Consumer medicine information

Diasp SR sustained release capsules

Dipyridamole; Aspirin

BRAND INFORMATION

Brand name

Diasp SR

Active ingredient

Dipyridamole; Aspirin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Diasp SR sustained release capsules.

What is in this leaflet

This leaflet answers some common questions about DIASP SR. It does not contain all available information.

It does not take the place of talking to your doctor or pharmacist.

Ask your doctor or pharmacist if you have any concerns or questions about taking this medicine.

Keep this information with your capsules. You may need to read it again.

What DIASP SR is used for

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

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

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

Before you take DIASP SR

When you must not take it

Do not take DIASP SR if you have an allergy to:

  • aspirin or non-steroidal anti-inflammatory medicines (NSAIDs)
  • dipyridamole
  • any of the other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take DIASP SR if you:

  • have fructose intolerance. Each capsule contains 4.56 mg sucrose, resulting in 9.12 mg sucrose per maximum daily dose.
  • have severe kidney disease
  • are taking the medicine ketorolac
  • are more than 6 months pregnant
  • have an ulcer of the stomach or intestine, or
  • any condition that increases your risk of bleeding.

Do not take this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine. The active ingredient in DIASP SR passes into breast milk.

Do not give this medicine to a child. There is limited information about the use of DIASP SR in children.

Do not give DIASP 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 DIASP SR can cause a very rare disease called ‘Reye’s Syndrome’ if DIASP SR is given to children or adolescents who have a fever or a viral infection (with or without a fever).

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have, or have had, any of the following conditions:

  • 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
  • hayfever
  • 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.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. This medicine should not be used during late pregnancy. Your doctor can discuss with you the risks and benefits involved.

The active ingredients in Diasp SR pass into breast milk. There is a possibility that your baby may be affected.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and DIASP SR may interfere with each other.

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

  • medicines used to thin your blood such as warfarin, dabigatran, apixaban, rivaroxaban 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
  • medicines used to treat rapid heart rhythm (e.g. quinidine and adenosine).
  • alcohol
  • alendronate, a medicine used to treat and prevent osteoporosis
  • antacids
  • methotrexate, a medicine used to treat certain types of cancer, auto immune diseases such as psoriasis and rheumatoid arthritis
  • medicines used to treat epilepsy (e.g .phenytoin and sodium valproate)
  • spironolactone, a diuretic (water pill)
  • corticosteroids (steroid hormones)
  • corticotropin (corticosteroids and substances which control the actions of corticosteroids)
  • quinidine
  • diltiazem
  • verapamil
  • nicotinic acid
  • fluoxetine or any other medicines known as selective serotonin reuptake inhibitors or SSRIs (used in the treatment of depression)
  • zafirlukast, a medicine used to prevent asthma symptoms
  • aspirin other NSAIDs (e.g. diclofenac, ibuprofen)
  • any medicine that promotes the excretion of uric acid in the urine (e.g. probenecid, sulphinpyrazone)
  • anagrelide, a medicine used to treat the overproduction of blood platelets.
  • any medicine which prevents blood cells from clotting (e.g. eptifibatide, ticlopidine, clopidogrel, tirofiban).

These medicines may be affected by DIASP SR or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

How to take DIASP SR

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

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 DIASP SR 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 DIASP SR 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.

When to take it

Take your medicine at about 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. It will also help you remember when to take it.

Swallow the capsule whole without chewing with a full glass of water.

How long to take it

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

DIASP SR helps control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well. Therefore you must take DIASP SR every day.

If you forget to take it

If you miss a dose, take it as soon as you remember. However, if you remember when it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

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.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Emergency at the nearest hospital, if you think that you or anyone else may have taken too much DIASP SR.

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 DIASP SR

Things you must do

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Tell your doctor or pharmacist if you begin taking any other medicine while you are taking DIASP SR. This applies to all medicines obtained with or without a doctor's prescription.

If you experience headache or migraine-like headache, especially when you start taking DIASP SR, do not treat the headache or migraine-like headache with analgesic doses of aspirin.

Tell your doctor or pharmacist if you experience headache or migraine-like headache, so that it can be properly treated.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

Diasp SR can slow down blood clotting.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you plan to have ‘pharmacological stress testing’, surgery or other treatment (even at the dentist), tell your doctor or dentist that you are taking DIASP SR.

Be careful driving or operating machinery until you know how DIASP SR 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.

Things you must not do

Do not take DIASP SR to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking DIASP SR.

All prescription medicines carry some risks. Your doctor has weighed the risks of you taking DIASP SR against the benefits they expect it will have for you.

If side effects occur, they are usually mild and transient when DIASP SR is used at the recommended dose. In most cases these effects diminish or disappear as treatment is continued.

The following side effects have been reported with DIASP SR:

  • headache or migraine-like headache, especially when you start taking DIASP SR
  • 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 (e.g. 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 effects during or after using DIASP SR, so that these may be properly treated.

Allergic reactions have been reported. Symptoms of an allergic reaction may include:

  • skin rash, hives or itching
  • swelling of the face, lips or tongue
  • difficulty in breathing.

Tell your doctor immediately if you have an allergic reaction. You may require urgent medical attention.

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 DIASP SR.

After taking DIASP SR

Storage

Leave all capsules in the container until it is time to take a dose. The container will protect the capsules.

DIASP SR should be kept in a cool, dry place where the temperature stays below 25°C. For example, do not leave your capsules in a car or store them in the bathroom. Heat and dampness will damage the capsules.

Keep DIASP SR where children cannot reach them.

Disposal

If your doctor tells you to stop taking this medicine, or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

DIASP SR is the brand name of the capsules prescribed for you by your doctor. One half of the capsule is red and the other half is ivory.

DIASP SR is available in 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.

There are also a number of other ingredients which are used in the formation of the capsule. These ingredients are:

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

Sponsor

Arrow Pharma Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
Australia

Australian registration number: DIASP SR – AUST R 210808

This leaflet was last revised in October 2018

Published by MIMS December 2018

BRAND INFORMATION

Brand name

Diasp SR

Active ingredient

Dipyridamole; Aspirin

Schedule

S4

 

1 Name of Medicine

Dipyridamole and asprin.

6.7 Physicochemical Properties

Dipyridamole.

An odourless, yellow crystalline powder with a bitter taste. It has a melting point in the range of 164-168°C, and is soluble in dilute acids, methanol, ethanol and chloroform. The molecular formula for dipyridamole is C24H40N8O4 and the molecular weight is 504.6. The chemical name for dipyridamole is 2,6-bis (diethanolamino)- 4,8-dipiperidino-pyrimido [5,4-d]pyrimidine.

Aspirin.

A white crystalline powder or colourless crystals, odourless or almost odourless, slightly soluble in water, freely soluble in alcohol, soluble in chloroform and in ether. It melts at about 143°C. The molecular formula for aspirin is C9H8O4 and the molecular weight is 180.2. Aspirin is commonly known as acetylsalicylic acid. The chemical name is 2-acetoxybenzoic acid.

Chemical structure.

The structural formulae for dipyridamole and aspirin are as follows:

CAS number.

Dipyridamole.

58-32-2.

Aspirin.

50-78-2.

2 Qualitative and Quantitative Composition

Each Diasp SR sustained release capsule contains dipyridamole 200 mg and aspirin 25 mg.

Excipients with known effects.

Sodium benzoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each Diasp SR sustained release capsule contains dipyridamole 200 mg in modified release form and aspirin 25 mg in standard release form. The gelatin shell of the capsule consists of a red opaque cap and an ivory opaque body.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 oxyradical and peroxyradicals.
Aspirin inhibits platelet aggregation by its irreversible acetylation of cyclo-oxygenase, which effectively blocks the activity of this enzyme in platelets.
The antithrombotic effects of dipyridamole and aspirin are additive.

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 Section 4.8 Adverse Effects (Undesirable 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).

5.2 Pharmacokinetic Properties

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 accumulation 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 L, 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 body weight 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.

5.3 Preclinical Safety Data

Genotoxicity.

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

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.

4 Clinical Particulars

4.1 Therapeutic Indications

Diasp SR sustained release capsules are indicated for the prevention of recurrent ischaemic stroke and transient ischaemic attacks.

4.3 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.

4.4 Special Warnings and Precautions for Use

Bleeding disorders.

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.
Caution should be advised in patients receiving concomitant medication which may increase the risk of bleeding, such as anticoagulants, antiplatelet agents, selective serotonin reuptake inhibitors (SSRIs), or anagrelide (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Cardiovascular disorders.

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.

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.

Stress testing with intravenous dipyridamole.

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.

Myasthenia gravis.

In patients with myasthenia gravis, readjustment of therapy may be necessary after changes in dipyridamole dosage (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Biliary 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 unconjugated dipyridamole in bile may be the mechanism responsible for the presence of dipyridamole in gallstones.

Aspirin related precautions.

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.
Aspirin have 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.

Hypersensitivity.

In addition, caution is advised in patients who are hypersensitive to nonsteroidal anti-inflammatory drugs.

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.

Use in the elderly.

No data available.

Paediatric use.

Dipyridamole/ aspirin sustained release capsules is not recommended for children.
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. Also see Paediatric use.

Effects on laboratory tests.

Investigations.

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

4.5 Interactions with Other Medicines and Other Forms of 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.
Aspirin has been shown, when given with anticoagulants, antiplatelet drugs, selective serotonin reuptake inhibitors (SSRIs), or anagrelide to increase the risk of bleeding.
Gastrointestinal side effects also increase when aspirin is administered concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids or chronic alcohol use.

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

Anticonvulsants.

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

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.

4.6 Fertility, Pregnancy and Lactation

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.
(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.
Animal studies covering the peri/ postnatal period have not been performed with the combination.
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.
Dipyridamole/ aspirin sustained release capsules are contraindicated in the third trimester of pregnancy.
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.
Dipyridamole/ aspirin sustained release capsules should only be used in lactating women when the potential benefits for the mother outweigh the possible risks to the newborn.

4.8 Adverse Effects (Undesirable 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 Section 5.1 Pharmacodynamic Properties, 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 = 20332, see Section 5.1 Pharmacodynamic Properties, 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 reactions are headache in some cases the headache is severe (migraine-like, especially at the beginning of treatment), dizziness and gastrointestinal events such as dyspepsia, diarrhoea, nausea and abdominal pain. The most important serious adverse reactions associated with dipyridamole/ aspirin sustained release capsules are bleeding events. 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 disorders.

Epistaxis.

Gastrointestinal disorders.

Vomiting, nausea, diarrhoea, dyspepsia, gastric ulcer, duodenal 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.
Dipyridamole 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.

Investigations.

Liver function test abnormal, blood uric acid increased (may lead to gout attacks), prothrombin time prolonged.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of 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.

4.7 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.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre (telephone 13 11 26).

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.
Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Slow intravenous 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.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients in Diasp SR sustained release capsules are: tartaric acid, povidone, methacrylic acid copolymer, purified talc, acacia, hypromellose, hypromellose phthalate, triacetin, simethicone, cetostearyl alcohol, sodium benzoate, microcrystalline cellulose, pregelatinised maize starch, stearic acid, sucrose, gelatin, titanium dioxide, iron oxide red and iron oxide yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from moisture.

6.5 Nature and Contents of Container

Capsules are packed in white opaque HDPE bottles with child resistant polypropylene closures and contain desiccant. Pack contains 60 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes