Consumer medicine information

Pletal Tablets

Cilostazol

BRAND INFORMATION

Brand name

Pletal Tablets

Active ingredient

Cilostazol

Schedule

What is in this leaflet

Please read this leaflet carefully before you start using PLETAL.

This leaflet answers some common questions about PLETAL.

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 PLETAL against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine.

You may need to read it again.

What PLETAL is used for

PLETAL is used to treat intermittent claudication. Blockage of the blood vessels to the legs, causes a distinctive type of pain called intermittent claudication. In this condition, which usually affects the calves, you experience muscle pain or cramping whenever you walk some distance, but the pain disappears when you rest. The pain occurs because the calf muscles are not receiving enough oxygen.

PLETAL is only recommended for patients whose symptoms have not improved sufficiently after making life-style modifications (such as stopping smoking and increasing exercise) and after other appropriate interventions. It is important that you continue the modifications you have made to your life-style whilst taking cilostazol.

PLETAL belongs to a group of medicines called phosphodiesterase inhibitors.

This medicine works by preventing blood clots and widening blood vessels.

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.

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

There is not enough information to recommend the use of this medicine for children under the age of 18 years.

Before you take PLETAL

When you must not take it

Do not take PLETAL if you have an allergy to:

any medicine containing cilostazol
any of the ingredients listed at the end of this leaflet
any other similar medicines (such as medicines of the same class).

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

Do not breast-feed if you are taking this medicine.

The active ingredient in PLETAL passes into breast milk and there is a possibility that your baby may be affected.

Do not take this medicine if you have any of the following conditions:

heart failure
unusual heart beat
bleeding tendency
moderate, or severe liver problems
severe kidney problems

Do not take this medicine if you are taking two or more medicines used to prevent blood clots such as warfarin, heparin, aspirin, clopidogrel, dabigatran, rivaroxaban, or apixaban.

Do not take this medicine if you are taking medicines used to:

treat high blood pressure such as diltiazem
treat peptic ulcer such as cimetidine, lansoprazole, or omeprazole
treat infections such as erythromycin, ketoconazole,
treat HIV such as lopinavir, ritonavir, tripranovir or indinavir

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:

stomach ulcer
diabetes
high blood pressure
damage to the brain in the past 6 months
surgery in the past 3 months
persistent chest pain at rest
heart attack or heart surgery in the last six months

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

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 PLETAL may interfere with each other.

These include:

medicines used to treat infection such as erythromycin or ketoconazole
medicines used to treat high cholesterol levels such as simvastatin or atorvastain

These medicines may be affected by PLETAL 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 PLETAL

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 usual dose is 100 mg taken two times each day.

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, PLETAL may not work as well and your problem may not improve.

How to take it

Swallow the tablets whole with a full glass of water.

When to take it

Pletal tablets should be taken 30 minutes before or two hours after breakfast and the evening meal.

Take your medicine at about the same time each day.

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

Your doctor will assess your progress after 3 months of treatment and may recommend that you discontinue cilostazol if the effect of treatment is insufficient.

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 it is less than 6 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for 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 Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much PLETAL. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Symptoms of an overdose may include:

diarrhoea
severe headache
unusual heartbeat

While you are using PLETAL

Things you must do

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

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.

It may affect other medicines used during surgery.

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

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

It may interfere with the results of some tests.

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

Your doctor may do some tests (blood test, clotting test, echocardiogram of the heart) from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take PLETAL 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.

If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects from other medicines you are taking. If possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Things to be careful of

Be careful driving or operating machinery until you know how PLETAL affects you.

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

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Side effects

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

This medicine helps most people with intermittent claudication, 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 lists 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:

unusual heart beat
headache or dizziness
diarrhoea or constipation
dyspepsia, nausea or vomiting
increased thirst and/or hunger
increased urination
inability to sleep
abnormal dreams
anxiety
rash
muscle pain
swelling of the feet, hands or face

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:

persistent bleeding (e.g. nose bleeds)
easy bruising
black or abnormal stools

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

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

frequent infections, sore throat, severe chills or fever
bleeding excessively
tiredness, looking pale with headaches or dizziness
unusual heart beat
chest pain or discomfort

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

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.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

After using PLETAL

Storage

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25C.

Do not store PLETAL 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

50 mg tablet (not currently marketed)

White, round, flat faced tablets debossed with "OG31" on one side.

100 mg tablet

White, round, flat faced tablets debossed with "OG30" on one side.

Pletal tablets are available in blister packs of 56 tablets.

Ingredients

PLETAL contains cilostazol as the active ingredient.

It also contains:

starch - maize
microcrystalline cellulose
carmellose calcium
hypromellose
magnesium stearate

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Distributor

PLETAL is distributed in Australia by:

Otsuka Australia Pharmaceutical Pty Ltd
Suite 2.03, Level 2
9 Help Street
Chatswood NSW 2067

® = Registered Trademark

This leaflet was revised in December 2017

50 mg tablet AUST R 140598
100 mg tablet AUST R 140599

BRAND INFORMATION

Brand name

Pletal Tablets

Active ingredient

Cilostazol

Schedule

Name of the medicine

Cilostazol.

Excipients.

Maize starch, microcrystalline cellulose, carmellose calcium, hypromellose and magnesium stearate.

Description

Chemical name: 6-[4-(1-cyclohexyl-1H- tetrazol-5-yl)butoxy]- 3,4-dihydro-2(1H)- quinolinone. Molecular formula: C₂₀H₂₇N₅O₂. MW: 369.47. CAS: 73963-72-1. Cilostazol is slightly soluble in methanol and ethanol and practically insoluble in water, 0.1N HCl, and 0.1N NaOH.
Pletal (cilostazol) is a quinolinone derivative which inhibits cellular phosphodiesterase (more specific for phosphodiesterase 3).

Pharmacology

Pharmacodynamics.

Pharmacotherapeutic group.

Antithrombotic agents, platelet aggregation inhibitor.
Animal studies have shown Pletal to have vasodilator effects and this has been demonstrated in small studies in man where ankle blood flow was measured by strain gauge plethysmography. Pletal also inhibits smooth muscle cell proliferation in rat and human smooth muscle cells in vitro, and inhibits the release of platelet derived growth factor and PF-4 from human platelets.
Studies in animals (in vivo and ex vivo) have shown that Pletal causes inhibition of platelet aggregation. The inhibition is effective against a range of aggregants (including shear stress, arachidonic acid, collagen, ADP and adrenaline); in man the inhibition lasts for up to 12 hours, and on cessation of administration of Pletal recovery of aggregation occurs within 48-96 hours, without rebound hyperaggregability.

Pharmacokinetics.

Absorption.

Following multiple doses of Pletal 100 mg twice daily in patients with peripheral vascular disease, steady state is achieved within 4 days. The C_max of Pletal and its two active metabolites increase less than proportionally with increasing doses. However, the AUC for Pletal and its metabolites increase approximately proportionately with dose.
Compared to the fasted state, the mean C_max of Pletal is 16% higher when dosed 30 minutes prior to a meal and 93% higher when dosed 2 hours after a meal. AUC_0-t is similar to the fasted state when taken 30 minutes prior to a meal but administration 2 hours after a meal increases AUC_0-t 22%. AUC_0-∞ is increased 5-7% when the dosing occurs 30 minutes prior to or 2 hours after a meal, compared to the fasting state.
Dosing within 10 minutes of a meal increases C_max, AUC_0-t, AUC_0-∞ by 86%, 21% and 19% respectively compared to the fasting state.
The absolute bioavailability of Pletal is not known.

Distribution.

Pletal is 95-98% protein bound, predominantly to albumin. The dehydro metabolite and 4'-trans-hydroxy metabolite are 97.4% and 66% protein bound respectively.

Metabolism.

Pletal is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. The primary isoenzymes involved in its metabolism are cytochrome P-450 CYP3A4, to a lesser extent, CYP2C19 and CYP2D6, and to an even lesser extent CYP1A2. There are two major metabolites, a dehydro-cilostazol and a 4'-trans-hydroxy cilostazol, both of which have similar apparent half-lives. The dehydro metabolite is about 4 times as active a platelet antiaggregant as the parent compound and the 4'-trans-hydroxy metabolite is 0.3-0.4 times as active.
There is no evidence that Pletal induces hepatic microsomal enzymes following repeated oral administration to rats.

Elimination.

The apparent elimination half-life of Pletal is 10.5 hours.
The primary route of elimination is urinary (74%) with the remainder excreted in the faeces. No measurable amount of unchanged Pletal is excreted in the urine, and less than 2% of the dose is excreted as the dehydro-cilostazol metabolite. Approximately 30% of the dose is excreted in the urine as the 4'-trans-hydroxy metabolite. The remainder is excreted as metabolites, none of which exceed 5% of the total excreted.

Elderly.

The pharmacokinetics of Pletal and its metabolites were not significantly affected by age or gender in healthy subjects aged between 50-80 years.

Renal insufficiency.

In subjects with severe renal impairment, the free fraction of Pletal was 27% higher and both C_max and AUC were 29% and 39% lower respectively than in subjects with normal renal function. The C_max and AUC of the dehydro metabolite were 41% and 47% lower respectively in the severely renally impaired subjects compared to subjects with normal renal function. The C_max and AUC of 4'-trans-hydroxy cilostazol were 173% and 209% greater in subjects with severe renal impairment.

Hepatic insufficiency.

There are no data in patients with moderate to severe hepatic impairment although Pletal is extensively metabolised by hepatic enzymes.

Clinical Trials

Peripheral artery occlusive disease is commonly divided in the Fontaine stages or Rutherford categories. The Fontaine system consists of 4 stages: stage I identifies those patients who are asymptomatic, stages IIa and IIb represent those patients with mild and moderate to severe intermittent claudication. Patients with ischemic rest pain are categorized as stage III, and stage IV represents patients with disease that has advanced to ulcerations and gangrene. In the Rutherford system, there are 4 grades (0-III) that are further divided into 6 categories according to the severity of symptoms. In the Rutherford system, grade 0 represents patients with asymptomatic disease characterized by a normal treadmill test. Grade I includes individuals with intermittent claudication, subcategorized according to severity from mild to moderate to severe. Grade II/category 4 identifies patients experiencing ischemic rest pain. Grade III/categories 5 and 6 represent patients with either limited or extended ischemic lesions. See Table 1.
Nine efficacy (8 phase III and 1 phase IV) and 1 safety (phase IV long-term) double blind, parallel group trials were conducted. In the 9 efficacy trials a total of 3,482 patients were randomised. All trials were multicentre, double blind, placebo controlled, parallel group trials and contained treatment groups of Pletal 100 mg bid and placebo. Patients recruited in these trials suffered from moderate to severe IC Fontaine Stage II (feeling pain when walking and with limited walking distance).
The patients enrolled in the efficacy trials were ≥ 40 years of age with symptomatic lower extremity PAD of ≥ 6 months in duration, and with no significant change in symptoms severity for a minimum of 3 months before enrolment. Claudication was defined uniformly in all trials as cramping, aching, fatigue, or any patient reported pain in 1 or both legs that occurred during walking and was sufficient to cause the subject to reduce the pace or cease ambulation. The definition of PAD required Doppler measurement of an ABI ≤ 0.90 (8 trials) or ≤ 0.80 (1 trial). A decrease in postexercise systolic ankle pressure of ≥ 10 mmHg was additional confirmatory evidence of PAD; patients lacking ABI criteria but who had a decrease of 20 mmHg were eligible for enrolment. Patients were not included if they had any of the following: Buerger's disease, pain at rest attributable to ischemia, ulceration, and gangrene, ischemic tissue necrosis, surgical or endovascular procedures within the past 3 months, unstable coronary artery disease or a coronary intervention within the past 6 months, deep vein thrombosis within the past 3 months, symptomatic cardiac arrhythmias or conditions other than claudication that limited exercise capacity. See Table 2.
From data generated in these nine placebo controlled studies (where 1,135 efficacy patients excluding 50 mg and 150 mg b.i.d. groups were exposed to Pletal), it has been demonstrated that Pletal improves exercise capacity as judged by changes in absolute claudication distance (ACD, or maximal walking distance) and initial claudication distance (ICD, or pain free walking distance) upon treadmill testing. Following 24 weeks treatment, Pletal 100 mg b.i.d. increases in ACD ranged from 60.4-129 metres, whilst mean ICD increases ranged from 47.3-93.6 metres.
A meta-analysis based on weighted mean differences across the nine studies indicated that there was a significant absolute overall postbaseline improvement of 42 m in maximal walking distance (ACD) for Pletal 100 mg b.i.d. over the improvement seen under placebo. This effect appeared lower in diabetics than in nondiabetics. See Tables 3, 4 and 5.
The Walking Impairment Questionnaire, which was administered in 7 of the nine clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of seven trials, patients treated with either Pletal 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers.
Effects on circulating plasma lipids have been examined in patients taking Pletal. After 12 weeks, as compared to placebo, Pletal 100 mg b.i.d. produced a reduction in triglycerides of 0.33 mmol/L (15%) and an increase in HDL cholesterol of 0.10 mmol/L (10%). A randomized, double blind, placebo controlled phase IV study (CASTLE) was conducted to assess the long-term effects of Pletal, with focus on mortality and safety. In total, 1,439 patients with intermittent claudication and no heart failure have been treated with Pletal or placebo for up to three years. See Table 6.
In the CASTLE study with a total of 1435 subjects the incidence of bleeding adverse events was similar in cilostazol and placebo groups. 717 subjects were treated with cilostazol. 368 of these subjects (51.3%) received concomitant aspirin, 37 subjects (5.2%) received concomitant clopidogrel and 158 (22.0%) were treated concomitantly both with aspirin and clopidogrel. Doses of aspirin in the CASTLE study ranged from 80-650 mg/day with more than 50% of patients in the study taking doses of 325 mg/day or higher. Treatment emergent bleeding events for patients taking concomitant clopidogrel and/or aspirin in the CASTLE study are summarised in Table 7.
With respect to mortality during CASTLE, the observed 36 month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8 to 8.4%) on Pletal and 6.8% (95% CI of 1.9 to 11.5%) on placebo. Long-term treatment with Pletal did not raise safety concerns.
Pletal has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischaemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalisation have not been evaluated. Similarly, there are no data on whether treatment with cilostazol results in a reduction in the number or frequency of adverse cardiovascular events.

Indications

Pletal is indicated for the symptomatic improvement of intermittent claudication as indicated by increased maximal and pain free walking distances in patients who do not have rest pain and who do not have evidence of peripheral tissue necrosis.
Pletal is for second line use, in patients for whom lifestyle modifications (including stopping smoking and supervised exercise programs) and other appropriate interventions have failed to sufficiently improve their intermittent claudication symptoms.

Contraindications

Known hypersensitivity to Pletal or to any of the excipients.
Severe renal impairment: creatinine clearance of ≤ 25 mL/min.
Moderate or severe hepatic impairment.
Congestive heart failure of any grade or severity.
Pregnancy and lactation.
Patients taking inhibitors of CYP3A4 or of CYP2C19 (e.g. cimetidine, diltiazem, erythromycin, ketoconazole, lansoprazole, omeprazole and inhibitors of HIV-1 proteases).
Patients with a known predisposition to bleeding (e.g. active peptic ulceration, recent (within six months) haemorrhagic stroke, surgery within the previous three months, proliferative diabetic retinopathy, poorly controlled hypertension) or any active or uncontrolled bleeding.
Patients with a history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopic beats, whether or not adequately treated.
Patients with prolongation of the QTc interval.
Patients with a history of severe tachyarrhythmia.
Patients treated concomitantly with two or more additional antiplatelet or anticoagulant agents (e.g. acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban or apixaban).
Patients with unstable angina pectoris, myocardial infarction within the last 6 months, or a coronary intervention in the last 6 months.

Precautions

The suitability of treatment with cilostazol should be carefully considered alongside other treatment options such as revascularisation.

Cardiovascular.

Events of left ventricular outflow tract obstruction have been reported in patients with sigmoid shaped interventricular septum. Pletal should be used with caution in patients at risk, especially in elderly patients. Additional tests or an echocardiogram can be performed if the patient develops a de novo cardiac murmur after starting cilostazol.
Based on its mechanism of action, cilostazol may induce tachycardia, palpitation, tachyarrhythmia and/or hypotension. The increase in heart rate associated with cilostazol is approximately 5 to 7 bpm; in patients at risk this consequently may induce angina pectoris.
Patients who may be at increased risk for serious cardiac adverse events as a result of increased heart rate, e.g. patients with stable coronary disease, should be closely monitored during treatment with cilostazol, while the use of cilostazol in patients with unstable angina pectoris, or myocardial infarction/ coronary intervention within the last 6 months, or a history of severe tachyarrhythmia is contraindicated.
Caution should be exercised when prescribing Pletal for patients with atrial or ventricular ectopy and patients with atrial fibrillation or flutter.
Caution is needed when coadministering Pletal with any other agent which has the potential to reduce blood pressure due to the possibility that there may be an additive hypotensive effect with a reflex tachycardia.

Hematologic.

There have been rare or very rare reports of haematological abnormalities including thrombocytopenia, leucopenia, agranulocytosis, pancytopenia and aplastic anaemia and patients should be closely monitored. Most patients recovered on discontinuation of Pletal however, some cases of pancytopenia and aplastic anaemia were fatal. Pletal therapy should be stopped promptly upon the emergence of haematological abnormalities.
In addition to reporting episodes of bleeding and easy bruising, patients should be warned to promptly report any other signs which might also suggest the early development of blood dyscrasia such as pyrexia and sore throat. A full blood count should be performed if infection is suspected or there is any other clinical evidence of blood dyscrasia. Pletal should be discontinued promptly if there is clinical or laboratory evidence of haematological abnormalities.

Use in patients at risk of bleeding or with other antiplatelet agents.

Patients treated with Pletal have an increased risk of bleeding which may be potentiated by coadministration with other agents with antiplatelet or anticoagulant properties. The patient should be warned to report any episode of bleeding or easy bruising whilst on therapy.
Due to Pletal's platelet aggregation inhibitory effect it is possible that an increased bleeding risk occurs in combination with surgery (including noninvasive measures such as tooth extraction). If a patient is to undergo elective surgery and antiplatelet effect is not necessary, Pletal should be stopped 5 days prior to surgery.
In case of retinal bleeding administration of Pletal should be stopped.
Pletal is relatively highly protein bound and thus there is a theoretical potential that antiplatelet activity could be enhanced as a result of displacement by other highly protein bound drugs.

Cardiovascular toxicity.

Repeat dose studies showed cardiovascular lesions in dogs at doses providing exposures below the clinical exposure based on AUC. Cardiovascular toxicity was manifested as haemorrhage and fibrosis of the myocardium and endocardium, arteritis and periarteritis, thickening of the coronary artery, smooth muscle degeneration in the tunica media and/or externa in dogs. The cardiovascular lesions were dose related in dogs.

Effects on fertility.

There were no apparent effects of Pletal on the fertility of male or female rats at oral doses of up to 1000 mg/kg/day (equivalent to 1-5 times the clinical exposure based on AUC).

Use in pregnancy.

(Category B3)
There is no experience of the use of Pletal in human pregnancy. Pletal should not be used by pregnant women.
Studies in animals have shown reproductive toxicity. In rats dosed during pregnancy, an increase in foetuses with external, visceral and skeletal abnormalities (retarded ossification, wavy or extra ribs, ventricular septal defects, unilateral anophthalmia and dilated renal pelvis) were noted at doses > 150 mg/kg/day (equivalent to 5 times the clinical exposure based on AUC). Exposure in late pregnancy resulted in an increased incidence of stillbirths and lower offspring weights at the same doses. An increased incidence of retardation of ossification of the sternum was observed in rabbits at doses greater than 150 mg/kg/day (equivalent to 5 times the recommended daily dose based on AUC).

Use in lactation.

It is not known whether Pletal is excreted into human milk. The transfer of Pletal to breast milk has been reported in animal studies. Therefore Pletal should not be used by breastfeeding mothers.

Use in the elderly.

The pharmacokinetics of Pletal and its metabolites were not significantly affected by age or gender in healthy subjects aged between 50-80 years.

Genotoxicity.

Pletal was not genotoxic in a battery of in vitro (bacterial reverse mutation in Salmonella typhimurium and Escherichia coli and forward mutation in mouse lymphoma cells) and in vivo (mouse micronucleus) assays. Increased chromosome aberrations occurred in an in vitro assay in Chinese hamster ovary cells, dependent on the incubation conditions. The weight of evidence from the assays suggests that Pletal presents no significant genotoxic potential at the proposed clinical dose.

Carcinogenicity.

Two year carcinogenicity studies have been conducted by the oral (dietary) route of administration in rats at doses up to 500 mg/kg/day, and in mice at doses up to 1000 mg/kg/day. Increased incidences of hepatocellular adenoma in female mice at 1000 mg/kg/day (0.7 times the clinical exposure based on AUC), and adrenal medullary adenoma in male rats at 500 mg/kg/day were documented (0.5 times the clinical exposure based on AUC). These tumours commonly occur in these animal species. The relevance to humans is unknown.

Effects on laboratory tests.

There are no data with regard to effects on laboratory tests.

Effects on ability to drive and use machines.

Pletal may cause dizziness and patients should be warned to exercise caution before they drive or operate machinery.

Interactions

Inhibitors of platelet aggregation.

Pletal is a PDE III inhibitor with antiplatelet activity. In a clinical study in healthy subjects, Pletal 150 mg b.i.d. for five days did not result in prolongation of bleeding time.

Aspirin.

Short-term (≤ 4 days) coadministration of aspirin with Pletal suggested a 23-25% increase in inhibition of ADP induced ex vivo platelet aggregation when compared to aspirin alone. There was no additive or synergistic effect on arachidonic acid induced platelet aggregation when compared to aspirin alone.
There were no apparent trends toward a greater incidence of haemorrhagic adverse effects in patients taking Pletal and aspirin compared to patients taking placebo and equivalent doses of aspirin. Nonetheless, patients taking Pletal in combination with aspirin should be monitored for bleeding events.

Clopidogrel and other antiplatelet drugs.

Concomitant administration of Pletal 150 mg b.i.d. and clopidogrel 75 mg daily for five days did not have a notable effect on the pharmacokinetics of Pletal, with an increase in AUC of only 9%. However, the AUC of the dehydro metabolite, which has about 4 times the potency of cilostazol in inhibiting platelet aggregation, increased by 24%. Concomitant administration of Pletal and clopidogrel did not have an appreciable effect on platelet count, prothrombin time (PT) or activated partial thromboplastin time (aPTT). All healthy subjects in the study had a prolongation of bleeding time on clopidogrel alone and concomitant administration with Pletal did not result in a significant additional effect on bleeding time. Caution is advised when coadministering Pletal with any drug that inhibits platelet aggregation. Consideration should be given to monitoring the bleeding time at intervals during coadministration. Pletal treatment is contraindicated in patients receiving two or more additional antiplatelet/ anticoagulant agents. A higher rate of haemorrhage was observed with the concomitant use of clopidogrel, aspirin and cilostazol in the CASTLE trial.
Cilostazol has not been evaluated in circumstances where clopidogrel coadministration and a high bleeding risk coexist, such as at the time of coronary stent insertion.

Anticoagulants.

In a single dose clinical study, no inhibition of the metabolism of warfarin or an effect on the coagulation parameters (PT, aPTT, bleeding time) was observed. However, caution is advised in patients receiving both Pletal and any anticoagulant agent, and frequent monitoring is required to reduce the possibility of bleeding. Pletal treatment is contraindicated in patients receiving two or more additional antiplatelet/ anticoagulant agents.

Nitrates and PDE-5 inhibitors.

Drug interactions between Pletal and nitrates or Pletal and PDE-5 inhibitors used for erectile dysfunction (such as sildenafil, vardenafil or taldenafil) have not been specifically studied. Ten to fifteen percent of patients were on concomitant Pletal and nitrates in the clinical studies but no targeted safety analysis is available. Therefore, caution should be exercised during coadministration of Pletal with nitrates or PDE-5 inhibitors.

Cytochrome P450 (CYP) enzyme inhibitors and substrates.

Pletal is contraindicated in patients taking inhibitors of CYP3A4 or CYP2C19 and examples of the many drugs which are known to inhibit either of these isoenzymes are given in Contraindications. It is recommended that caution be exercised during coadministration with substrates of CYP3A4 or CYP2C19 (e.g. cisapride, midazolam, nifedipine and verapamil) as this may result in increased plasma levels of these drugs.
Pletal is extensively metabolised by CYP enzymes, particularly CYP3A4 and to a lesser extent CYP2C19 and CYP2D6 although other enzymes are also involved. Some of the metabolites, particularly the dehydro metabolite, possess cilostazol-like activity. The effects of coadministration with CYP enzyme inhibitors are complex and Pletal is contraindicated in patients taking inhibitors of CYP3A4 or CYP2C19.
Pletal was shown to inhibit CYP3A4, CYP2C19 and CYP2C9 in vitro, but only at concentrations more than twice the plasma C_max at the recommended clinical dose.

Inhibitors and substrates of CYP3A4.

Coadministration of single doses of ketoconazole (strong inhibitor of CYP3A4 and inhibitor of 2C19) 400 mg and Pletal 100 mg resulted in a > 2-fold increase in AUC of Pletal and increased systemic exposure to 4'-trans-hydroxy metabolite.
In healthy subjects dosed with Pletal 100 mg b.i.d., mean AUC Pletal increased by 44% on coadministration with diltiazem (CYP3A4 inhibitor) at 180 mg once daily. Coadministration did not affect exposure to the dehydro metabolite but there were increases in AUC of the 4'-trans-hydroxy metabolite. In patients in clinical trials, concomitant use with diltiazem was shown to increase the AUC of Pletal by 53%.
Administration of a single dose of 100 mg Pletal with 240 mL grapefruit juice (CYP3A4 inhibitor) did not have a notable effect on the pharmacokinetics of Pletal.
An interaction study with warfarin did not demonstrate significant effects on the pharmacokinetics of R-warfarin (CYP3A4 substrate) or S-warfarin (CYP2C9 substrate). However, the AUCs for lovastatin (CYP3A4 substrate) and its β-hydroxy acid were increased by more than 70% when given with Pletal. Caution is advised in cases of coadministration with statins metabolised by CYP3A4, for example simvastatin, atorvastatin and lovastatin.
Administration of 100 mg Pletal on the seventh day of erythromycin (moderate inhibitor of CYP3A4) 500 mg t.i.d. resulted in an increase in AUC Pletal by 74%, accompanied by a 24% decrease in AUC of the dehydro metabolite but with notable increases in AUC of the 4'-trans-hydroxy metabolite.

Inhibitors of CYP2C19.

Administration of a single dose of 100 mg Pletal on day 7 of dosing with omeprazole 40 mg once daily increased C_max and AUC Pletal by 18% and 26%, respectively. C_max and AUC of the dehydro metabolite increased by 29% and 69% while exposure to the 4'-trans-hydroxy metabolite decreased by 31%.

Inhibitors of CYP2D6.

Concomitant administration of quinidine with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.

Adverse Effects

Clinical trials.

The most commonly reported adverse reactions in clinical trials were headache (in > 30%), diarrhoea and abnormal stools (in > 15% each). These reactions were usually of mild to moderate intensity and were sometimes alleviated by reducing the dose.
Adverse reactions reported as being at least possibly drug related and occurring more commonly with Pletal 100 mg b.i.d. than in the placebo groups in clinical trials are listed below.
The frequencies correspond with the following. Very common: (≥ 1/10). Common: (≥ 1/100 to < 1/10). Uncommon: (≥ 1/1,000 to < 1/100). Rare: (≥ 1/10,000 to < 1/1000). Very rare: (< 1/10,000).

Blood and the lymphatic system disorders.

Common: ecchymosis. Uncommon: anaemia. Rare: bleeding time increased, thrombocythemia.

Haemorrhagic disorders.

Uncommon: haemorrhages (eye, nose, gastrointestinal, cardiovascular).

Endocrine disorders.

Uncommon: diabetes mellitus.

Metabolism and nutrition disorders.

Common: oedema (peripheral, face). Uncommon: hyperglycaemia.

Nervous system disorders.

Common: dizziness. Uncommon: insomnia, anxiety, abnormal dreams.

Cardiac disorders.

Common: palpitation, tachycardia, angina pectoris, arrhythmia, ventricular extrasystoles. Uncommon: myocardial infarction, atrial fibrillation, congestive heart failure, supraventricular tachycardia, ventricular tachycardia, syncope, postural hypotension.

Respiratory, thoracic and mediastinal disorders.

Common: rhinitis, pharyngitis. Uncommon: dyspnoea, pneumonia, cough.

Gastrointestinal disorders.

Very common: diarrhoea, abnormal stools. Common: nausea and vomiting, dyspepsia, flatulence. Uncommon: gastritis.

Skin and subcutaneous tissue disorders.

Common: rash, pruritus.

Musculoskeletal, connective tissue and bone disorders.

Uncommon: myalgia.

Renal and urinary disorders.

Rare: kidney failure, kidney function abnormal.

General disorders and administration site conditions.

Very common: headache. Common: chest pain, abdominal pain, asthenia. Uncommon: chills, allergic reaction.
An increase in the incidence of palpitation and peripheral oedema was observed when Pletal was combined with other vasodilators that cause reflex tachycardia e.g. dihydropyridine calcium channel blockers.
The only adverse event resulting in discontinuation of therapy in ≥ 3% of patients treated with Pletal was headache. Other frequent causes of discontinuation included palpitation and diarrhoea (both 1.1%).
Pletal per se may carry an increased risk of bleeding and this risk may be potentiated by coadministration with any other agent with such potential.
The risk of intraocular bleeding may be higher in patients with diabetes.
An increase in the frequency of diarrhoea and palpitation has been found in patients older than 70 years.

Postmarketing experience.

Additional reactions not reported during clinical trials but reported rarely or very rarely in the postmarketing period are listed below.

Infections and infestations.

Interstitial pneumonia.

Blood and the lymphatic system disorders.

Bleeding tendency, thrombocytopenia, granulocytopenia, agranulocytosis, leucopenia, pancytopenia, aplastic anaemia.

Cardiac disorders.

Torsades de pointes, QTc prolongation occurred in patients with cardiac disorders, e.g. complete atrioventricular block, cardiac failure and bradyarrythmia when treated with Pletal (Pletal was used "off label" due to its positive chronotropic action).

Haemorrhagic disorders.

Haemorrhages (cerebral, respiratory tract, pulmonary, muscle).

Metabolism and nutrition disorders.

Anorexia.

Nervous system disorders.

Paresis, hypaesthesia.

Eye disorders.

Conjunctivitis.

Ear and labyrinth disorders.

Tinnitus.

Vascular disorders.

Hot flushes, hypertension, hypotension.

Hepatobiliary disorders.

Hepatitis, hepatic function abnormal, jaundice.

Gastrointestinal disorders.

Melena.

Skin and subcutaneous tissue disorders.

Subcutaneous haemorrhage, eczema, skin eruptions including Stevens-Johnson syndrome or toxic epidermal necrolysis, urticaria.

Renal and urinary disorder.

Haematuria, increased urinary frequency.

General disorders and administration site conditions.

Pyrexia, malaise, pain.

Investigations.

Uric acid level increased, BUN increased, blood creatinine increased.

Dosage and Administration

The recommended dosage of Pletal is 100 mg twice a day. Doses of 150 mg twice daily were investigated, however 100 mg twice daily provided the optimal risk to benefit ratio.
Pletal should be taken 30 minutes before or two hours after breakfast and the evening meal. Taking Pletal with food has been shown to increase the maximum plasma concentrations (C_max) of Pletal, which may be associated with an increased incidence of adverse effects.
Pletal treatment should be initiated by a physician experienced in the management of intermittent claudication. The patient should be reassessed after 3 months of treatment with a view to discontinuing Pletal where an inadequate effect is observed or symptoms have not improved.
Patients should continue with their lifestyle modifications (smoking cessation and exercise), and pharmacological interventions (such as lipid lowering and antiplatelet treatment) to reduce the risk of cardiovascular events. Pletal is not a substitute for such treatments.