Cilostazol

This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

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.

Included as part of the "PRECAUTIONS" Section

Cilostazol is a prescription medication used to reduce the symptoms of intermittent claudication (pain in the legs when walking due to narrowing of blood vessels). Cilostazol belongs to a group of drugs called phosphodiesterase III inhibitors, which help to improve blood flow to the legs.

This medication comes in tablet form and is usually taken by mouth two times a day, at least 30 minutes before or two hours after breakfast and dinner.

Common side effects of cilostazol include headache, diarrhea, dizziness, and rapid or irregular heartbeat.

Cilostazol can also cause dizziness. Do not drive or operate heavy machinery until you know how cilostazol affects you.

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 cilostazol, there are no specific foods that you must exclude from your diet when receiving this medication.

• Peripheral Vascular Disease

Do not take cilostazol if you have congestive heart failure.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Cilostazol is usually taken twice a day on an empty stomach, at least 30 minutes before or 2 hours after breakfast or dinner.

Take the medicine at the same time each day.

It may take up to 12 weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve after 4 weeks of treatment.

Store at room temperature away from moisture and heat.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• chest pain, pounding heartbeats or fluttering in your chest;

• a light-headed feeling, like you might pass out;

• fever, chills, body aches, flu symptoms;

• bloody urine, painful urination;

• shortness of breath, even with mild exertion; or

• swelling of your ankles or feet.

Common side effects may include:

• headache, dizziness;

• diarrhea, abnormal bowel movements;

• upset stomach; or

• runny nose.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Contraindications

• CHF of any severity.1 2 (See Boxed Warning.)

• Hemostatic disorders or active pathologic bleeding, such as bleeding peptic ulcer or intracranial bleeding.1

• Known hypersensitivity to cilostazol or any ingredient in the formulation.1 17

Warnings/Precautions

General Precautions

Consider possible adverse cardiovascular effects (e.g., increased heart rate) when used in patients with heart disease (e.g., CAD).1 13 Long-term effects not known in patients with underlying heart disease more severe than that studied in clinical trials (i.e., no recent MI or stroke, no arrhythmias, no unstable angina or other signs of rapidly progressing cardiovascular disease).1 2 13 19 Do not use in patients with CHF.1 (See Boxed Warning.)

Limited information regarding safety and efficacy of concurrent use with clopidogrel.1 Unknown whether concurrent clopidogrel therapy has additive effect on bleeding time.1 Use caution and monitor bleeding times during concomitant therapy.1

Possible thrombocytopenia or leukopenia progressing to agranulocytosis if cilostazol is not immediately discontinued; agranulocytosis reversible with discontinuance of cilostazol.1

Specific Populations

Category C.1

Distributed into milk in rats;1 discontinue nursing or drug because of potential risk in nursing infants.1

Safety and efficacy not established in children <18 years of age.1 2 13

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 2

Not studied in patients with moderate to severe hepatic impairment;1 2 19 use with caution.1 13

Use with particular caution in patients with severe renal impairment (Clcr <25 mL/minute).1 Safety and efficacy not established in patients undergoing hemodialysis.1 2 (See Elimination Route under Pharmacokinetics.)

Common Adverse Effects

Headache, diarrhea, abnormal (e.g., loose) stools, dizziness, infection, palpitation, pharyngitis, back pain, nausea, peripheral edema, rhinitis, dyspepsia, increased cough, tachycardia.1 3 4 9 10 17

• Quinolinone-derivative selective phosphodiesterase (PDE) type 3 inhibitor; platelet-aggregation inhibitor and arterial vasodilator.1 7 8

• Appears to inhibit activation of cellular PDE type 3, resulting in suppressed degradation and increased concentrations of cyclic adenosine-3′,5′-monophosphate (cAMP) in platelets and blood vessels.1 7 8 17 Increased cAMP concentrations appear to mediate arterial vasodilation and inhibition of platelet aggregation.1 2 7 8 17

• Favorably alters concentrations of certain lipoproteins; reduces plasma triglycerides and increases HDL-cholesterol concentrations.1 2 3 9 12 13 No effect on plasma concentrations of total cholesterol, LDL-cholesterol, or lipoprotein(a) (Lp[a]).12 13

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Fast or irregular heartbeat
• fever

• Abnormal bleeding
• bloody or black tarry stools
• bruises or red spots on the skin
• fainting
• nausea, heartburn, or indigestion (severe or continuing)
• nosebleeds
• stiff neck
• stomach pain, cramping, or burning (severe)
• swelling of the tongue
• vomiting of blood or material that looks like coffee grounds

• Bleeding gums
• bleeding tendency
• blistering, peeling, loosening of the skin
• blood in the urine or stools
• blurred vision
• chest pain
• chills
• clay-colored stools
• confusion
• cough or hoarseness
• coughing up blood
• dark urine
• diarrhea
• difficulty with breathing
• drowsiness
• fever with or without chills
• general feeling of tiredness or weakness
• headache, sudden and severe
• inability to speak
• itching of the eyes
• itching of the skin
• joint or muscle pain
• light-colored stools
• loss of appetite
• loss of consciousness
• lower back or side pain
• nausea and vomiting
• painful or difficult urination
• pinpoint red spots on the skin
• red skin lesions, often with a purple center
• red, irritated eyes
• seizures
• skin rash
• slurred speech
• sores, ulcers, or white spots on the lips or in the mouth
• stomach pain
• swollen glands
• temporary blindness
• unpleasant breath odor
• unusual bleeding or bruising
• unusual tiredness or weakness
• weakness in the arm or leg on one side of the body, sudden and severe
• weakness of part of the body
• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur:

• Dizziness or lightheadedness when getting up suddenly from a lying or sitting position

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• dizziness
• gas
• headache
• increased cough
• pain or stiffness in the muscles
• pounding heartbeat
• runny or stuffy nose
• sore throat
• swelling of the arms or legs

• Bone pain
• burning feeling in the throat or chest
• difficulty with swallowing
• hives
• pain or stiffness in the joints
• ringing or buzzing in the ears
• swelling of the face, fingers, or lower legs

• Bruising
• feeling of warmth
• pain
• redness of the face, neck, arms and occasionally, upper chest

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• 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.

• Antiplatelet Agent
• Phosphodiesterase-3 Enzyme Inhibitor
• Vasodilator

Intermittent claudication: Reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.

Intermittent claudication: Oral: 100 mg twice daily. Note: The American College of Chest Physicians recommends use when refractory to exercise therapy and smoking cessation; use in combination with either aspirin or clopidogrel (ACCP [Guyatt 2012]).

Note: Discontinue treatment if symptoms are not improved after 3 months of therapy.

PCI (following elective stent placement) (off-label use): Oral: 100 mg twice daily in combination with aspirin or clopidogrel. Note: Only recommended in patients with an allergy or intolerance to either aspirin or clopidogrel (ACCP [Guyatt 2012]).

Secondary prevention of noncardioembolic stroke or TIA (off-label use): Oral: 100 mg twice daily. Note: Clopidogrel or aspirin/extended release dipyridamole recommended over the use of cilostazol (ACCP [Guyatt 2012]).

Dosage adjustment with concomitant medications:

CYP2C19 inhibitors (eg, fluconazole, omeprazole, ticlopidine): Reduce cilostazol to 50 mg twice daily.

Strong or moderate CYP3A4 inhibitors (eg, diltiazem, erythromycin, itraconazole, ketoconazole): Reduce cilostazol to 50 mg twice daily.

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Data not available