, especially in the subgroup of patients in whom TIA was the qualifying event. As was observed for stroke, the efficacy of aspirin and dipyridamole when coprescribed was additive, being double that of either drug alone. Other relevant events from which occurrence was modified by treatment included ischaemic events, vascular events, and other vascular events (mostly deep venous thrombosis or peripheral arterial occlusion).
The ESPS2 trial shows the efficacy of both sustained release dipyridamole and low dose aspirin in preventing stroke. Stroke prevention is even more effective when aspirin and dipyridamole are combined, the benefit being additive. The study also shows that such therapy can prevent recurrence of TIA in patients with a previous history of TIA or stroke.
The results of the ESPS2 study are supported by the European/ Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) study that studied a combination treatment of dipyridamole 200 mg twice daily (83% of patients treated with the extended release dipyridamole formulation) and aspirin 30-325 mg daily. A total of 2739 patients who had experienced ischaemic stroke of arterial origin were enrolled in the aspirin alone (n = 1376) and combination aspirin plus dipyridamole (n = 1363) arms. The primary outcome event was the composite of death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or major bleeding complications, whichever occurred first. In the intention to treat analysis, patients in the aspirin plus dipyridamole group showed a 20% risk reduction (p < 0.05) for the primary composite endpoint compared with those in the aspirin alone group (12.7% [173/1363] versus 15.7% [216/1376]; hazard ratio [HR] 0.80, 95% CI 0.66-0.98).
The PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes) study was a randomised, parallel group, international, double blind, double dummy, active and placebo controlled, 2 x 2 factorial study to compare dipyridamole/ aspirin sustained release capsules with clopidogrel, and telmisartan with matching placebo in the prevention of stroke in patients who had previously experienced an ischaemic stroke, mainly of noncardioembolic origin. A total of 20,332 patients were randomised to dipyridamole/ aspirin sustained release capsules (n = 10,181) or clopidogrel (n = 10,151), both given on a background of standard treatment. For the dipyridamole/ aspirin sustained release capsules versus clopidogrel comparison, the primary objective of the trial was to demonstrate noninferiority of dipyridamole/ aspirin sustained release capsules compared to clopidogrel (noninferiority margin 1.075) on the primary endpoint, which was the time to first recurrent stroke of any type. Hypothesis test was performed using hazard ratios and time to event analyses (Kaplan-Meier). The mean exposure to the antiplatelet medication was 2.0 years in the dipyridamole/ aspirin sustained release capsules group and 2.2 years in the clopidogrel group, reflecting a higher frequency of permanent premature discontinuation of dipyridamole/ aspirin sustained release capsules (35.1%) versus clopidogrel (28.9%). This difference was primarily due to the higher incidence of discontinuations due to adverse events in the dipyridamole/ aspirin sustained release capsules group (16.4%) than in the clopidogrel group (10.7%). Headache, dizziness, vomiting and nausea were the most commonly reported adverse events that contributed to the difference between the two treatment groups (see Adverse Effects).
The incidence of the primary endpoint was similar in both treatment groups (9.0% for dipyridamole/ aspirin sustained release capsules versus 8.8% for clopidogrel; HR 1.01, 95% CI 0.92-1.11). The primary objective of the trial in demonstrating the noninferiority of dipyridamole/ aspirin sustained release capsules versus clopidogrel could not be established and therefore all secondary and tertiary endpoint analysis are considered to be exploratory in nature. For the prespecified secondary composite endpoint of recurrent stroke, myocardial infarction, or death due to vascular causes, similar rates were observed between the dipyridamole/ aspirin sustained release capsules and clopidogrel treatment groups (13.1% in both treatment groups).

Indications

Dipyridamole/Aspirin 200/25 sustained release capsules are indicated for the prevention of recurrent ischaemic stroke and transient ischaemic attacks.

Contraindications

Hypersensitivity to any of the components of the product or salicylates.
Patients with rare hereditary problems of fructose intolerance and/or galactose intolerance (e.g. galactosaemia) should not take this medicine.
Concurrent use with ketorolac.
Severe renal impairment.
Patients with active gastric or duodenal ulcers or bleeding disorders.
Patients in the last trimester of pregnancy.

Precautions

Due to the risk of bleeding, as with other antiplatelet agents, dipyridamole/ aspirin sustained release capsules should be used with caution in patients at increased bleeding risk and patients should be followed carefully for any signs of bleeding, including occult bleeding.
Because dipyridamole is a potent vasodilator, high doses should be used with caution in patients with severe coronary artery disease (e.g. unstable angina or recently sustained myocardial infarction), subvalvular aortic stenosis, or haemodynamic instability (e.g. decompensated heart failure).
Headache or migraine-like headache which may occur especially at the beginning of dipyridamole/ aspirin sustained release capsules therapy should not be treated with analgesic doses of aspirin.
Patients treated with regular oral doses of dipyridamole/ aspirin sustained release capsules should not receive additional intravenous dipyridamole. If pharmacological stress testing with intravenous dipyridamole is considered necessary, drugs containing oral dipyridamole (e.g. dipyridamole/ aspirin sustained release capsules, dipyridamole) should be discontinued for twenty four hours prior to the stress testing. Failure to do so may impair the sensitivity of the test.
In patients with myasthenia gravis, readjustment of therapy may be necessary after changes in dipyridamole dosage (see Interactions with Other Medicines).
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 unconjugated dipyridamole in bile may be the mechanism responsible for the presence of dipyridamole in gallstones.
Due to the aspirin component, dipyridamole/ aspirin sustained release capsules should be used in caution in patients with asthma, allergic rhinitis, nasal polyps, chronic or recurring gastric or duodenal complaints, impaired renal or hepatic function or glucose-6-phosphate dehydrogenase deficiency.
In addition, caution is advised in patients who are hypersensitive to nonsteroidal anti-inflammatory drugs.
There is a possible association between aspirin and Reye's syndrome when given to children. Therefore, dipyridamole/ aspirin sustained release capsules should not be used in children and adolescents with feverish diseases or viral infections with or without fever, because of the risk of Reye's syndrome. Reye's syndrome is a very rare disease, which affects the brain and liver, and can be fatal (see Paediatric use).
Aspirin has been shown to enhance the effect of anticoagulants (e.g. coumarin derivatives and heparin), antiplatelet drugs (e.g. clopidogrel, ticlopidine) and valproic acid which may result in an increased risk of side effects. Selective serotonin reuptake inhibitors (SSRIs) may increase the risk of bleeding. Gastrointestinal side effects also increase when aspirin is administered concomitantly with NSAIDs, corticosteroids or chronic alcohol use.

Effects on fertility.

No studies on the effects on human fertility have been conducted. In mice, single oral doses (up to 1000 mg/kg) of a combination (1:5 ratio) of dipyridamole and aspirin did not cause impairment of male fertility.

Use in pregnancy.

(Category C)
Aspirin inhibits prostaglandin synthesis. When given late in pregnancy, it may cause premature closure of the foetal ductus arteriosus, delay labour and birth. Aspirin increases bleeding time both in the newborn infant and in the mother because of its antiplatelet effects. Products containing aspirin should be avoided in the last trimester.
Reproduction studies in rats and rabbits with dipyridamole and aspirin (1:4.4) showed enhanced foetal loss at oral doses of 405.5 and 135 mg/kg/day, respectively. Maternal weight loss was also reported at these dose levels. The maximum exposure to dipyridamole in these studies was approximately equal to the human exposure to dipyridamole at the maximum recommended clinical dose, based on body surface.
There are, however, no adequate and well controlled studies in pregnant women with dipyridamole and aspirin. Because animal reproduction studies are not always predictive of human response, this product should be used during early pregnancy only if clearly needed and avoided in the last trimester.

Use in lactation.

Dipyridamole and salicylates are excreted in breast milk. Chronic high doses of aspirin can cause adverse effects in the infant. Although the dose of aspirin in dipyridamole/ aspirin sustained release capsules is relatively low, caution should be used when dipyridamole/ aspirin sustained release capsules is administered to nursing mothers.

Paediatric use.

Dipyridamole/ aspirin sustained release capsules are not recommended for children.

Genotoxicity.

Dipyridamole and aspirin (1:4) were not genotoxic in assays for gene mutations (bacteria and mammalian cells) and chromosomal abberations.

Carcinogenicity.

The carcinogenic potential was investigated in rats and mice at maximum doses of 450 mg/kg/day, divided as 75 mg/kg/day dipyridamole and 375 mg/kg/day aspirin. There was no indication of carcinogenic potential.

Effects on ability to drive and use machines.

No studies on the effect on the ability to drive and use machines have been performed. However, patients should be advised that symptoms such as dizziness and confusional state have been reported in clinical trials. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience such symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Effect on laboratory tests.

Investigations.

Abnormal liver function test, increased blood uric acid (may lead to attacks of gout), prolonged prothrombin time.

Interaction with alcohol.

Patients should be advised against coadministration of dipyridamole/ aspirin sustained release capsules with alcohol as this may lead to a rapid release and absorption of dipyridamole, and a possible increased risk of adverse events.

Interactions

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.

Adenosine.

Dipyridamole increases the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage should be considered.

Alcohol.

In vitro data have shown that the presence of alcohol leads to an increased rate of release of dipyridamole from the sustained release pellets in the capsule.

Alendronate.

The incidence of gastrointestinal side effects is increased in patients taking aspirin in combination with alendronate.

Antacids.

Antacids may increase urinary salicylate excretion, leading to decreased plasma salicylate levels. It is not known whether this would significantly reduce the effectiveness of dipyridamole/ aspirin sustained release capsules.

Anticoagulants (e.g. coumarin derivatives, heparin).

Aspirin has been shown to enhance the effect of anticoagulants which may increase the risk of bleeding.

Antihypertensive agents.

Dipyridamole may increase the hypotensive effect of blood pressure lowering drugs. Aspirin has been shown to decrease the effectiveness of angiotensin converting enzyme inhibitors by inhibiting the synthesis of prostaglandins.

Antiplatelet agents (such as eptifibatide, ticlopidine, clopidogrel, tirofiban).

The effects of dipyridamole/ aspirin sustained release capsules and other drugs which inhibit platelet aggregation may be additive, leading to an increased risk of bleeding.

Cholinesterase inhibitors.

Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors thereby potentially aggravating myasthenia gravis.

Corticosteroids.

Aspirin may increase the risk of gastrointestinal side effects, including bleeding, when administered corticosteroids. Corticosteroids may increase the clearance of aspirin.

Corticotropin.

Corticotropin may increase urinary salicylate excretion, leading to decreased plasma salicylate levels. It is not known whether this would significantly reduce the effectiveness of dipyridamole/ aspirin sustained release capsules.

Diltiazem.

Diltiazem enhances the inhibitory effect of aspirin on platelet aggregation and may increase the risk of bleeding.

Ethanol.

Ethanol potentiates aspirin induced prolongation of bleeding time and may increase gastrointestinal blood loss due to irritation by aspirin.

Fluoxetine.

Aspirin may produce an allergic reaction in patients known to be allergic to fluoxetine.

Hypoglycaemic agents.

Aspirin may increase the effect of insulin and oral hypoglycaemic agents. This is most likely with aspirin doses greater than 650 mg/day and may not be clinically significant in patients taking dipyridamole/ aspirin sustained release capsules, however caution should be exercised.

Methotrexate.

Aspirin may increase the toxicity of methotrexate.

Nicotinic acid.

Aspirin may decrease the clearance and increase plasma levels of nicotinic acid.

Nonsteroidal anti-inflammatory drugs (NSAIDs).

Aspirin may increase the risk of gastrointestinal side effects, including bleeding, when administered with NSAIDs. Aspirin displaces diclofenac from its binding sites, reducing diclofenac effectiveness.
The concomitant administration of ibuprofen with aspirin may limit the beneficial cardiovascular effects of aspirin in patients with increased cardiovascular risk.

Phenytoin.

Aspirin has been shown to enhance the effect of phenytoin, which may result in an increased risk of side effects.

Quinidine.

Quinidine may increase the inhibitory effect of aspirin on platelet aggregation and may increase the risk of bleeding.

Selective serotonin reuptake inhibitors (SSRIs).

Concurrent use of aspirin and SSRIs may increase the risk of bleeding.

Sodium valproate.

Aspirin may alter the metabolism and protein binding of valproate, leading to increased levels of unbound drug which may result in an increased risk of side effects. Unbound valproate should be monitored in patients taking sodium valproate and dipyridamole/ aspirin sustained release capsules.

Spironolactone.

Aspirin may decrease the natriuretic effect of spironolactone.

Thrombolytic agents.

Aspirin with dipyridamole 200 mg sustained release capsule increases the risk of bleeding in patients receiving thrombolytic agents. Dipyridamole/ aspirin sustained release capsules and thrombolytic agents should be used concurrently only with extreme caution and patients should be closely monitored for evidence of internal or external bleeding.

Uricosuric agents (e.g. probenecid, sulphinpyrazone).

High dose aspirin may inhibit the effect of uricosuric agents (e.g. probenecid, sulphinpyrazone). The effect of dipyridamole/ aspirin sustained release capsules on the action of uricosuric agents may not be clinically significant.

Verapamil.

Verapamil may inhibit platelet aggregation and increase the risk of bleeding if combined with dipyridamole/ aspirin sustained release capsules.

Zafirlukast.

Concurrent use of aspirin and zafirlukast may result in increased plasma levels of zafirlukast. The clinical significance of this interaction is unknown.

Adverse Effects

Clinical trial data.

Two large scale trials (ESPS-2, PRoFESS) enrolling a total of 26,934 patients, including 11,831 patients who were allocated to dipyridamole/ aspirin sustained release capsules, were used to define the adverse effect profile of dipyridamole/ aspirin sustained release capsules. In addition, from spontaneous reporting also those events where facts and evidence qualified these as adverse reactions with a possible causal relationship to dipyridamole/ aspirin sustained release capsules have been included.
In the pivotal clinical trial ESPS-2 (N = 6602, see Clinical Trials), discontinuations due to adverse events were 25%, 25%, 19% and 21% in patients treated with dipyridamole/ aspirin sustained release capsules, dipyridamole 200 mg sustained release capsules, aspirin, and placebo, respectively. The adverse events that most commonly led to discontinuation of dipyridamole/ aspirin sustained release capsules were headache (10%), nausea (6%) and dizziness (5%). The most common adverse events reported in patients treated with dipyridamole/ aspirin sustained release capsules in the pivotal clinical trial (ESPS2) are presented in Table 1.
In the PRoFESS trial (N = 20,332, see Clinical Trials), discontinuations due to adverse events were 16.4% for dipyridamole/ aspirin sustained release capsules and 10.7% for clopidogrel. The difference was mainly due to higher incidence of discontinuations due to headache [5.9% (n = 593) versus 0.9% (n = 87)], dizziness [1.3% (n = 134) versus 0.5% (n = 52)], vomiting [1.6% (n = 158) versus 0.4% (n = 37)] and nausea [1.5% (n = 155) versus 0.6% (n = 58)] in the dipyridamole/ aspirin sustained release capsules group compared to the clopidogrel group.
Analysis of the bleeding events in the patients treated with dipyridamole/ aspirin sustained release capsules in the two large scale trials (ESPS-2, PRoFESS) are presented in Table 2. Bleeding events are distributed over several system organ classes (SOC); a summary description of bleeding is given in Table 2.
Adverse reactions at therapeutic doses of dipyridamole/ aspirin sustained release capsules are usually mild and transient. The most commonly reported adverse reaction is headache, and in some cases the headache is severe (migraine-like, especially at the beginning of treatment). In most cases, adverse effects reduce or disappear as treatment is continued.
Adverse reactions of dipyridamole/ aspirin sustained release capsules reported from clinical trials and postmarketing experience are listed below according to system organ classes.

Blood and lymphatic system disorders.

Thrombocytopenia (reduction of platelet count), anaemia, iron deficiency anaemia due to occult gastrointestinal bleeding.

Immune system disorders.

Hypersensitivity reactions including rash, urticaria, severe bronchospasm and angioedema.

Nervous system disorders.

Haemorrhage intracranial, dizziness, headache, also migraine-like headache (especially at the beginning of treatment).

Eye disorders.

Eye haemorrhage.

Cardiac disorders.

Tachycardia, worsening of symptoms of coronary artery disease, syncope.

Vascular disorders.

Hypotension, hot flushes.

Respiratory, thoracic and mediastinal disorder.

Epistaxis.

Gastrointestinal disorders.

Vomiting, nausea, diarrhoea, dyspepsia, gastroduodenal ulcer, erosive gastritis, gastrointestinal haemorrhage, abdominal pain.

Skin and subcutaneous tissue disorders.

Skin haemorrhages including contusion, ecchymosis and haematoma.

Musculoskeletal, connective tissue and bone disorders.

Myalgia.

Investigations.

Bleeding time prolonged.

Injury, poisoning and procedural complications.

Postprocedural haemorrhage, operative haemorrhage.
Additional established adverse effects for the relevant monocompounds are the following and are also considered listed for dipyridamole/ aspirin.

Dipyridamole.

Additional adverse effects reported with dipyridamole monotherapy were as follows.
Dipyrdamole has been shown to be incorporated into gallstones.

Aspirin.

Additional adverse effects reported with aspirin monotherapy were as follows.

Blood and lymphatic system disorders.

Disseminated intravascular coagulation, coagulopathy. Aspirin may cause haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency.

Immune system disorders.

Anaphylactic reactions (especially in patients with asthma).

Metabolism and nutritional disorders.

Hypoglycaemia (children), hyperglycaemia, thirst, dehydration, hyperkalaemia, metabolic acidosis, respiratory alkalosis.

Psychiatric disorders.

Confusional state.

Nervous system disorders.

Agitation, brain oedema, lethargy, convulsion.

Ear and labyrinth disorders.

Tinnitus, deafness.

Cardiac disorders.

Arrhythmia.

Respiratory, thoracic and mediastinal disorders.

Dyspnoea, gingival bleeding, laryngeal oedema, hyperventilation, pulmonary oedema, tachypnoea.

Gastrointestinal disorders.

Gastric ulcer perforation, duodenal ulcer perforation, melaena, haematemesis, pancreatitis.

Hepatobiliary disorders.

Hepatitis, Reye's syndrome.

Skin and subcutaneous tissue disorders.

Erythema exsudativum multiforme.

Musculoskeletal, connective tissue and bone disorders.

Rhabdomyolysis.

Renal and urinary disorders.

Renal failure, interstitial nephritis, renal papillary necrosis, proteinuria.

Pregnancy, puerperium and perinatal conditions.

Prolonged pregnancy, prolonged labour, small for dates baby, stillbirth, antepartum haemorrhage, postpartum haemorrhage.

General disorders and administration site conditions.

Pyrexia, hypothermia.

Dosage and Administration

The recommended dose is one capsule twice daily, usually one in the morning and one in the evening, preferably with meals.
The capsules should be swallowed whole without chewing.

Alternative regimen in case of intolerable headaches.

In the event of intolerable headaches during initial treatment, switch to one capsule at bedtime and low dose aspirin (for example, 75-150 mg) in the morning. Because there are no long-term, clinical outcome data with this regimen and headaches become less of a problem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.

Overdosage

Symptoms.

For dipyridamole, symptoms such as feeling warm, flushes, sweating, restlessness, feeling of weakness, dizziness, drop in blood pressure, tachycardia and anginal complaints may occur.
The signs and symptoms of mild acute aspirin overdose are hyperventilation, tinnitus, nausea, vomiting, impairment of vision and hearing, dizziness and confusion. In severe poisoning, delirium, tremor, dyspnoea, sweating, bleeding, dehydration, disturbances of the acid-base balance and electrolyte composition of the plasma, hypothermia and coma may be seen.

Treatment.

General supportive measures should be employed, including administration of activated charcoal.
Slow i.v. administration of xanthine derivatives (aminophylline 50-100 mg over 30 to 60 seconds) may reverse the haemodynamic effects of dipyridamole overdose. If 250 mg aminophylline does not relieve anginal complaints, sublingual nitroglycerin may be administered. Due to its wide distribution to tissues and its predominantly hepatic elimination, dipyridamole is not likely to be accessible to enhanced removal procedures.
Apart from general measures, treatment of aspirin overdosage consists chiefly of measures to accelerate the excretion (forced alkaline diuresis) and to restore the acid-base and electrolyte balance. Infusions of sodium bicarbonate and potassium chloride solutions may be given. In severe cases haemodialysis may be necessary.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Capsules (opaque, red/ivory, sustained release), dipyridamole 200 mg (modified release form) and aspirin 25 mg (standard release form): 60's (white opaque HDPE bottle with child resistant polypropylene closure and containing dessicant, AUST R 210813).

Storage

Store below 25°C. Protect from moisture.

Poison Schedule

S4.