Consumer medicine information

Asasantin SR

Dipyridamole; Aspirin

BRAND INFORMATION

Brand name

Asasantin SR

Active ingredient

Dipyridamole; Aspirin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Asasantin SR.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Asasantin SR against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet. More recent information may be available. The latest Consumer Medicine Information is available from your pharmacist, doctor, or from www.medicines.org.au and may contain important information about the medicine and its use of which you should be aware.

Keep this leaflet with the medicine. You may need to read it again.

What Asasantin SR is used for

Asasantin SR contains dipyridamole and aspirin. It is used to help prevent the recurrence of stroke in people who have had a previous stroke or transient ischaemic attack (TIA).

This type of medication is called an antithrombotic agent. An antithrombotic agent is a drug that reduces the formation of blood clots (thrombi).

Dipyridamole and aspirin work by preventing blood clots from forming. These drugs work on the blood cells which help blood to clot (platelets) and help prevent them from clumping and sticking together. This reduces the risk of forming blood clots that can lead to a stroke. The effects of these drugs are additive.

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 Asasantin SR

When you must not take it

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

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

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 Asasantin SR if you:

  • have severe kidney disease
  • are taking the medicine ketorolac
  • have an ulcer of the stomach or intestine
  • have any conditions that increases your risk of bleeding.

Do not take this medicine if you are intolerant to fructose or galactose.

Each capsule contains 53 mg lactose monohydrate and 11.3 mg sucrose resulting in 106 mg lactose monohydrate and 22.6 mg sucrose per maximum recommended daily dose.

Do not take this medicine if you are more than 6 months pregnant. It may affect your developing baby if you take it during late pregnancy.

Do not give this medicine to a child. Safety and effectiveness in children have not been established.

Do not give Asasantin 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 Asasantin SR 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).

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.

If you are not sure whether you should start taking this medicine, talk to your doctor.

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:

  • any heart condition (e.g. angina, heart attack or failure, heart valve problems)
  • any bleeding disorder (a condition that affects the way your blood normally clots)
  • severe muscle disease (myasthenia gravis)
  • gallstones
  • asthma or hay fever
  • any unusual growth or tumour inside the nose (e.g. nasal polyps)
  • long-term stomach or 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).

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 Asasantin 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 Asasantin SR may interfere with each other. These include:

  • medicines used to thin your blood (e.g. warfarin, dabigatran, apixaban, rivaroxaban) or prevent blood cells from clotting (e.g. eptifibatide, ticlopidine, clopidogrel, tirofiban)
  • other NSAIDs (e.g. diclofenac, ibuprofen)
  • metamizole, a medicine used to treat pain
  • any medicines used to treat high blood pressure (e.g. diltiazem and verapamil)
  • medicines used to treat rapid heart rhythm or assess heart function (e.g. quinidine, adenosine and regadenoson)
  • medicines used to treat myasthenia gravis (e.g. neostigmine, distigmine and related medicines)
  • medicines used to control blood sugar levels
  • alcohol
  • alendronate, a medicine used to treat and prevent osteoporosis
  • antacids
  • methotrexate, a medicine used to treat certain types of cancer, autoimmune diseases such as psoriasis and rheumatoid arthritis
  • medicines used to treat epilepsy (e.g. phenytoin and sodium valproate)
  • medicines used in the treatment of depression known as selective serotonin reuptake inhibitors (SSRIs) (e.g. fluoxetine)
  • spironolactone, a diuretic (water pill)
  • corticosteroids and substances that control the actions of corticosteroids (e.g. corticotropin)
  • nicotinic acid
  • zafirlukast, a medicine used to prevent asthma symptoms
  • medicines that promote the excretion of uric acid in the urine (e.g. probenecid)
  • anagrelide, a medicine used to treat the overproduction of blood platelets.

These medicines may be affected by Asasantin 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 Asasantin 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.

Tell your doctor if you experience headaches when you first start Asasantin SR at the recommended dose.

Your doctor may change your dose for one week. The changed dose will be one Asasantin SR capsule at bedtime and low dose aspirin (e.g. 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 capsules whole with a full glass of water.

When to take it

Take your medicine at about the same time each day, usually one in the morning and one in the evening, 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.

How long to take it

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

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If you miss a dose, take it as soon as you remember.

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

Symptoms of an 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 Asasantin SR

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Asasantin SR.

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

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. Asasantin SR can slow down blood clotting.

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

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

Do not treat the headache or migraine-like headache with aspirin.

Tell your doctor or dentist that you are taking Asasantin SR if you plan to have 'pharmacological stress testing' or other treatments (even at the dentist).

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take Asasantin 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.

Things to be careful of

Be careful driving or operating machinery until you know how Asasantin 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.

Side effects

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

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • headache or migraine-like headache, especially when you start taking Asasantin SR
  • dizziness
  • indigestion, vomiting, nausea, stomach pain, diarrhoea.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • muscle aches and pains
  • hot flushes
  • symptoms of low blood pressure (e.g. lightheadedness)
  • signs of anaemia (e.g. tiredness, being short of breath, dizziness, looking pale)
  • symptoms of a reduced blood platelet count (e.g. bruising or bleeding more easily than normal, reddish or purplish blotches under the skin).

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Emergency at your nearest hospital:

  • vomiting blood or material that looks like coffee grounds or bleeding from the back passage (rectum), black sticky bowel motions (stools) or bloody diarrhoea
  • bleeding (including nose bleeds, bleeding within the head, bleeding in the eyes or increased bleeding during or after surgery)
  • fainting
  • worsening of symptoms of heart disease (e.g. chest pain, fast heart beat)
  • skin rash, hives or itching, swelling of the face, lips or tongue, difficulty in breathing.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using Asasantin SR

Storage

Keep your capsules in the bottle until it is time to take them. If you take the capsules out of the bottle they may not keep well.

Keep your capsules in a cool, dry place where the temperature stays below 30°C.

Do not store Asasantin SR 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 it 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 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

Asasantin SR is the brand name of your medicine. One half of the capsule is red and the other half is ivory.

Asasantin SR capsules are available in bottles of 20*, 30*, 50*, 60 or 100* capsules.

* Not distributed in Australia.

Ingredients

Active ingredients

Asasantin SR capsules contain:

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

Inactive ingredients:

  • tartaric acid
  • povidone
  • methacrylic acid copolymer
  • purified talc
  • acacia
  • hypromellose
  • hypromellose phthalate
  • triacetin
  • dimeticone
  • stearic acid
  • lactose monohydrate
  • aluminium stearate
  • colloidal anhydrous silica
  • maize starch
  • microcrystalline cellulose
  • sucrose
  • gelatin
  • titanium dioxide (as colouring agent)
  • iron oxide red (as colouring agent)
  • iron oxide yellow (as colouring agent).

Supplier

Asasantin SR is supplied in Australia by:

Boehringer Ingelheim Pty Limited
ABN 52 000 452 308
Sydney, Australia
www.boehringer-ingelheim.com.au

This Consumer Medicine Information was updated in November 2019.

® Asasantin is a registered trademark of Boehringer Ingelheim.

© Boehringer Ingelheim Pty Limited 2019.

Australian Registration Number

AUST R 68051

Published by MIMS January 2020

BRAND INFORMATION

Brand name

Asasantin SR

Active ingredient

Dipyridamole; Aspirin

Schedule

S4

 

1 Name of Medicine

Dipyridamole and aspirin.

6.7 Physicochemical Properties

Dipyridamole.

Dipyridamole is 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.
Chemical name: 2,6-bis(diethanolamino)- 4,8-dipiperidino-pyrimido [5,4-d]pyrimidine.
Molecular formula: C24H40N8O4.
Molecular Weight: 504.6.

Aspirin.

Aspirin is 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.
Chemical name: 2-acetoxybenzoic acid (commonly known as acetylsalicylic acid).
Molecular formula: C9H8O4.
Molecular weight: 180.2.

Chemical structure.


CAS number.

Dipyridamole: 58-32-2; aspirin: 50-78-2.

2 Qualitative and Quantitative Composition

Each Asasantin 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.

Excipients with known effect.

Each Asasantin SR 200 mg/25 mg capsule contains 53 mg of lactose monohydrate.
Each Asasantin SR 200 mg/25 mg capsule contains 11.3 mg of sucrose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

See Section 2 Qualitative and Quantitative Composition.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antithrombotic agents, platelet aggregation inhibitors excl. heparin.
ATC code: B01AC07 (dipyridamole), B01AC06 (acetylsalicylic acid).

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 cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) which potentiates the aggregation inhibiting effects of adenosine on platelets; and inhibition of cyclic guanosine monophosphate-PDE (cGMP-PDE) 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 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 oxy- 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.

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; Persantin SR (dipyridamole 200 mg) twice daily; and Asasantin SR (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 to 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 end point 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 Asasantin SR 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 Asasantin SR (n = 10,181) or clopidogrel (n = 10,151), both given on a background of standard treatment. For the Asasantin SR versus clopidogrel comparison, the primary objective of the trial was to demonstrate noninferiority of Asasantin SR 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 Asasantin SR group and 2.2 years in the clopidogrel group, reflecting a higher frequency of permanent premature discontinuation of Asasantin SR (35.1%) versus clopidogrel (28.9%). This difference was primarily due to the higher incidence of discontinuations due to adverse events in the Asasantin SR 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 (also see Section 4.8 Adverse Effects (Undesirable Effects)).
The incidence of the primary endpoint was similar in both treatment groups (9.0% for Asasantin SR 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 Asasantin SR 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 Asasantin SR and clopidogrel treatment groups (13.1% in both treatment groups).

5.2 Pharmacokinetic Properties

Absorption.

Dipyridamole.

Plasma concentrations of dipyridamole from the Asasantin SR 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 Asasantin SR formulation administered twice daily are about 1.76 (1.22-2.71) microgram/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%.

Aspirin.

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. 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.

Distribution.

Dipyridamole.

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.

Aspirin.

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. Plasma aspirin concentrations decline rapidly with a half-life of approximately 15 minutes.
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.

Metabolism and excretion.

Dipyridamole.

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.

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 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Asasantin 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 conditions of fructose intolerance and/or galactose intolerance (e.g. galactosaemia) should not take this medicine. Each Asasantin SR capsule contains 53 mg lactose monohydrate and 11.3 mg sucrose resulting in 22.6 mg sucrose and 106 mg of lactose monohydrate per maximum recommended daily dose.
Concurrent use with ketorolac.
Severe renal impairment.
Patients with active gastric or duodenal ulcers or bleeding disorders.
Patients in the last trimester of pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

Bleeding disorders.

Due to the risk of bleeding, as with other antiplatelet agents, Asasantin SR 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 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
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).

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.

Headache or migraine-like headache.

Headache or migraine-like headache which may occur especially at the beginning of Asasantin SR therapy should not be treated with analgesic doses of aspirin (see Section 4.2 Dose and Method of Administration).

Hypersensitivity.

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

Aspirin related precautions.

Due to the aspirin component, Asasantin SR should be used with caution in patients with asthma, allergic rhinitis, nasal polyps, chronic or recurring gastric or duodenal complaints, impaired renal or hepatic function (see Section 5.2 Pharmacokinetic Properties) or glucose-6-phosphate dehydrogenase deficiency.
Aspirin has been shown to enhance the effect of anticoagulants, antiplatelet drugs, valproate and phenytoin which may result in an increased risk of side effects. The use of aspirin with selective serotonin reuptake inhibitors (SSRIs) or anagrelide may increase the risk of bleeding. Gastrointestinal side effects also increase when aspirin is administered concomitantly with NSAIDs, corticosteroids or chronic alcohol use (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Stress testing with intravenous dipyridamole and other adenosinergic agents.

Patients treated with regular oral doses of Asasantin SR should not receive additional intravenous dipyridamole. If pharmacological stress testing with intravenous dipyridamole or other adenosinergic agents (e.g. adenosine, regadenoson) is considered necessary, drugs containing oral dipyridamole (e.g. Asasantin SR, Persantin) should be interrupted for 24 hours prior to administration of intravenous dipyridamole or 48 hours prior to administration of other adenosinergic agents because the risk of cardiovascular side effects may increase. Intake of oral dipyridamole 24 hours prior to stress testing with intravenous dipyridamole may impair the sensitivity of the test.

Use in the elderly.

No data available.

Paediatric use.

Asasantin SR is not recommended for children.
There is a possible association between aspirin and Reye's syndrome when given to children. Therefore, Asasantin SR 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.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Investigations.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs affecting bleeding.

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.

Anticoagulants.

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

Antiplatelet agents.

The effects of Asasantin SR and other drugs which inhibit platelet aggregation may be additive, leading to an increased risk of bleeding.

Selective serotonin reuptake inhibitors (SSRIs).

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

Thrombolytic agents.

Aspirin with Persantin SR increases the risk of bleeding in patients receiving thrombolytic agents. Asasantin SR and thrombolytic agents should be used concurrently only with extreme caution and patients should be closely monitored for evidence of internal or external bleeding.

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.

Quinidine.

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

Verapamil.

Verapamil may inhibit platelet aggregation and increase the risk of bleeding if combined with Asasantin SR.

Drugs affecting the cardiovascular system.

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.

Adenosinergic agents (e.g. adenosine, regadenoson).

Dipyridamole increases the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage should be considered. Dipyridamole also increases the cardiovascular effects of regadenoson, an adenosine A2A-receptor agonist. The risk of cardiovascular side effects may be increased when dipyridamole is not withheld for 48 hours prior to stress testing with intravenous adenosinergic agents.

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 Asasantin SR, however caution should be exercised.

Drugs increasing gastrointestinal side effects.

Gastrointestinal side effects also increase when aspirin is administered concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids or chronic alcohol use.

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.

Metamizole.

Metamizole may reduce the effect of acetylsalicylic acid on platelet aggregation, when taken concomitantly. Therefore, this combination should be used with caution in patients taking low dose acetylsalicylic acid for cardioprotection.

Alendronate.

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

Corticosteroids.

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

Pharmacokinetic interactions.

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 Asasantin SR.

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 Asasantin SR.

Nicotinic acid.

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

Spironolactone.

Aspirin may decrease the natriuretic effect of spironolactone.

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

High dose aspirin may inhibit the effect of uricosuric agents (e.g. probenecid, sulphinpyrazone). The effect of Asasantin SR on the action of uricosuric agents may not be clinically significant.

Zafirlukast.

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

General.

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

Methotrexate.

Aspirin may increase the toxicity of methotrexate.

Cholinesterase inhibitors.

Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors thereby potentially aggravating myasthenia gravis (see Section 4.4 Special Warnings and Precautions for Use).

Fluoxetine.

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

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 fetal 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 fetal 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, Asasantin SR should only be administered during first and second trimester of pregnancy when the potential benefits for the mother outweigh the possible risks for the fetus.
Asasantin SR is contraindicated in the third trimester of pregnancy.
 Dipyridamole and salicylates are excreted in breast milk (see Section 5.2 Pharmacokinetic Properties). Chronic high doses of aspirin can cause adverse effects in the infant.
Although the dose of aspirin in Asasantin SR is relatively low, caution should be used when Asasantin SR is administered to nursing mothers.
Asasantin SR 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)

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 http://www.tga.gov.au/reporting-problems.

Summary of the safety profile.

Two large scale trials (ESPS-2, PRoFESS) enrolling a total of 26,934 patients (including 11,831 patients who were allocated to Asasantin SR) were used to define the safety profile of Asasantin SR. These data are supplemented with the extensive Asasantin SR postmarketing experience.
Adverse reactions at therapeutic doses of Asasantin SR are usually mild and transient and in most cases, adverse effects reduce or disappear as treatment is continued. The most frequently 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 Asasantin SR are bleeding events.
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 Asasantin SR, Persantin SR, aspirin, and placebo, respectively. The adverse events that most commonly led to discontinuation of Asasantin SR were headache (10%), nausea (6%) and dizziness (5%). The most common adverse events reported in patients treated with Asasantin SR in the pivotal clinical trial (ESPS2) are presented in Table 1.
In the PRoFESS trial (N = 20,332, see Section 5.1 Pharmacodynamic Properties), discontinuations due to adverse events were 16.4% for Asasantin SR 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 Asasantin SR group compared to the clopidogrel group.
Analysis of the bleeding events in the patients treated with Asasantin SR 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 of Asasantin SR reported from clinical trials and postmarketing experience are listed in Table 3 according to system organ classes.

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 (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric population.

Asasantin SR is not recommended for children (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

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. 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 on 131126 (Australia).

Symptoms.

Experience with dipyridamole overdose is limited. Symptoms such as feeling warm, flushes, sweating, restlessness, feeling of weakness, dizziness and anginal complaints can be expected. A drop in blood pressure and tachycardia might be observed.
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.
Dizziness and tinnitus can, particularly in elderly patients, be symptoms of overdose.

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 excipients in Asasantin SR sustained-release capsules are: tartaric acid, povidone, methacrylic acid copolymer, purified talc, acacia, hypromellose, hypromellose phthalate, triacetin, dimeticone 350, stearic acid, lactose monohydrate, aluminium stearate, colloidal anhydrous silica, maize starch, microcrystalline cellulose, 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 30°C. Protect from moisture.

6.5 Nature and Contents of Container

Asasantin SR capsules are packed in white polypropylene bottles with child-resistant closures and contains a desiccant. Packs contain 20*, 30*, 50*, 60 or 100* capsules.
* Not currently distributed in Australia.

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