Pletal

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• severe headache
• dizziness
• fainting
• diarrhea
• fast or irregular heartbeat

Cilostazol is a medication for the treatment of intermittent claudication, a condition caused by narrowing of the arteries that supply the legs with blood. Patients with intermittent claudication develop pain when they walk because not enough oxygen-containing blood reaches the active leg muscles. Cilostazol reduces the pain of intermittent claudication by dilating the arteries, thereby improving the flow of blood and oxygen to the legs. (It does this by decreasing the action of an enzyme, phosphodiesterase III.) It also reduces the ability of blood to clot. Cilostazol enables patients with intermittent claudication to walk longer and faster before developing pain. Cilostazol has a different mechanism of action than pentoxifylline (Trental), the other drug approved for intermittent claudication. (Pentoxifylline improves blood flow by making it easier for red blood cells to pass through vessels. It also decreases the viscosity of blood.). The FDA approved cilostazol in January 1999.

Common Side Effects of Cilostazol

Tell your doctor if any of the following side effects are severe or don't go away:

• Diarrhea
• Nausea
• Stomach pain or gas
• Heartburn or indigestion
• Headache
• Dizziness or lightheadedness
• Increased frequency of coughing
• Muscle pain

Serious Side Effects of Cilostazol

Tell your doctor right away if you experience any of the following serious side effects:

• Fast or irregular heartbeat
• Unusual bruising or bleeding
• Sudden, severe headache or vomiting
• Vision changes
• Unusual weight gain
• Swelling of the hands, arms, feet, ankles, or lower legs
• Dark, tarry, or bloody stools
• Vomit that looks like coffee grounds
• Signs of infection, which may include fever, sore throat, rash, or chills

>10%

Headache (27-34%)

Diarrhea (12-19%)

Abnormal stools (12-15%)

Infection (10-14%)

Rhinitis (7-12%)

Pharyngitis (7-10%)

1-10%

Dizziness (9-10%)

Palpitations (5-10%)

Peripheral edema (7-9%)

Back pain (6-7%)

Dyspepsia (6%)

Abdominal pain (4-5%)

Tachycardia (4%)

Increased cough (3-4%)

Myalgia (2-3%)

Atrial fibrillation (<2%)

CHF (<2%)

MI (<2%)

Hematemesis (<2%)

Ecchymosis (<2%)

Blood in eye (<2%)

Epistaxis (<2%)

Hemoptysis (<2%)

Nausea

Frequency Not Defined

Decreased platelet aggregation

Agranulocytosis

Aplastic anemia

Leukopenia

Thrombocytopenia

Stevens-Johnson syndrome

Postmarketing Reports

Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia, granulocytopenia, thrombocytopenia, leukopenia, bleeding tendency

Cardiovascular: Torsades de pointes, QTc prolongation, left ventricular outflow tract obstruction

GI: GI hemorrhage

General: Pain, chest pain, hot flushes, extradural or subdural hematoma, hyperglycemia, hyperuricemia, increased BUN, elevated BP, decreased platelet or white blood cell (WBC) count

Hepatic: Hepatic dysfunction, abnormal liver function tests, jaundice

Neurologic: Intracranial or cerebral hemorrhage, cerebrovascular accident (CVA)

Respiratory: Pulmonary hemorrhage, interstitial pneumonia

Skin: Subcutaneous hemorrhage, pruritus, skin eruptions such as Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa)

Vascular: Subacute thrombosis

Black Box Warnings

Cilostazol and metabolites are inhibitors of phosphodiesterase III; such activity has been shown to decrease survival of patients with class III-IV CHF; contraindicated in patients with CHF of any severity

Contraindications

Congestive heart failure of any severity

Hypersensitivity

Hemostatic disorders or active pathologic bleeding (eg, bleeding peptic ulcer, intracranial bleeding) due to reversible platelet aggregation

Cautions

Use with caution in liver and renal disease

Leukopenia that progresses to agranulocytosis may occur (in which case, discontinue therapy)

Discontinue therapy if thrombocytopenia occurs

Use with caution in patients taking platelet aggregation inhibitors

Do not administer for at least 4-6 half-lives before elective surgical procedures

Avoid grapefruit juice

Response may be seen as early as 2-4 weeks after initiation, but treatment may be needed for up to 12 weeks

Left ventricular outflow tract obstruction reported in patients with sigmoid shaped interventricular septum; monitor patients for development of new systolic murmur or cardiac symptoms after initiating therapy

Dosage can be reduced or discontinued without rebound effects (eg, platelet hyperaggregability)

Cilostazol may induce tachycardia, palpitation, tachyarrhythmia and/or hypotension; patients with history of ischemic heart disease may be at risk for exacerbations of angina pectoris or myocardial infarction

Plasma concentrations and overall pharmacological activity are increased when cilostazol is administered with strong or moderate CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, diltiazem) and strong CYP2C19 inhibitors (eg, ticlopidine, fluconazole, omeprazole); dose reduction to 50 mg twice daily should be considered

Mechanism of Action

Inhibits phosphodiesterase III, causing cyclic adenosine monophosphate (cAMP) to increase, which in turn inhibits platelet aggregation; causes homogeneous vasodilation, especially in femoral vascular beds

Absorption

Onset: 2-12 weeks

Distribution

Protein bound: 95-98% (especially albumin)

Metabolism

Metabolized by CYP3A4 (major), CYP2C19

Metabolites: 4'-trans-hydroxy-cilostazol, 3,4-dehydro-cilostazol

Elimination

Half-life: 11-13 hr

Dialyzable: No

Excretion: Urine (74%), feces (20%)

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Patients with Heart Failure [see BOX WARNING]
• Tachycardia [see WARNINGS AND PRECAUTIONS]
• Left Ventricular Outflow Tract Obstruction [see WARNINGS AND PRECAUTIONS]
• Hematologic Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Hemostatic Disorders or Active Pathologic Bleeding [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions were assessed in eight placebo-controlled clinical trials involving patients exposed to either 50 or 100 mg twice daily PLETAL (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on PLETAL and 134 days for patients on placebo.

The most frequent adverse reaction resulting in discontinuation of therapy in more than 3% of patients treated with PLETAL was headache [50 mg twice daily (1.3%), 100 mg twice daily (3.5%) and placebo (0.3%)]. Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for PLETAL (all doses) versus 0.1% for placebo.

The most common adverse reactions, occurring in at least 2% of patients treated with PLETAL 50 or 100 mg twice daily, are shown in Table 1.

Table 1: Most Common Adverse Reactions in Patients on PLETAL (PLT) 50 or 100 mg Twice Daily(Incidence at least 2% and Occurring More Frequently (≥ 2%) in the 100 mg Twice Daily Group than on Placebo)

Less frequent clinical significant adverse reactions (less than 2%) that were experienced by patients treated with PLETAL 50 mg twice daily or 100 mg twice daily in the eight controlled clinical trials and that occurred at a frequency in the 100 mg twice daily group greater than in the placebo group are listed below.

Body as a whole: fever, generalized edema, malaise

Cardiovascular: atrial fibrillation, heart failure, myocardial infarction, nodal arrhythmia, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardia

Digestive: anorexia, melena

Hematologic and Lymphatic: anemia

Metabolic and Nutritional: increased creatinine, hyperuricemia

Nervous: insomnia

Respiratory: epistaxis

Skin and Appendages: urticaria

Special Senses: conjunctivitis, retinal hemorrhage, tinnitus

Urogenital: urinary frequency

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of PLETAL. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Aplastic anemia, granulocytopenia, pancytopenia, bleeding tendency

Torsade de pointes and QTc prolongation in patients with cardiac disorders (e.g. complete atrioventricular block, heart failure; and bradyarrythmia), angina pectoris.

Gastrointestinal hemorrhage, vomiting, flatulence, nausea

Pain, chest pain, hot flushes

Hepatic dysfunction/abnormal liver function tests, jaundice

Anaphylaxis, angioedema, and hypersensitivity

Blood glucose increased, blood uric acid increased, increase in BUN (blood urea increased), blood pressure increase

Intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident, extradural hematoma and subdural hematoma

Hematuria

Pulmonary hemorrhage, interstitial pneumonia

Hemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa), rash.

Subacute stent thrombosis, hypertension.

Read the entire FDA prescribing information for Pletal (Cilostazol)

• Otsuka America Pharmaceutical, Inc.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Pletal, there are no specific foods that you must exclude from your diet when receiving this medication.

• Importance of providing patient a copy of manufacturer’s patient information each time therapy is prescribed.1

• Importance of adherence to prescribed directions for use.1

• Importance of not taking cilostazol if CHF (e.g., shortness of breath, swelling of the legs) is present.1 19

• Importance of taking cilostazol at least one-half hour before or 2 hours after food.1 19

• Importance of informing patient that up to 12 weeks of cilostazol therapy may be required before symptomatic relief of intermittent claudication occurs.1 19

• Importance of informing patient that cardiovascular risk during long-term use or in patients with severe underlying heart disease currently is not known.1 19

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 19

• Importance of informing patients of other important precautionary information. (See Cautions.)1

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of cilostazol in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of cilostazol in the elderly.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Defibrotide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab
• Abiraterone
• Aceclofenac
• Acemetacin
• Alipogene Tiparvovec
• Alteplase, Recombinant
• Amiodarone
• Amtolmetin Guacil
• Anagrelide
• Apixaban
• Aprepitant
• Argatroban
• Aspirin
• Atazanavir
• Betrixaban
• Bivalirudin
• Boceprevir
• Bromfenac
• Bufexamac
• Celecoxib
• Ceritinib
• Choline Salicylate
• Ciprofloxacin
• Citalopram
• Clarithromycin
• Clonixin
• Clopidogrel
• Cobicistat
• Conivaptan
• Crizotinib
• Dabigatran Etexilate
• Danaparoid
• Delavirdine
• Desirudin
• Desvenlafaxine
• Dexibuprofen
• Dexketoprofen
• Diclofenac
• Diflunisal
• Diltiazem
• Dipyridamole
• Dipyrone
• Dronedarone
• Droxicam
• Duloxetine
• Edoxaban
• Eptifibatide
• Erythromycin
• Escitalopram
• Eslicarbazepine Acetate
• Esomeprazole
• Etodolac
• Etofenamate
• Etoricoxib
• Etravirine
• Felbinac
• Fenoprofen
• Fepradinol
• Feprazone
• Floctafenine
• Fluconazole
• Flufenamic Acid
• Fluoxetine
• Flurbiprofen
• Fluvoxamine
• Fondaparinux
• Fosaprepitant
• Ginkgo
• Heparin
• Ibuprofen
• Idelalisib
• Imatinib
• Indinavir
• Indomethacin
• Itraconazole
• Ketoconazole
• Ketoprofen
• Ketorolac
• Lansoprazole
• Lepirudin
• Letrozole
• Levomilnacipran
• Lopinavir
• Lornoxicam
• Loxoprofen
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Meloxicam
• Miconazole
• Mifepristone
• Milnacipran
• Moclobemide
• Morniflumate
• Nabumetone
• Naproxen
• Nefazodone
• Nelfinavir
• Nepafenac
• Netupitant
• Niflumic Acid
• Nilotinib
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Omeprazole
• Oxaprozin
• Oxcarbazepine
• Oxyphenbutazone
• Pantoprazole
• Parecoxib
• Paroxetine
• Phenindione
• Phenprocoumon
• Phenylbutazone
• Piketoprofen
• Piperaquine
• Piracetam
• Piroxicam
• Posaconazole
• Prasugrel
• Proglumetacin
• Propyphenazone
• Proquazone
• Protein C
• Rabeprazole
• Regorafenib
• Ritonavir
• Rivaroxaban
• Rofecoxib
• Salicylic Acid
• Salsalate
• Saquinavir
• Sertraline
• Sodium Salicylate
• Sulfinpyrazone
• Sulindac
• Telaprevir
• Telithromycin
• Tenoxicam
• Tiaprofenic Acid
• Ticagrelor
• Ticlopidine
• Tipranavir
• Tirofiban
• Tolfenamic Acid
• Tolmetin
• Valdecoxib
• Venlafaxine
• Verapamil
• Vilazodone
• Voriconazole
• Vortioxetine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Bitter Orange

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Active bleeding (including peptic ulcers, bleeding in the brain) or
• Blood clotting problems or
• Congestive heart failure—Should not be used in patients with these conditions.

• Heart rhythm problems (eg, tachycardia) or
• Ischemic heart disease, history of or
• Kidney disease or
• Leukopenia (low white blood cells) or
• Liver disease or
• Thrombocytopenia (low number of platelets)—Use with caution. May make these conditions worse.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine should come with a patient information leaflet. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions.

It is best to take this medicine at the same time each day.

Do not eat grapefruit or drink grapefruit juice while you are using this medicine.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For treatment of peripheral vascular disease (circulation problems):
    • Adults—100 milligrams (mg) two times a day, taken at least 30 minutes before or 2 hours after breakfast and dinner. Your doctor may adjust your dose as needed.
    • Children—Use and dose must be determined by a doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Pregnancy

Teratogenic Effects

Pregnancy Category C.

Pletal has been shown to be teratogenic in rats at doses that are greater than 5-times the human MRHD on a body surface area basis. There are no adequate and well-controlled studies in pregnant women.

In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD, and exposure to 3,4-dehydro-cilostazol was barely detectable.

When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).

Nursing Mothers

Transfer of cilostazol into milk has been reported in rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Pletal, discontinue nursing or discontinue Pletal.

Pediatric Use

Safety and effectiveness of Pletal in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects (n = 2,274) in clinical studies of Pletal, 56 percent were 65 years old and over, while 16 percent were 75 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be excluded. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites.

Hepatic Impairment

No dose adjustment is required in patients with mild hepatic impairment. Patients with moderate or severe hepatic impairment have not been studied in clinical trials and dosing recommendations cannot be provided [see Clinical Pharmacology (12.3)].

Renal Impairment

No dose adjustment is required in patients with renal impairment. Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95-98%) [see Clinical Pharmacology (12.3)].

Applies to cilostazol: oral tablet

Nervous system

Nervous system side effects have commonly included headache (34%) resulting in discontinuation in 3.5% of patients. Dizziness (10%) and vertigo (2%) have also been reported. Other less frequently reported side effects have included asthenia, hyperesthesia, and paresthesia. Postmarketing reports have included intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident, extradural hematoma and subdural hematoma.[Ref]

Cardiovascular

An increase in ventricular premature beats and nonsustained ventricular tachycardia have been seen in Holter monitored patients. Cardiovascular damage including endocardial hemorrhage, left ventricular fibrosis, and necrosis of smooth muscle in coronary arteries has been demonstrated in dogs after 52 weeks of cilostazol (the active ingredient contained in Pletal) administration.

In the AT-BAT study, one patient died during a bradycardic episode 46 hours after a successful PCI, another patient required surgical revascularization, and one patient experienced no reflow requiring a temporary intra-aortic balloon.[Ref]

Cardiovascular side effects have included palpitations (10%) and tachycardia (4%). Peripheral edema has been reported in 7% of patients, and hypertension and angina pectoris have been reported in 2% of patients. Atrial fibrillation, atrial flutter, cerebral infarct, cerebral ischemia, congestive heart failure, heart arrest, hemorrhage, hypotension, myocardial infarction, myocardial ischemia, nodal arrhythmia, postural hypotension, supraventricular tachycardia, syncope, varicose vein, vasodilation, ventricular extrasystoles, and ventricular tachycardia have also been reported. Post marketing reports have included torsades de pointes and QTc prolongation in patients with cardiac disorders, e.g. complete atrioventricular block, cardiac failure and bradyarrhythmia. In these reports cilostazol was used "off label" due to its positive chronotropic action.[Ref]

Gastrointestinal

Gastrointestinal side effects have included diarrhea (19%), nausea (7%), dyspepsia (6%), abdominal pain (5%), flatulence (3%) and vomiting (2%). Other gastrointestinal side effects have included anorexia, cholelithiasis, colitis, duodenal ulcer, duodenitis, esophageal hemorrhage, esophagitis, increased GGT, gastritis, gastroenteritis, gum hemorrhage, hematemesis, melena, peptic ulcer, periodontal abscess, rectal hemorrhage, stomach ulcer, and tongue edema.[Ref]

Musculoskeletal

Musculoskeletal side effects have included back pain (7%), myalgia (3%), leg cramps (2%), and arthritis (2%).[Ref]

Respiratory

Respiratory side effects have included pharyngitis (10%), rhinitis (7%), increased cough (4%), dyspnea (2%), and bronchitis (2%). Postmarketing reports have included pulmonary hemorrhage and interstitial pneumonia.[Ref]

Dermatologic

Dermatologic side effects have included rash in 2% of patients. Postmarketing reports have included pruritus and skin eruptions including Stevens-Johnson syndrome.[Ref]

Hematologic

In the AT-BAT study, one patient who did not undergo PCI had major bleeding during CABG on the day following angiography, nine patients had minor bleeding (mostly due to access site bleeding), and two patients developed moderate thrombocytopenia.[Ref]

Hematologic side effects have included postmarketing reports of thrombocytopenia, aplastic anemia, leukopenia, and bleeding tendencies.[Ref]

Hepatic

Hepatic side effects have included postmarketing reports of jaundice, hepatic dysfunction and abnormal liver function tests.[Ref]

Renal

Renal side effects have included postmarketing reports of increased BUN and hematuria.[Ref]

Some side effects of Pletal may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.