Consumer medicine information

Persantin SR 200 mg

Dipyridamole

BRAND INFORMATION

Brand name

Persantin SR

Active ingredient

Dipyridamole

Schedule

What is in this leaflet

This leaflet answers some common questions about Persantin 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 Persantin 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 Persantin SR is used for

Persantin SR contains dipyridamole. 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 anticoagulant. Some people refer to anticoagulant medicines as "blood thinners".

Dipyridamole works by preventing blood clots from forming. It works on the blood cells that help blood to clot (platelets) and prevents them from clumping and sticking together. This reduces the risk of forming blood clots that can lead to a stroke. Dipyridamole also widens the blood vessels of the heart.

Persantin SR is prescribed either alone or in conjunction with aspirin.

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 Persantin SR

When you must not take it

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

any medicine containing dipyridamole
any of the 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 this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breast-feed if you are taking this medicine. The active ingredient in Persantin SR passes into breast milk.

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

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 medical conditions:

any heart condition (e.g. angina, heart attack or failure, heart valve problems)
severe muscle disease (myasthenia gravis)
gallstones.

Tell your doctor if you are pregnant or plan to become pregnant. Persantin SR should not be used during pregnancy.

Tell your doctor if you are breastfeeding or intend to breast-feed. Persantin SR is not recommended in women who are breastfeeding.

If you have not told your doctor about any of the above, tell him/her before you start taking Persantin SR.

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 Persantin SR may interfere with each other. These include:

aspirin
medicines used to thin your blood (e.g. warfarin)
medicines used to treat high blood pressure
medicines used to treat myasthenia gravis (e.g neostigmine, distigmine and related medicines)
a medicine used to treat rapid heart rhythm or assess heart function (e.g. adenosine and regadenoson).

These medicines may be affected by Persantin 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 Persantin 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 (200 mg) twice a day.

How to take it

Swallow the capsules whole with a full glass of water.

Do not chew the capsules.

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 to. 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 Persantin 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, weakness and dizziness. There may be effects on the heart and circulation causing chest pain, an increase in pulse rate and a drop in blood pressure.

While you are taking Persantin 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 Persantin 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. Persantin SR can slow down blood clotting.

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

Tell your doctor or dentist that you are taking Persantin SR if you plan to have 'pharmacological stress testing'.

Things you must not do

Do not take Persantin 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 Persantin SR affects you. This medicine may cause dizziness or light-headedness 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 Persantin 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, dizziness
indigestion, diarrhoea, nausea, stomach pain, vomiting
muscle aches and pains
hot flushes
low blood pressure (dizziness, light-headedness), fast heart beat.

These are usually mild and short-lived.

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

feeling of tightness, pressure or heaviness in the chest - symptoms of angina
unusual bruising or bleeding - symptoms of a reduction in blood platelet count (thrombocytopenia)
tiredness, headaches, being short of breath when exercising, dizziness and looking pale - symptoms of a decrease in red blood cells count (anaemia)
increased bleeding during or after a procedure or surgery
fever, sweating and chills; steady, severe abdominal pain that persists for longer than a few hours; or a yellowing of the skin or whites of the eyes (jaundice) - these may be symptoms of gallstones
abdominal pain or discomfort that is often worse at night, nausea and vomiting, loss of appetite and weight - these may be symptoms of stomach/duodenal ulcers.

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:

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 Persantin 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 Persantin 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 them. 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

Persantin SR is the brand name of the capsules that has been prescribed for you by your doctor. One half of the capsule is red and the other half is orange.

Persantin SR is available in packs of 10*, 20*, 30*, 50*, 60 or 100* capsules.

* Not distributed in Australia.

Ingredients

Each Persantin SR capsule contains 200 mg of dipyridamole in a sustained-release formulation as the active ingredient.

Persantin SR capsules also contain the following ingredients:

tartaric acid
povidone
methacrylic acid copolymer
purified talc
acacia
hypromellose
hypromellose phthalate
triacetin
dimeticone 350
stearic acid
gelatin
titanium dioxide (as colouring agent)
iron oxide red (as colouring agent)
iron oxide yellow (as colouring agent).

Supplier

Persantin SR is supplied in Australia by:

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

This leaflet was revised in November 2019.

® Persantin is a registered trade mark of Boehringer Ingelheim.

Australian Registration Number

AUST R 73209

Published by MIMS January 2020

BRAND INFORMATION

Brand name

Persantin SR

Active ingredient

Dipyridamole

Schedule

1 Name of Medicine

Dipyridamole.

6.7 Physicochemical Properties

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.
Laboratory Code: R-A 8-BS.
Molecular Formula: C₂₄H₄₀N₈O₄.
Molecular Weight: 504.6.

Chemical structure.

CAS number.

58-32-2.

2 Qualitative and Quantitative Composition

Each Persantin SR 200 mg sustained-release capsule contains dipyridamole 200 mg. The gelatin shell of the capsule consists of a red opaque cap and an orange opaque body.
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.

Mechanism of action.

Persantin SR 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 anti-aggregating effects of EDRF (endothelium derived relaxing factor).
Persantin SR is also a coronary vasodilator.

Clinical trials.

The second European Stroke Prevention Study (ESPS2) was conducted to investigate the effect of sustained release dipyridamole 200 mg (Persantin SR) 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 = 6,602) who had experienced a recent ischaemic stroke or TIA. There were 4 parallel treatment groups organised in a 2x2 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 Persantin SR (dipyridamole 200 mg) with aspirin 25 mg (Asasantin SR) 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) than treatment with either aspirin alone (risk reduction = 18%, p < 0.01) or dipyridamole alone (risk reduction = 16%, p < 0.01). 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.

5.2 Pharmacokinetic Properties

Absorption and plasma concentrations.

Plasma concentrations of dipyridamole from the Persantin SR formulation rise after a lag time of about 30 minutes. Peak plasma levels occur about 2-3 hours after administration, and then decline slowly. Plasma concentrations are quite variable in healthy volunteers and steady-state conditions are generally reached within 3 days. Peak concentrations at steady-state conditions with a daily dose of 400 mg are about 1.9 (1.2-3.4) microgram/mL. There is no cumulation with repetitive dosing. The decline in plasma concentration after oral administration fits a two compartment model. The alpha half-life (the initial decline following peak plasma concentration), which represents elimination of the majority of administered drug, has been reported to be about 30-60 minutes and the beta half-life (the terminal decline in plasma concentration) is approximately 10-12 hours. Total plasma clearance is about 12 L/hour. Dipyridamole may undergo enterohepatic recirculation.
The absolute bioavailability of Persantin SR is limited by first pass hepatic metabolism 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 and excretion.

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%.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

Persantin SR 200 mg sustained release capsules are indicated for the secondary prevention of ischaemic stroke and transient ischaemic attacks in conjunction with low dose aspirin. Persantin SR can be used alone if aspirin is not tolerated.

4.3 Contraindications

Hypersensitivity to dipyridamole or to any excipients in the product.

4.4 Special Warnings and Precautions for Use

Cardiovascular disorders.

Because Persantin SR is a potent vasodilator, it 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).

Stress testing with intravenous dipyridamole and other adenosinergic agents.

Patients treated with regular oral doses of Persantin 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.

Myasthenia gravis.

During treatment with Persantin SR readjustment of therapy may be necessary in patients with myasthenia gravis (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, and 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.

Use in the elderly.

No data available.

Paediatric use.

Persantin SR is not recommended for children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 A_2A-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.

Drugs affecting coagulation.

When dipyridamole is used in combination with any substances impacting coagulation such as anticoagulants and antiplatelets, the safety profile for these medicines must be observed. Addition of dipyridamole to aspirin does not increase the incidence of bleeding events. When dipyridamole was administered concomitantly with warfarin, bleeding was no greater in frequency or severity than that observed when warfarin was administered alone.
In the ESPS2 study, Persantin SR was studied in conjunction with aspirin 25 mg twice daily (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The use of Persantin SR with higher doses of aspirin has not been studied, however higher doses of aspirin in combination with dipyridamole have been used in other studies (e.g. ESPS1).

Antihypertensives.

Dipyridamole may increase the hypotensive effect of blood pressure lowering drugs.

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).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies on the effect on human fertility have been conducted with Persantin SR.
(Category B1)
There is inadequate evidence of safety in human pregnancy. Studies in animals have not shown evidence of an increased occurrence of foetal damage.
However, the usual precautions regarding the use of medication at this time, especially during the first trimester, should be observed.
Dipyridamole has been reported to distribute into breast milk. Caution should therefore be used when the drug is administered to nursing mothers.

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.

The following adverse reactions have been reported during use of Persantin SR in the clinical trials and in the post marketing experience.

Blood and lymphatic system disorders.

Thrombocytopenia.

Immune system disorders.

Hypersensitivity, angioedema.

Nervous system disorders.

Headache, dizziness.

Cardiac disorders.

Angina pectoris, tachycardia.

Vascular disorders.

Hypotension, hot flush.

Respiratory, thoracic and mediastinal disorders.

Bronchospasm.

Gastrointestinal disorders.

Diarrhoea, nausea, vomiting.

Skin and subcutaneous tissue disorders.

Rash, urticaria.

Musculoskeletal, connective tissue and bone disorders.

Myalgia.

Injury, poisoning and procedural complications.

Postprocedural haemorrhage, procedural haemorrhage.
Dipyridamole has been shown to be incorporated into gallstones (see Section 4.4 Special Warnings and Precautions for Use).
There have been isolated cases of gastroduodenal ulcer and anaemia reported in the clinical study.

Clinical trials data.

Table 1 shows adverse events reported in the pivotal clinical trial (ESPS2).

Adverse effects at therapeutic doses are usually mild and transient.

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 food.
The capsules should be swallowed whole without chewing.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.
However, patients should be advised that they may experience undesirable effects such as dizziness during treatment with Persantin SR. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience dizziness 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.

Symptoms such as feeling warm, flushes, sweating, tachycardia, restlessness, feeling of weakness, dizziness, drop in blood pressure and anginal complaints may occur.

Treatment.

General supportive measures. Since the vasodilating action of Persantin SR is counteracted by xanthine derivatives, slow i.v. administration of aminophylline (50-100 mg over 30 to 60 seconds) may be helpful. If 250 mg aminophylline does not relieve anginal complaints, sublingual nitroglycerin may be administered.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients in Persantin SR 200 mg sustained-release capsules are: tartaric acid, povidone, methacrylic acid copolymer, purified talc, acacia, hypromellose, hypromellose phthalate, triacetin, dimeticone 350, stearic acid, 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

Persantin SR capsules are packed in white polypropylene bottles with child-resistant closures filled with desiccant. Packs contain 10*, 20*, 30*, 50*, 60 or 100* capsules.
*Not 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.

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Consumer medicine information

Persantin SR 200 mg

Dipyridamole

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BRAND INFORMATION

Persantin SR 200 mg