PLETAL - PACKAGE LEAFLET - LEAFLETS

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Pletal - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Cilostazol

Pletal 50 mg tablets

Pletal package inserts are available for pack sizes:

Pletal 50 mg tablets
Pletal 100 mg tablets

Indications Why is Pletal used? What is it for?

Pletal belongs to a group of medicines called phosphodiesterase type 3 inhibitors.

It works in a number of ways, including by dilating certain blood vessels and reducing the clotting activity of certain blood cells called platelets within blood vessels.

Pletal was prescribed for "intermittent claudication". Intermittent claudication is the cramp-like pain in the legs when walking and is caused by insufficient blood supply to the legs. Pletal by improving blood circulation in the legs allows her to walk pain-free for a greater distance.

Pletal is only recommended for patients whose symptoms have not improved sufficiently after changing their lifestyle (for example, quitting smoking and exercising more) and after taking other measures. It is important that you continue to follow the changes you have made to your lifestyle while taking Pletal.

Contraindications When Pletal should not be used

Do not take Pletal

if you are allergic to cilostazol or any of the other ingredients of this medicine
if you suffer from a condition called 'heart failure'.
if you have persistent chest pain when you are at rest, or if you have had a 'heart attack' or any heart surgery in the past six months.
if you have or have suffered in the past from fainting caused by heart disease, or from severe heartbeat disturbances.
if you know you have a disorder that increases the risk of bleeding or bruising, for example:
one or more active stomach ulcers.
a stroke that occurred within the past six months.
eye problems if you have diabetes.
if your blood pressure is not well controlled.
if you are taking both acetylsalicylic acid and clopidogrel, or any combination of two or more medicines that may increase the risk of bleeding [if in doubt, consult your doctor or pharmacist]
if you have severe kidney disease or severe or moderate liver disease.
if you are pregnant.

Precautions for use What you need to know before taking Pletal

Before taking Pletal, be sure to tell your doctor:

if you have a severe heart problem, or any problem with your heartbeat.
if you have blood pressure problems.

During treatment with Pletal make sure:

if you are going to have surgery, including tooth extraction, tell your doctor or dentist that you are taking Pletal.
if you bruise or bleed easily, stop taking Pletal and tell your doctor.

Interactions Which drugs or foods can modify the effect of Pletal

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Tell your doctor specifically if you are taking certain medicines that are routinely used for painful and / or inflammatory disorders of the muscles or joints, or if you are taking medicines that reduce blood clotting. These medicines include:

acetylsalicylic acid
clopidogrel
anticoagulants (eg warfarin, dabigatran, rivaroxaban, apixaban or low molecular weight heparins).

If you are taking these medicines together with Pletal, your doctor may do some routine blood tests.

Some medicines can interfere with the effect of Pletal if they are taken at the same time. They can increase the side effects of Pletal, or reduce the effectiveness of Pletal. Pletal can do the same with other drugs. Before you start taking Pletal, tell your doctor if you are taking:

erythromycin, clarithromycin or rifampicin (antibiotics)
ketoconazole (to treat fungal infections)
omeprazole (to treat "excessive stomach acid)
diltiazem (for high blood pressure or chest pain)
cisapride (to treat stomach upset)
lovastatin, simvastatin or atorvastatin (for excessive blood cholesterol levels)
halofantrine (to treat malaria)
pimozide (to treat mental illness)
ergot derivatives (for migraine, eg ergotamine, dihydroergotamine)
carbamazepine or phenytoin (to treat seizures)
St. John's wort (medicinal plant based medicine)

If you are unsure whether the above applies to the medicines you are taking, ask your doctor or pharmacist.

Before taking Pletal, tell your doctor if you are taking medicines for high blood pressure (hypertension), as Pletal can potentiate the blood pressure lowering effect. If your blood pressure drops to too low levels, your heart rate may increase. These may increase. medicines include:

diuretics (e.g. hydrochlorothiazide, furosemide)
calcium channel blockers (e.g. verapamil, amlodipine)
ACE inhibitors (e.g. captopril, lisinopril)
angiotensin II receptor antagonists (eg valsartan, candesartan)
beta-blockers (e.g. labetalol, carvedilol);

However, it may be possible to take the medicines listed above with Pletal and your doctor can decide what is right for you.

Pletal with food and drink

Pletal tablets should be taken 30 minutes before breakfast and dinner. Always take the tablets with water.

Warnings It is important to know that:

Pregnancy and breastfeeding

Pletal MUST NOT be used during pregnancy. For women who are breastfeeding, the use of Pletal IS NOT RECOMMENDED. If you are pregnant, think you may be pregnant or are planning to become pregnant, or are breast-feeding, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Pletal can cause dizziness. If you feel dizzy after taking Pletal tablets, DO NOT drive or use any tools or machines, and tell your doctor or pharmacist.

Dose, Method and Time of Administration How to use Pletal: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The usual dose is two 50 mg tablets twice a day (morning and evening). This dose does not require modification for older people. However, your doctor may prescribe a lower dose if you are taking other medicines that can interfere with the effect of Pletal.
Pletal tablets should be taken 30 minutes before breakfast and dinner. Always take the tablets with water.

You may feel the benefits of taking Pletal within 4-12 weeks of treatment. Your doctor will evaluate your progress after 3 months of treatment and may recommend that you stop taking Pletal if the treatment effect is insufficient.

Pletal is not suitable for children.

Overdose What to do if you have taken too much Pletal

If you take more Pletal than you should

If for any reason you have taken more Pletal tablets than you should, you may have signs and symptoms such as severe headache, diarrhea, drop in blood pressure and irregular heartbeat.

If you have taken more tablets than your prescribed dose, contact your doctor or the nearest hospital immediately. Remember to take your medicine pack with you so that it is clear what you have taken.

If you forget to take Pletal

If you miss a dose, don't worry; wait until it is time for the next dose and take the next tablet, then continue as normal. DO NOT take a double dose to make up for a forgotten tablet.

If you stop taking Pletal

If you stop taking Pletal, the pain in your legs may come back or get worse. Therefore, only stop taking Pletal if you notice side effects that require urgent medical attention (see section 4), or if your doctor tells you to.

Side Effects What are the side effects of Pletal

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you experience any of the following side effects, you may need urgent medical attention. Stop taking Pletal and contact a doctor or go to the nearest hospital immediately.

stroke
heart attack
heart problems which can cause shortness of breath or swelling of the ankles
irregular heartbeat (new or worsening)
noticeable bleeding
easy bruising
severe illness with blistering of the skin, mouth, eyes and genitals
yellowing of the skin or whites of the eyes, due to liver or blood problems (jaundice)

Also tell your doctor immediately if you have a fever or sore throat. Some blood tests may be needed and your doctor will decide how to continue the treatment.

The following effects have been reported for Pletal. Tell your doctor as soon as possible in the following cases:

Very common side effects (affects more than 1 in 10 people)

headache
abnormal stools
diarrhea

Common side effects (affects less than 1 in 10 people, but more than 1 in 100 people)

rapid heartbeats
strong heartbeats (palpitations)
chest pain
dizziness
sore throat
runny nose (rhinitis)
abdominal pain
feeling of abdominal discomfort (indigestion)
nausea or vomiting
loss of appetite (anorexia)
excessive belching or flatulence
swelling of the ankles, feet or face
skin rash (rash) or change in the appearance of the skin
itchy skin
patchy bleeding under the skin
sense of generalized weakness

Uncommon side effects (affects less than 1 in 100 people, but more than 1 in 1,000 people)

heart attack
irregular heartbeat (new or worsening)
heart problems which can cause shortness of breath or swollen ankles - pneumonia
cough
chills
unexplained bleeding
propensity to bleed (for example stomach, eyes or muscles, nosebleeds and blood in saliva or urine)
reduction in the number of red blood cells in the blood
dizziness when standing up
fainting
sense of anxiety
insomnia
unusual dreams
allergic reaction
generalized pains
diabetes and increased blood sugar
stomach pain (gastritis)
malaise

In people with diabetes, the risk of bleeding into the inside of the eye may increase.

Rare side effects (affects less than 1 in 1,000 people, but more than 1 in 10,000 people)

tendency to bleed for longer than usual
increase in the number of platelets in the blood
kidney problems

The following side effects have been reported while using Pletal, but their frequency is not known:

changes in blood pressure
reduction in the number of red blood cells, white blood cells and platelets in the blood
respiratory difficulties
motor difficulties
fever
hot flashes
eczema and other skin rashes (rash)
reduced skin sensitivity
watery or viscous eyes (conjunctivitis)
ringing in the ears (tinnitus)
liver problems, including hepatitis
changes in urine

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse

By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after 'EXP'. The expiry date refers to the last day of that month.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What Pletal contains

The active ingredient is cilostazol.One tablet contains 50 mg of cilostazol.
The other ingredients are maize starch, microcrystalline cellulose, carmellose calcium, hypromellose and magnesium stearate.

What Pletal looks like and contents of the pack

The Pletal 50 mg tablet is a white, round, flat tablet with "OG31" on one side.

The medicine is available in packs of 14, 20, 28, 30, 50, 56, 98, 100, 112 or 168 tablets, or in hospital packs of 70 (5x14) tablets.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Pletal can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on the ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical data of 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 HOLDER OF THE ALL AUTHORIZATION "PLACING ON MARKETING 08.0 AUTHORIZATION NUMBER" PLACING ON MARKET09.0 DATE OF PR IMA AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIOPharmaceuticals, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORAN PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

PLETAL 50 MG

▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 50 mg of cilostazol.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablet.

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

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Pletal is indicated to increase pain-free walking distance and maximum distance in patients with intermittent claudication, without pain at rest and without necrosis of peripheral tissues (peripheral arterial disease - Fontaine class II).

Pletal is indicated second-line in patients in whom lifestyle modifications (including smoking cessation and [supervised] physical activity programs) and other appropriate interventions have not sufficiently improved symptoms of intermittent claudication.

04.2 Posology and method of administration

Dosage

The recommended dose of cilostazol is 100 mg twice a day. Cilostazol should be taken 30 minutes before breakfast and dinner. Taking cilostazol with food has shown an increase in maximum concentrations (Cmax) of cilostazol in plasma, which may be associated with an increased frequency of adverse reactions.

Cilostazol treatment should be started by physicians experienced in the management of intermittent claudication (see also section 4.4).

The physician should re-examine the patient after 3 months of treatment, for the possible discontinuation of cilostazol where an inadequate effect is observed or the symptoms have not improved.

Patients on cilostazol therapy should continue lifestyle changes (smoking cessation and physical activity) and pharmacological interventions (e.g. lipid-lowering and antiplatelet therapy) to reduce the risk of cardiovascular events. Cilostazol is not a substitute for such drug therapies.

Dose reduction to 50 mg twice daily is recommended in patients receiving drugs that are strong inhibitors of CYP3A4, such as certain macrolides, azole antifungals, protease inhibitors, or drugs that markedly inhibit CYP2C19, such as omeprazole (see sections 4.4 and 4.5 ).

Senior citizens

There are no special dosage requirements for the elderly.

Pediatric population

The safety and efficacy of in children have not been established.

Kidney failure

No dose adjustment is necessary in patients with creatinine clearance> 25 ml / min. Cilostazol is contraindicated in patients with creatinine clearance 25 ml / min.

Hepatic insufficiency

It is not necessary to adjust the dose in patients with mild hepatic insufficiency. There are no data available in patients with moderate or severe hepatic impairment. Since cilostazol is extensively metabolised by hepatic enzymes, it is contraindicated in patients with moderate or severe hepatic impairment.

04.3 Contraindications

- Known hypersensitivity to cilostazol or to any of the excipients

- Severe renal insufficiency: creatinine clearance 25 ml / min

- Moderate or severe liver failure Congestive heart failure Pregnancy

- Patients with known haemorrhagic predisposition (e.g. active peptic ulceration, recent haemorrhagic stroke [within the last six months], proliferative diabetic retinopathy, poorly controlled hypertension)

- Patients with a history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopias, whether or not adequately treated, and in patients with QTc interval prolongation

- Patients with a history of severe tachyarrhythmia

- Patients treated concurrently with two or more supplemental antiplatelet agents or anticoagulants (e.g. acetylsalicylic acid, clopidogrel, heparin, warfarin, acenocoumarol, dabigatran, rivaroxaban or apixaban)

- Patients with angina pectoris unstable, myocardial infarction within the past 6 months, or undergoing coronary intervention within the past 6 months.

04.4 Special warnings and appropriate precautions for use

The appropriateness of cilostazol treatment should be carefully considered in conjunction with other therapeutic options, such as revascularization.

Based on its mechanism of action, cilostazol can induce tachycardia, palpitations, tachyarrhythmia and / or hypotension. The increase in heart rate associated with cilostazol ranges from approximately 5 to 7 beats per minute; consequently, in patients at risk this can induce angina pectoris.

Patients possibly at increased risk of serious cardiac adverse events due to increased heart rate, for example patients with stable coronary artery disease, should be carefully monitored during treatment with cilostazol, while the use of cilostazol is contraindicated in patients with unstable angina pectoris. , or with myocardial infarction / coronary intervention within the past 6 months, or with a history of severe tachyarrhythmia (see section 4.3).

Caution should be exercised when prescribing cilostazol to patients with atrial or ventricular ectopy and to patients with atrial fibrillation or flutter.

Patients should be advised of the need to report any bleeding or easy bruising during therapy. Cilostazol should be discontinued in case of retinal haemorrhage. For further information on bleeding risks, see sections 4.3 and 4.5.

Due to the inhibitory effect of cilostazol on platelet aggregation, an increased risk of bleeding may occur in conjunction with surgical procedures (including minor invasive procedures, such as tooth extraction). If a patient is to undergo elective surgery which does not require an antiplatelet effect, the administration of cilostazol must be interrupted 5 days before the intervention.

There have been rare or very rare reports of haematological abnormalities, including thrombocytopenia, leukopenia, agranulocytosis, pancytopenia and aplastic anemia (see section 4.8). Most patients recovered from discontinuation of cilostazol. However, some cases of pancytopenia and aplastic anemia were fatal.

In addition to reporting bleeding and easy bruising episodes, patients should be advised of the need to promptly report any other signs that may suggest early onset of blood dyscrasia, such as pyrexia and sore throat. A complete blood count should be performed. performed in cases of suspected infection, or in the presence of other clinical evidence of blood dyscrasia Treatment with cilostazol should be discontinued promptly if clinical or laboratory evidence of haematological abnormalities arises.

In the case of patients treated with strong inhibitors of CYP3A4 or CYP2C19, the levels of cilostazol in the plasma showed an increase. In such cases a cilostazol dose of 50 mg twice daily is recommended (for further information, see section 4.5).

Caution is warranted in co-administration of cilostazol and any other agent with potential hypotensive effect due to the possibility of additive hypotensive effects with reflex tachycardia. See also section 4.8.

Attention should be paid to co-administration of cilostazol and any other platelet antiplatelet agents. See sections 4.3 and 4.5.

04.5 Interactions with other medicinal products and other forms of interaction

Antiplatelet agents

Cilostazol is a phosphodiesterase (PDE) III inhibitor with antiplatelet activity. In a clinical study in healthy subjects, administration of cilostazol 150 mg twice daily for five days did not lead to prolongation of bleeding time.

Acetylsalicylic acid (ASA)

Short-term (4 days) co-administration of ASA and cilostazol suggested a 23-25% increase in inhibition of adenosine diphosphate (ADP) -induced platelet aggregation. ex vivo, compared to the ASA alone.

There was no apparent trend towards a higher frequency of haemorrhagic adverse events in patients receiving cilostazol and ASA compared to patients taking placebo and equivalent doses of ASA.

Clopidogrel and other antiplatelet agents

Concomitant administration of cilostazol and clopidogrel had no effect on platelet count, prothrombin time (PT) or activated partial thromboplastin time (aPTT). All healthy subjects in the study had prolonged bleeding times with clopidogrel alone and concomitant administration with cilostazol did not lead to any relevant additional effects on bleeding times. Caution is advised when co-administering cilostazol and any other antiplatelet agents. The opportunity for periodic monitoring of bleeding times should be considered. Cilostazol treatment is contraindicated in patients receiving two or more additional antiplatelet / anticoagulants (see section 4.3).

A higher rate of bleeding was observed with concomitant use of clopidogrel, ASA and cilostazol in the CASTLE study.

Oral anticoagulants such as warfarin

In a single dose clinical study, no inhibition of the metabolism of warfarin or any effect on coagulation parameters (PT, aPTT, bleeding time) could be observed. However, caution is advised for patients receiving both the cilostazol than an anticoagulant, and frequent monitoring is necessary to reduce the risk of bleeding.

Treatment with cilostazol is contraindicated in patients receiving two or more additional antiplatelet / anticoagulants (see section 4.3).

Cytochrome P-450 (CYP) enzyme inhibitors

Cilostazol is extensively metabolised by CYP enzymes, particularly CYP3A4 and CYP2C19, and to a lesser extent CYP1A2. The dehydro metabolite, whose potency is 4 to 7 times greater than that of cilostazol in inhibiting platelet aggregation, appears to be formed primarily via CYP3A4. The 4 "-trans-hydroxy metabolite, with potency one-fifth that of cilostazol, appears to be formed predominantly via CYP2C19. Consequently, CYP3A4 inhibitor drugs (e.g. some macrolides, azole antifungals, protease inhibitors) or of CYP2C19 (such as proton pump inhibitors [PPI]) enhance overall pharmacological activity and may potentiate the undesirable effects of cilostazol. Consequently, for patients taking concomitant strong inhibitors of CYP3A4 or CYP2C19 the recommended dose is 50 mg twice daily (see section 4.2).

Administration of cilostazol with erythromycin (a CYP3A4 inhibitor) resulted in a 72% increase in the AUC of cilostazol, accompanied by a 6% increase in the AUC of the metabolite dehydro and a 119% increase in the AUC of the metabolite 4 " -trans-hydroxy.

Based on AUC, the overall pharmacological activity of cilostazol increases by 34% with co-administration with erythromycin. Based on these data, the recommended dose of cilostazol is 50 mg twice daily in the presence of erythromycin and similar agents (e.g. clarithromycin).

Co-administration of ketoconazole (a CYP3A4 inhibitor) with cilostazol resulted in a 117% increase in AUC for cilostazol, accompanied by a 15% decrease in AUC for the metabolite dehydro, and an 87% increase in AUC. for the 4 "-trans-hydroxy metabolite. Based on AUC, the overall pharmacological activity of cilostazol increases by 35% when co-administered with ketoconazole. Based on these data, the recommended dose of cilostazol is 50 mg twice daily. day in the presence of ketoconazole and similar agents (for example itraconazole).

Administration of cilostazol with diltiazem (a weak inhibitor of CYP3A4) resulted in a 44% increase in the AUC for cilostazol, accompanied by a 4% increase in the AUC of the dehydro metabolite and a 43% increase in the AUC of the metabolite. 4 "-trans-hydroxy. Based on AUC, the overall pharmacological activity of cilostazol increases by 19% when co-administered with diltiazem. Based on these data, no dose adjustment is required.

Administration of a single 100 mg dose of cilostazol with 240 ml of grapefruit juice (an intestinal CYP3A4 inhibitor) had no relevant effect on the pharmacokinetics of cilostazol. Based on these data, no dose adjustment is necessary. However, a clinically relevant effect on cilostazol is possible with larger quantities of grapefruit juice.

Administration of cilostazol with omeprazole (a CYP2C19 inhibitor) increased the AUC for cilostazol by 22%, with a 68% increase in the AUC for the metabolite dehydro, and a 36% decrease in the AUC for the metabolite 4 "- trans-hydroxy Based on AUC, overall pharmacological activity increases by 47% with co-administration with omeprazole Based on these data, the recommended dose of cilostazol is 50 mg twice daily in the presence of omeprazole.

Substrates of cytochrome P-450 enzymes

Cilostazol has been shown to increase the AUC of lovastatin (a sensitive substrate for CYP3A4) and its hydroxy acid by 70%. Caution is advised when co-administering cilostazol with CYP3A4 substrates with a narrow therapeutic index (such as cisapride, halofantrine, pimozide, ergot derivatives). Caution is recommended when co-administered with statins metabolised by CYP3A4, eg simvastatin, atorvastatin and lovastatin.

Inducers of cytochrome P-450 enzymes

The effect of inducers of CYP3A4 and CYP2C19 (such as carbamazepine, phenytoin, rifampicin and St. John's wort) on the pharmacokinetics of cilostazol has not been evaluated. The antiplatelet effect may theoretically be altered and should be carefully monitored in case of co-administration of cilostazol and inducers of CYP3A4 and CYP2C19.

In clinical studies, cigarette smoking (which induces CYP1A2) reduced plasma concentrations of cilostazol by 18%.

Other potential interactions

Caution is warranted when co-administering cilostazol with any other blood pressure lowering agent due to the possibility of an additional hypotensive effect with reflex tachycardia.

04.6 Pregnancy and lactation

Pregnancy

There are no adequate data from the use of cilostazol in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. It should not be used during pregnancy (see section 5.3). see section 4.3).

Feeding time

The excretion of cilostazol into human breast milk has been reported in animal studies. The excretion of cilostazol into human breast milk is not known. Due to the potential harmful effect to the breastfed infant from a mother being treated, the use of is not recommended during breastfeeding.

Fertility

Cilostazol did not affect fertility in animal studies.

04.7 Effects on ability to drive and use machines

Cilostazol can cause dizziness and patients should be advised to proceed with caution before driving or operating machinery.

04.8 Undesirable effects

The most commonly reported adverse reactions in clinical trials were headache (in> 30%), diarrhea and abnormal stools (each in> 15%). These reactions were usually mild to moderate in intensity and were sometimes alleviated by reducing the dose.

Adverse reactions reported in clinical trials and post-marketing are included in the table below.

The frequencies correspond to: very common (≥1 / 10); common (≥1 / 100,

The frequencies of reactions observed in the post-marketing period are considered unknown (frequency cannot be estimated from the available data).

Disorders of the blood and lymphatic system Common: bruising Uncommon: anemia Rare: prolongation of bleeding time, thrombocythemia Not known: bleeding tendency, thrombocytopenia, granulocytopenia, agranulocytosis, leukopenia, pancytopenia, aplastic anemia Disorders of the immune system Uncommon: allergic reaction Metabolism and nutrition disorders Common: edema (peripheral, facial), anorexia Uncommon: hyperglycaemia, diabetes mellitus Psychiatric disorders Uncommon: anxiety Nervous system disorders Very common: headache Common: dizziness Uncommon: insomnia, dream disturbances Not known: paresis, hypoesthesia Eye disorders Not known: conjunctivitis Ear and labyrinth disorders Not known: tinnitus Cardiac pathologies Common: palpitations, tachycardia, angina pectoris, arrhythmia, ventricular extrasystoles Uncommon: myocardial infarction, atrial fibrillation, congestive heart failure, supraventricular tachycardia, ventricular tachycardia, syncope Vascular pathologies Uncommon: ocular haemorrhage, epistaxis, gastrointestinal haemorrhage, unspecified haemorrhage, orthostatic hypotension Not known: Flushing, hypertension, hypotension, cerebral haemorrhage, pulmonary haemorrhage, muscle haemorrhage, respiratory tract haemorrhage, subcutaneous haemorrhage Respiratory, thoracic and mediastinal disorders Common: rhinitis, pharyngitis Uncommon: dyspnoea, pneumonia, cough Not known: interstitial pneumonia Gastrointestinal disorders Very common: diarrhea, abnormal stools Common: nausea and vomiting, dyspepsia, flatulence, abdominal pain Uncommon: gastritis Hepatobiliary disorders Not known: hepatitis, liver function abnormalities, jaundice Skin and subcutaneous tissue disorders Common: rash, pruritus Not known: eczema, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria Musculoskeletal and connective tissue disorders Uncommon: myalgia Renal and urinary disorders Rare: renal failure, renal impairment Not known: haematuria, pollakiuria General disorders and administration site conditions Common: chest pain, asthenia Uncommon: chills, malaise Not known: pyrexia, pain Diagnostic tests Not known: increased uric acid levels, increased blood urea nitrogen, increased blood creatinine

An increase in the frequency of palpitations and peripheral edema has been observed when cilostazol is administered concomitantly with other vasodilators that cause reflex tachycardia, such as calcium channel blockers derived from dihydropyridine.

The only adverse event leading to discontinuation of therapy in 3% of patients treated with cilostazol was headache. Other frequent causes of discontinuation included palpitations and diarrhea (each in 1.1%).

By itself cilostazol may carry an increased risk of bleeding, which in turn is enhanced by the co-administration of any other agent characterized by this effect.

The risk of intraocular haemorrhage may be higher in diabetic patients.

An increased frequency of diarrhea and palpitations has been seen in patients over 70 years of age.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

04.9 Overdose

Information on acute overdose in humans is limited. Predictable signs and symptoms are severe headache, diarrhea, tachycardia and possibly cardiac arrhythmia.

Patients should be placed under observation, instituting appropriate supportive therapies. Proceed with gastric evacuation by inducing vomiting or gastric lavage, as appropriate.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antithrombotic agents, antiplatelet agents excluding heparin.

ATC code: B01A C.

From data generated in nine placebo-controlled studies (in which 1,634 patients were exposed to cilostazol), cilostazol was shown to improve the ability to exercise by varying the Distance of claudication absolute (ACD, or maximal walking distance) and the Distance ofclaudication initial (ICD, or pain-free walking distance), as evidenced by the tests with the "treadmill test". After 24 weeks of treatment, administration of cilostazol 100 mg twice daily resulted in increases in mean ACD between 60.4 and 129.1 meters, and also in mean increases in ICD between 47.3 and 93.6 meters.

A meta-analysis based on weighted mean differences between the nine studies indicated a significant post-baseline absolute overall increase of 42 m in maximal walking distance (ACD) for cilostazol 100 mg twice daily compared to the improvement seen with placebo. This corresponds to a relative improvement of 100% compared to placebo. This effect was lower in diabetic subjects than in non-diabetic patients.

Animal studies have shown vasodilatory effects of cilostazol, attested in small human studies, in which blood flow to the ankle was measured with strain-gauge plethysmography. Cilostazol also inhibits the proliferation of smooth muscle cells in rats and human muscle cells in vitro; it also inhibits the platelet release reaction of platelet-derived growth factor and PF-4 in human platelets.

Animal and human studies (in vivo and ex vivo) showed a "reversible inhibition of" platelet aggregation by cilostazol. The inhibition is effective against various aggregates (including shear stress, arachidonic acid, collagen, ADP and adrenaline); in man, this inhibition lasts up to 12 hours and upon cessation of the administration of cilostazol, the recovery of the " aggregation within 48-96 hours, without rebound hyperaggregability. Effects on circulating plasma lipids were examined in patients treated with

. After 12 weeks, compared to placebo, 100 mg twice daily 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 was conducted to evaluate the long-term effects of cilostazol, particularly in terms of mortality and safety. In total, 1,439 patients with intermittent, non-cardioscompensated claudication received cilostazol or placebo therapy for up to three years. Regarding mortality, the 36-month Kaplan-Meier event rate for deaths while on study drug therapy, with a median time of 18 months of study drug intake, was 5.6% ( 95% CI between 2.8 and 8.4%) for cilostazol, and 6.8% (95% CI between 1.9 and 11.5%) for placebo. No safety concerns emerged from long-term treatment with cilostazol.

05.2 "Pharmacokinetic properties

Following multiple doses of cilostazol 100 mg twice daily in patients with peripheral vascular disease, steady state is achieved within 4 days.

The Cmax of cilostazol and its major circulating metabolites increases less than proportionally with increasing doses. However, the AUC for cilostazol and its metabolites increases almost proportionally to dose.

The apparent elimination half-life for cilostazol is 10.5 hours. The main metabolites are two: a dehydro-cilostazol and a 4 "-trans-hydroxy cilostazol, both with similar apparent half-lives. The dehydro metabolite is 4-7 times more active as a platelet antiaggregant than the parent compound, while in the case of the 4 "-trans-hydroxy metabolite this activity is equal to one fifth. The plasma concentrations (measured by the AUC) of the dehydro and 4 "-trans-hydroxy are ≈41% and ≈12% of the cilostazol concentrations.

Cilostazol is eliminated primarily by metabolism and subsequent urinary excretion of metabolites. The main isoenzymes involved in its biotransformation are cytochrome P-450 CYP3A4, to a lesser extent CYP2C19, and even less CYP1A2.

The primary route of elimination is urinary (74%) with the remaining volume excreted in the faeces. No measurable amount of cilostazol is excreted unchanged in the urine, and less than 2% of the dose is excreted as the dehydro metabolite of cilostazol. 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 exceeds 5% of the total excreted.

Cilostazol binds 95-98% to proteins, primarily albumin. The dehydro metabolite and the 4 "-trans-hydroxy metabolite have a protein binding of 97.4% and 66%, respectively.

There is no evidence of the induction of hepatic microsomal enzymes by cilostazol.

The pharmacokinetics of cilostazol and its metabolites were not significantly affected by age or sex in healthy subjects ranging in age from 50 to 80 years.

In subjects with severe renal insufficiency, the free fraction of cilostazol was 27% higher, and both Cmax and AUC were 29% and 39% lower, respectively, compared to subjects with normal renal function. The Cmax and AUC of the dehydro metabolite were 41% and 47% lower, respectively, in subjects with severe renal impairment, compared to subjects with normal renal function. The Cmax and AUC of the 4 "-trans-hydroxy metabolite were 173% and 209% higher, respectively, in subjects with severe renal impairment. Cilostazol should not be administered to patients with creatinine clearance.

There are no data in patients with moderate to severe hepatic impairment, and as cilostazol is extensively metabolised by hepatic enzymes, the medicinal product should not be used in such patients (see section 4.3).

05.3 Preclinical safety data

Cilostazol and many of its metabolites are phosphodiesterase (PDE) III inhibitors that suppress the degradation of cyclic AMP, resulting in an increase in cAMP in various tissue types, including platelets and blood vessels. As with other positive inotropes and vasodilators, cilostazol produced cardiovascular lesions in dogs. These lesions did not occur in rats and monkeys and are considered specific to the canine species. QTc testing in dogs and monkeys showed no prolongation after administration of cilostazol or its metabolites. .

Mutagenicity studies were negative in terms of bacterial gene mutation, bacterial DNA repair, mammary cell gene mutation, and murine bone marrow chromosomal aberration in vivo. In tests in vitro on Chinese hamster ovary cells, cilostazol produced a weak but significant increase in the frequency of chromosomal aberrations. No unusual neoplastic outcomes were observed in carcinogenicity fed up to two years in rats, with oral (dietary) doses up to 500 mg / kg / day, and in mice at doses up to 1,000 mg / kg / day.

In rats treated during pregnancy, fetal weights were lower. An increase in fetuses with external, visceral and skeletal malformations was also found with high doses. At lower doses, delays in ossification were observed. Exposure to late gestation caused higher rates of stillbirth and lower weight offspring. An "increased frequency of delay in ossification of the sternum" emerged in rabbits.