Consumer medicine information

Persantin Ampoules

Dipyridamole

BRAND INFORMATION

Brand name

Persantin Ampoules

Active ingredient

Dipyridamole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Persantin Ampoules.

What is in this leaflet

This leaflet answers some common questions about Persantin Ampoule.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

Ask your doctor or pharmacist if you have any questions about your medicine or if you have any concerns about being treated with Persantin.

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. You may need to read it again later.

What Persantin Ampoule is used for

Persantin is a heart medicine. It is used as a tool in detecting potential problems on how the heart functions in times of stress. It is therefore useful in predicting the likelihood of the risks of heart disease.

Persantin increases blood flow to the heart by causing the blood-supplying arteries to widen.

Ask your doctor if you have any questions about why this medicine is being given to you. Your doctor may have prescribed it for another reason.

Before you are given Persantin Ampoule

When you should not be given it

You should not be given Persantin 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.

You should not be given this medicine in states of shock or collapse.

You should not be given this medicine if you have any serious heart conditions such as:

  • heart attack or failure
  • angina
  • abnormal changes in rhythm or rate of the heart beat (irregular, fast or slow)
  • heart valve problems
  • blockage of the lung artery
  • inflammation of the heart muscle (myocarditis), inner lining of the heart (endocarditis) or membrane enclosing the heart (pericarditis)
  • tear in the wall of the aorta (major artery in the body).

You should not be given this medicine if you are pregnant or are breast-feeding. It may affect your developing baby if you have it during pregnancy.

The active ingredient in Persantin passes into breast milk.

This medicine should not be given to a child. There is limited information about the use of Persantin Ampoule in children.

Persantin must not be used after the expiry date printed on the pack or ampoule or if the packaging is torn or shows signs of tampering.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given 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 or heart disease
  • asthma
  • high or low blood pressure
  • unexplained fainting or mini-stroke
  • severe muscle disease (myasthenia gravis).

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.

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

Taking other medicines

Tell your doctor 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 may interfere with each other.

In particular tell your doctor if you are taking:

  • aspirin
  • any medicine containing dipyridamole (e.g. Persantin® SR or Asasantin® SR capsules)
  • medicines used to thin your blood such as warfarin
  • medicines used to treat asthma, bronchitis and emphysema such as theophylline
  • medicines used to treat high blood pressure
  • neostigmine, distigmine and related medicines (used, for example, in the treatment of myasthenia gravis)
  • medicines used to treat rapid heart rhythm such as adenosine.

These medicines may be affected by Persantin 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 being given this medicine.

Avoid drinks such as tea, coffee and cola (which contain caffeine) for 24 hours before treatment with Persantin Ampoule. This is because the caffeine in these drinks can decrease the effects of the medicine.

How Persantin Ampoule is given

How it is given

Persantin Ampoule is given as an infusion (drip) into your veins, over several minutes.

How much is given

Your doctor will decide what dose you will receive, based on your body weight.

PERFUSION IMAGING:
The recommended dose is 0.14 mg/kg/min (0.56 mg/kg total) infused over 4 minutes.

STRESS ECHO TESTING:
The recommended dose is 0.56 mg/kg over a 4 minute period, followed by 4 minutes of no dose, and if echo monitoring shows no changes, by an additional 0.28 mg/kg over 2 minutes. The cumulative dosage is 0.84 mg/kg over 10 minutes. The protocol may also be given in 6 minutes.

If you have too much (overdose)

As Persantin Ampoule is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

Symptoms of an 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.

Tell your doctor or nurse immediately if you experience any signs of overdose, or, if you are not in hospital, go to the Emergency department at your nearest hospital. You may need urgent medical attention.

While you are being given Persantin Ampoule

Things you must do

Tell any other doctors, dentists, and pharmacists who treat you that you have been given this medicine.

Tell your doctor if you are pregnant or if you think you may be pregnant or are breast-feeding.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well while you are being given Persantin Ampoule.

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 lists of side effects. You may not experience any of them.

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

Some of the side effects of Persantin are related to the way the medicine works on the heart and circulation. Persantin causes widening of the arteries and if these widen too much there may be a fall in blood pressure which may cause problems with the blood circulation. These side effects include:

  • angina
  • heart attack
  • heart failure
  • stroke or mini-stroke
  • changes in heart beat (faster, slower or irregular).

The following side effects have also been reported with Persantin:

  • headache
  • vomiting, nausea, diarrhoea
  • muscle aches and pains
  • dizziness
  • stomach pain
  • tingling or numbness of the hands or feet
  • hot flushes
  • allergic reactions (such as rash, hives, difficulty in breathing, and swelling of the face, lips, mouth, etc)
  • fits/convulsions
  • sudden collapse.

Tell your doctor or nurse as soon as possible if you experience any side effects during or after treatment with Persantin Ampoule, so that these may be properly treated.

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

You should tell your doctor or nurse if you notice anything unusual, during or after treatment with Persantin Ampoule.

After being given Persantin Ampoule

Persantin Ampoules will be stored in the pharmacy or ward below 25°C. Each ampoule can only be used once and unused contents of opened ampoules must be discarded.

Product Description

What it looks like

Persantin Ampoule is a clear, yellow solution. It comes in a glass ampoule.

Ingredients

Each Persantin Ampoule contains 10mg of dipyridamole as the active ingredient in 2mL of solution. It also contains tartaric acid, macrogol 600, hydrochloric acid and water for injections.

Supplier

Persantin Ampoule 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 October 2019.

® Persantin is a registered trademark of Boehringer Ingelheim.

© Boehringer Ingelheim Pty Limited 2019.

Australian Registration Number

AUST R 17934

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Persantin Ampoules

Active ingredient

Dipyridamole

Schedule

S4

 

1 Name of Medicine

Dipyridamole 10 mg/2 mL.

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.
Approved Name: Dipyridamole.
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

Persantin Ampoules contain dipyridamole 10 mg in 2 mL and are intended for intravenous administration.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Persantin 10 mg/2 mL solution for injection is a clear, yellow solution practically free from suspended particles.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Dipyridamole is a coronary vasodilator. It produces vasodilation indirectly via two mechanisms, namely the inhibition of adenosine uptake which leads to an increase in the circulating adenosine, and the inhibition of cGMP-phosphodiesterase.
Vasodilation induced by intravenous Persantin leads to regional redistribution of coronary blood flow and may lead to abnormalities in the distribution of imaging agent and ventricular function in patients with coronary artery disease. The normal vessels dilate with enhanced flow, leaving relatively reduced pressure and flow across areas of haemodynamically important coronary stenoses.
Dipyridamole also has an antithrombotic action.

Clinical trials.

In a review of published literature dipyridamole perfusion imaging was examined in 32 studies. With the exception of one study, dipyridamole perfusion imaging was compared with coronary arteriography. A single study compared exercise and dipyridamole in patients undergoing thallium-201 myocardial imaging. A total of 2240 patients were assessed in these studies. Information on the total number of patients with coronary artery disease was not available. With the exception of one study where sensitivity was only 37%, sensitivity ranged from 67% to 100%. There was one study with a specificity of 28%, specificity in remaining studies ranged from 50% to 96%. Pooling these studies gave a combined sensitivity of 86% and specificity of 74%.
Dipyridamole stress echocardiography was compared with coronary arteriography in 28 studies. A total of 2137 patients were assessed with 1296 (61%) diagnosed as having coronary artery disease. Sensitivity of dipyridamole stress echocardiography ranged from 32% to 100% and specificity from 72% to 100%. The combined results from these studies gave a sensitivity of 73% and specificity of 91%.
The prognosis following dipyridamole stress testing was examined in 59 studies where patients had undergone dipyridamole perfusion imaging. All but 3 studies confirmed that an abnormal dipyridamole stress study was associated with more subsequent cardiac events than a normal study. Prognosis following dipyridamole stress echocardiography was examined in 21 studies. An abnormal test was predictive of more subsequent cardiac events than a normal study. Typically, with either technique in a group of patients with intermediate risk of coronary artery disease, an abnormal study suggested a cardiac event post-operatively in 20% and a normal study in only 2%.

5.2 Pharmacokinetic Properties

(Most pharmacokinetic data refer to healthy volunteers.)
Adequate curve fitting is achieved by a 3 compartment model.
(a) A rapid alpha phase, with a half-life of about 3 minutes, presumably reflecting distribution of the drug from the central compartment to peripheral compartments.
(b) A beta phase, with a half-life of about 40 minutes, which represents the elimination of most of the administered drug and, together with the alpha phase, accounts for about 70% of the total area under the plasma concentration time curve (AUC).
(c) A final, prolonged terminal elimination phase (gamma) with a half-life of about 15 hours. This represents about 30% of the total AUC and probably represents the rediffusion of a smaller proportion of the administered dose from remotely accessible tissues of low capacity back into the central compartment. This may also reflect some enterohepatic recycling (which is evident from smaller secondary peaks several hours after the end of the infusion at time points which are related to food intake).
At the end of a 4 minute infusion of 0.5 mg/kg, mean dipyridamole plasma concentration was 6.30 ± 0.32 microgram/mL, while at 1 hour afterwards the mean plasma concentration was 1.13 ± 0.36 microgram/mL.

Distribution.

On account of its high lipophilicity, log P 3.92 (n-octanol/0.1 N NaOH), dipyridamole distributes to many organs. In animals, dipyridamole is distributed preferentially to the liver, then to the lungs, kidneys, spleen and heart. Dipyridamole does not cross the blood-brain barrier.
The apparent volume of distribution of the central compartment (Vc) is about 5 L (similar to plasma volume). The apparent volume of distribution at steady state is about 100 to 140 L, reflecting distribution to various compartments. Total clearance is approximately 200 mL/min and mean residence time is about 7 hours.
Placental transfer of dipyridamole is very low. It is known to be excreted into breast milk.
Protein binding of dipyridamole is about 97 to 99%. It is primarily bound to alpha-1-acid glycoprotein and albumin.

Metabolism and excretion.

Dipyridamole is metabolised in the liver predominantly to form a monoglucuronide and only small amounts of diglucuronide, desalkyl dipyridamole and a hydroxy compound. After intravenous treatment, the amount of glucuronides is about 10%. 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 Ampoules are indicated as an alternative to exercise in myocardial imaging.

4.3 Contraindications

Hypersensitivity to any of the components of the product.
Acute myocardial infarction. Unstable angina. Uncontrolled cardiac arrhythmias causing symptoms or haemodynamic compromise. Symptomatic severe aortic stenosis. Uncontrolled symptomatic heart failure. Acute pulmonary embolus or pulmonary infarction. Acute myocarditis or pericarditis. Active endocarditis. Acute aortic dissection.
Patients already receiving treatment with regular oral dipyridamole should not receive additional intravenous Persantin.

4.4 Special Warnings and Precautions for Use

The potential clinical information to be gained through use of intravenous Persantin as an adjunct in myocardial imaging must be weighed against the risk to the patient. Comparable reactions to exercise-induced stress may occur, and therefore appropriate monitoring is indicated. Patients with a history of severe coronary heart disease may be at a greater risk.
Patients with asthma, baseline hypotension (systolic pressure < 90 mmHg), recent unexplained syncope or transient ischaemic attacks should not be treated with intravenous dipyridamole.
Caution should be taken in patients with left main coronary stenosis, moderate stenotic valvular heart disease, electrolytic abnormalities, severe arterial hypertension (systolic pressure > 200 mmHg and/or diastolic pressure > 110 mmHg), tachyarrhythmias or bradyarrhythmias, hypertrophic cardiomyopathy and other forms of outflow tract obstruction, or high-degree atrioventricular block.
Patients using dipyridamole, theophylline or caffeine chronically should not undergo testing for at least 24 hours after withdrawal of therapy because adenosine blood levels could be unpredictably high. If pharmacological stress testing with intravenous dipyridamole is considered necessary, drugs containing oral dipyridamole (e.g. Asasantin SR, Persantin) should be discontinued for twenty-four hours prior to the stress testing. Failure to do so may impair the sensitivity of the test.
In patients with myasthenia gravis, the possibility of an interaction between dipyridamole and cholinesterase inhibitors should be considered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Serious adverse reactions associated with the intravenous administration of Persantin for myocardial imaging have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
Most of the adverse effects of dipyridamole may be reversed with intravenous aminophylline, but it is not recommended that this be given routinely. If variant angina (elevated ST segments) is induced by dipyridamole, then it may be worsened by aminophylline and alternative vasodilators such as nitrates should be given.

Use in the elderly.

No data available.

Paediatric use.

Safety and efficacy in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Xanthine derivatives (e.g. caffeine and theophylline) can weaken the vasodilating effect of dipyridamole and should therefore be avoided 24 hours before myocardial imaging with intravenous Persantin.
Dipyridamole increases the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage should be considered.
Dipyridamole may increase the hypotensive effect of blood pressure lowering drugs and may counteract the anticholinesterase effect of cholinesterase inhibitors thereby potentially aggravating myasthenia gravis.
When dipyridamole is used in combination with anticoagulants or aspirin, the statements on intolerance and risks for these preparations 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies on the effect on human fertility have been conducted with intravenous Persantin.
(Category B1)
Drugs in this category have been taken by only a limited number of pregnant women and women of child-bearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the foetus having been observed. 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 https://www.tga.gov.au/reporting-problems.
When intravenous Persantin is used as an adjunct to myocardial perfusion imaging, the following adverse effects have been reported:

Immune system disorders.

Hypersensitivity, anaphylactoid reactions, angioedema.

Nervous system disorders.

Headache, dizziness, paraesthesia, transient ischaemic attacks, cerebrovascular accident, convulsion.

Cardiac disorders.

Chest pain/ angina pectoris, arrhythmia, tachycardia, myocardial infarction, bradycardia, cardiac arrest, ventricular fibrillation, syncope, sinus arrest, atrioventricular block.

Vascular disorders.

Hypotension, hot flush.

Respiratory, thoracic and mediastinal disorders.

Bronchospasm, laryngospasm.

Gastrointestinal disorders.

Nausea, abdominal pain, diarrhoea, vomiting.

Skin and subcutaneous tissue disorders.

Urticaria, rash.

Musculoskeletal, connective tissue and bone disorders.

Myalgia.

General disorders and administration site conditions.

Cardiac death, oedema.

Investigations.

Electrocardiogram ST-T change, electrocardiogram change.
There have also been rare reports of cerebral seizure/ grand mal seizure. For high doses of intravenous dipyridamole, as used in cardiac imaging, more frequent and severe adverse reactions have been reported than those reported during oral administration of dipyridamole at the recommended doses in therapeutic indications. Nevertheless, all available data suggest that the benefit/ risk ratio is at least as favourable as the benefit/ risk ratio of conventional exercise testing.
When intravenous Persantin was used as an adjunct to myocardial perfusion imaging in a study of 3911 patients, the adverse events occurring at a frequency of 1% or greater in patients are shown in Table 1.
Safety data were obtained from a review of 7 published studies (n = 89,482) and serious adverse events are reported in Table 2.

Monitoring of patients.

When myocardial imaging is performed with intravenous Persantin, parenteral aminophylline should be readily available for relieving adverse effects such as bronchospasm or chest pain. Vital signs should be monitored during and for 10-15 minutes following the intravenous infusion of Persantin and an electrocardiographic tracing should be obtained using at least one chest lead. Should severe chest pain or bronchospasm occur, aminophylline may be administered by slow intravenous injection (50-100 mg over 30 to 60 seconds) in doses ranging from 50 to 250 mg. Nitroglycerin (sublingual or intravenous) may be administered if aminophylline fails to completely eliminate ischaemia. If chest pain continues despite use of aminophylline and nitroglycerin, the possibility of myocardial infarction should be considered.
In the case of severe hypotension, the patient should be placed in a supine position with the head tilted down if necessary, before administration of parenteral aminophylline.
If 250 mg aminophylline does not relieve chest pain symptoms within a few minutes, sublingual nitroglycerin may be administered.
If the clinical condition of a patient with an adverse effect permits a one minute delay in the administration of parenteral aminophylline, the imaging agent may be injected and allowed to circulate for one minute before the injection of aminophylline. This will allow initial perfusion imaging to be performed before reversal of the pharmacological effects of intravenous Persantin on the coronary circulation.

4.2 Dose and Method of Administration

Perfusion imaging.

The dose of intravenous Persantin as an adjunct to myocardial perfusion imaging should be adjusted according to the weight of the patient. The recommended dose is 0.14 mg/kg/min (0.56 mg/kg total) infused over 4 minutes. Although the maximum tolerated dose has not been determined, clinical experience suggests that a total dose beyond 60 mg is not needed for any patient.

Stress echo.

The recommended protocol for intravenous dosing is 0.56 mg/kg over a 4 minute period, followed by four minutes of no dose and, if echo monitoring performed and analysed in real time shows no changes, by an additional 0.28 mg/kg over 2 minutes, yielding a cumulative dosage of 0.84 mg/kg over 10 minutes. This 'high dose' protocol may also be given in 6 minutes. Most experience has been gained using a total dose of 0.84 mg/kg over 10 minutes or 6 minutes, therefore it is not recommended to exceed this dose for diagnostic testing.
Prior to intravenous administration, Persantin should be diluted in at least a 1:2 ratio with sodium chloride 0.45% or 0.9% or glucose 5% to a total volume of approximately 20 to 50 mL. Infusion of undiluted Persantin may cause local irritation. The imaging agent should be injected within 5 minutes following administration of intravenous Persantin.
Persantin for intravenous administration should not be mixed with other drugs in the same syringe or infusion container.

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 intravenous Persantin. 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.

No cases of overdosage in humans have been reported in this indication. It is unlikely that overdosage will occur because of the nature of use (i.e. single intravenous administration in controlled settings).
Signs and symptoms as described, see Section 4.8 Adverse Effects (Undesirable Effects) would be expected to occur. These could be severe in certain individuals.

Treatment.

Symptomatic therapy is recommended.
Should severe chest pain or bronchospasm occur, parenteral aminophylline may be administered by slow intravenous injection (50-100 mg over 30 to 60 seconds) in doses ranging from 50 to 250 mg. Nitroglycerin (sublingual or intravenous) may be administered if aminophylline fails to completely eliminate ischaemia.
Due to its wide distribution to tissues and its predominantly hepatic elimination, dipyridamole is not likely to be accessible to enhanced removal procedures.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients are: tartaric acid, macrogol 600, hydrochloric acid (to adjust pH) and water for injections.

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.

6.5 Nature and Contents of Container

Persantin Ampoules 10 mg/2 mL are supplied in glass ampoules.
Boxes of 5 ampoules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes