HIGHLIGHTS OF PRESCRIBING INFORMATION --------------------- DOSAGE FORMS AND STRENGTHS -------------------­

These highlights do not include all the information needed to use • Tablets: 50 mg and 100 mg (3)
PLETAL safely and effectively. See full prescribing information for
PLETAL. ------------------------------ CONTRAINDICATIONS ----------------------------­
• Heart failure of any severity (4)
PLETAL (cilostazol) tablets, for oral use. • Hypersensitivity to cilostazol or any components of PLETAL (4)
Initial U.S. Approval: 1999
----------------------- WARNINGS AND PRECAUTIONS ---------------------­
WARNING: CONTRAINDICATED IN HEART FAILURE
• Risks of tachycardia, palpitation, tachyarrhythmia or hypotension. Risks of
PATIENTS
exacerbations of angina pectoris or myocardial infarction in patients with a
See full prescribing information for complete boxed warning. history of ischemic heart disease (5.2)
• PLETAL is contraindicated in patients with heart failure of any • Left ventricular outflow tract obstruction has been reported in patients with
severity. Cilostazol and several of its metabolites are inhibitors of sigmoid shaped interventricular septum.(5.1).
phosphodiesterase III. Several drugs with the pharmacologic effect • Risks of thrombocytopenia or leukopenia progressing to agranulocytosis­
have caused decreased survival compared to placebo patients with monitor platelets and white blood cell counts (5.3)
class III-IV heart failure. (4) • Avoid use in patients with hemostatic disorders or active pathologic
bleeding (5.4)

-------------------------- RECENT MAJOR CHANGES -------------------------­

Warnings and Precautions, Left Ventricular Outflow Obstruction (5.2) ------------------------------ ADVERSE REACTIONS ----------------------------­
05/2017 Most common adverse reactions greater than or equal to 2% and at least twice
that for placebo in patients on 100 mg twice daily are headache, diarrhea,
--------------------------- INDICATIONS AND USAGE -------------------------­ abnormal stools, and palpitation (6.1)
PLETAL is a phosphodiesterase III inhibitor (PDE III inhibitor) indicated for
the reduction of symptoms of intermittent claudication, as demonstrated by an To report SUSPECTED ADVERSE REACTIONS, contact Otsuka
increased walking distance (1) America Pharmaceutical, Inc. at 1-877-438-9927 or FDA at 1-800-FDA­
1088 or www.fda.gov/medwatch.
---------------------- DOSAGE AND ADMINISTRATION ---------------------­
• The recommended dosage of PLETAL is 100 mg twice daily taken at least ------------------------------ DRUG INTERACTIONS ----------------------------­
half an hour before or two hours after breakfast and dinner (2.1) • Strong and moderate CYP3A4 and CYP2C19 inhibitors: Increase exposure
• Reduce the dose to 50 mg twice daily when coadministered with CYP3A4 to PLETAL. Reduce PLETAL dose (2.2, 7.1)
inhibitors such as ketoconazole, itraconazole, erythromycin, and diltiazem,
or CYP2C19 inhibitors such as ticlopidine, fluconazole, and omeprazole See 17 for PATIENT COUNSELING INFORMATION and FDA-
(2.2) approved patient labeling
Revised: 05/2017

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: CONTRAINDICATED IN HEART FAILURE PATIENTS 8.3 Nursing Mothers
1 INDICATIONS AND USAGE 8.4 Pediatric Use
2 DOSAGE AND ADMINISTRATION 8.5 Geriatric Use
2.1 Recommended dosage 8.6 Hepatic Impairment
2.2 Dose Reduction with CYP3A4 and CYP2C19 Inhibitors 8.7 Renal Impairment
3 DOSAGE FORMS AND STRENGTHS 10 OVERDOSAGE
4 CONTRAINDICATIONS 11 DESCRIPTION
5 WARNINGS AND PRECAUTIONS 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
51 Tachycardia
12.3 Pharmacokinetics
5.2 Left Ventricular Outflow Tract Obstruction
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.3 Hematologic Adverse Reactions 13.2 Animal Toxicology and/or Pharmacology
5.4 Hemostatic Disorders or Active Pathologic Bleeding 14 CLINICAL STUDIES
6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING
6.1 Clinical Trials Experience 16.1 How supplied
6.2 Postmarketing Experience 16.2 Storage and handling
7 DRUG INTERACTIONS 17 PATIENT COUNSELING INFORMATION
7.1 Inhibitors of CYP3A4 or CYP2C19
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
*Sections or subsections omitted from the full prescribing information are not listed.

Reference ID: 4099638

 FULL PRESCRIBING INFORMATION

WARNING: CONTRAINDICATED IN HEART FAILURE PATIENTS

PLETAL is contraindicated in patients with heart failure of any severity. Cilostazol and several of its
metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused
decreased survival compared to placebo in patients with class III-IV heart failure [see Contraindications (4)].

1 INDICATIONS AND USAGE

PLETAL is indicated for the reduction of symptoms of intermittent claudication, as demonstrated by an increased walking
distance.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended dosage

The recommended dosage of PLETAL is 100 mg twice daily taken at least half an hour before or two hours after breakfast
and dinner.

Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be
needed before a beneficial effect is experienced. If symptoms are unimproved after 3 months, discontinue PLETAL.

2.2 Dose Reduction with CYP3A4 and CYP2C19 Inhibitors

Reduce dose to 50 mg twice daily when coadministered with strong or moderate inhibitors of CYP3A4 (e.g.,
ketoconazole, itraconazole, erythromycin, and diltiazem) or inhibitors of CYP2C19 (e.g., ticlopidine, fluconazole, and
omeprazole) [see Drug Interactions (7.1)]

3 DOSAGE FORMS AND STRENGTHS

PLETAL is available as 50 mg triangular and 100 mg round, white debossed tablets.

4 CONTRAINDICATIONS

PLETAL is contraindicated in patients with:

• Heart failure of any severity: Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III.
Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with
class III-IV heart failure.
• Hypersensitivity to cilostazol or any components of PLETAL (e.g., anaphylaxis, angioedema)

5 WARNINGS AND PRECAUTIONS

5.1 Tachycardia
Cilostazol may induce tachycardia, palpitation, tachyarrhythmia or hypotension. The increase in heart rate associated with
cilostazol is approximately 5 to 7 bpm. Patients with a history of ischemic heart disease may be at risk for exacerbations
of angina pectoris or myocardial infarction.

5.2 Left Ventricular Outflow Tract Obstruction

Left ventricular outflow tract obstruction has been reported in patients with sigmoid shaped interventricular septum.
Monitor patients for the development of a new systolic murmur or cardiac symptoms after starting cilostazol.

Reference ID: 4099638

 5.3 Hematologic Adverse Reactions
Cases of thrombocytopenia or leukopenia progressing to agranulocytosis when PLETAL was not immediately
discontinued have been reported. Agranulocytosis is reversible on discontinuation of PLETAL. Monitor platelets and
white blood cell counts periodically.

5.4 Hemostatic Disorders or Active Pathologic Bleeding

PLETAL inhibits platelet aggregation in a reversible manner. PLETAL has not been studied in patients with hemostatic
disorders or active pathologic bleeding. Avoid use of PLETAL in these patients.

6 ADVERSE REACTIONS

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

- Patients with Heart Failure [see Boxed Warning]

- Tachycardia [see Warnings and Precautions (5.1)]

Left Ventricular Outflow Tract Obstruction [see Warnings and Precautions (5.2)]

- Hematologic Adverse Reactions [see Warnings and Precautions (5.3)]

- Hemostatic Disorders or Active Pathologic Bleeding [see Warnings and Precautions (5.4)]

6.1 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.

Reference ID: 4099638

 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)

Adverse Reactions Placebo PLT 50 mg twice daily PLT 100 mg twice daily
(N=973) (N=303) (N=998)
Headache 14% 27% 34%
Diarrhea 7% 12% 19%
Abnormal stools 4% 12% 15%
Palpitation 1% 5% 10%
Dizziness 6% 9% 10%
Pharyngitis 7% 7% 10%
Infection 8% 14% 10%
Peripheral edema 4% 9% 7%
Rhinitis 5% 12% 7%
Dyspepsia 4% 6% 6%
Abdominal pain 3% 4% 5%
Tachycardia 1% 4% 4%

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

6.2 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.

Reference ID: 4099638

 Blood and lymphatic system disorders:

Aplastic anemia, granulocytopenia, pancytopenia, bleeding tendency

Cardiac disorders:

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

Gastrointestinal disorders:

Gastrointestinal hemorrhage, vomiting, flatulence, nausea

General disorders and administration site conditions:

Pain, chest pain, hot flushes

Hepatobiliary disorders:

Hepatic dysfunction/abnormal liver function tests, jaundice

Immune system disorders:

Anaphylaxis, angioedema, and hypersensitivity

Investigations:

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

Nervous system disorders:

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

Renal and urinary disorders:

Hematuria

Respiratory, thoracic and mediastinal disorders:

Pulmonary hemorrhage, interstitial pneumonia

Skin and subcutaneous tissue disorders:

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

Vascular disorders:

Subacute stent thrombosis, hypertension.

7 DRUG INTERACTIONS

7.1 Inhibitors of CYP3A4 or CYP2C19

Inhibitors of CYP3A4

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 Coadministration of strong (e.g., ketoconazole) and moderate (e.g., erythromycin, diltiazem and grapefruit juice) CYP3A4
inhibitors can increase exposure to PLETAL. Reduce PLETAL dose to 50 mg twice daily when coadministered with
strong or moderate inhibitors of CYP3A4 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Inhibitors of CYP2C19

Coadministration with CYP2C19 inhibitors (e.g., omeprazole) increases systemic exposure of PLETAL active
metabolites. Reduce PLETAL dose to 50 mg twice daily when coadministered with strong or moderate inhibitors of
CYP2C19 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 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).

8.3 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.

8.4 Pediatric Use

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

8.5 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.

Reference ID: 4099638

 8.6 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)].

8.7 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)].

10 OVERDOSAGE

Information on acute overdosage with PLETAL in humans is limited. The signs and symptoms of an acute overdose can
be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and
possibly cardiac arrhythmias. The patient should be carefully observed and given supportive treatment. Since cilostazol is
highly protein-bound, it is unlikely that it can be efficiently removed by hemodialysis or peritoneal dialysis. The oral LD50
of cilostazol is greater than 5 g per kg in mice and rats and greater than 2 g per kg in dogs.

11 DESCRIPTION

PLETAL (cilostazol) is a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for
phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol
is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.

The structural formula is:

Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in methanol and ethanol,
and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.

PLETAL (cilostazol) tablets for oral administration are available in 50 mg triangular and 100 mg round, white debossed
tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients:
carboxymethylcellulose calcium, corn starch, hydroxypropyl methylcellulose 2910, magnesium stearate, and
microcrystalline cellulose.

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 12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

PLETAL and several of its metabolites inhibit phosphodiesterase III activity and suppress cAMP degradation with a
resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation,
respectively.

PLETAL reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen,
arachidonic acid, epinephrine, and shear stress.

Cardiovascular effects:

Cilostazol affects both vascular beds and cardiovascular function. It produces heterogeneous dilation of vascular beds,
with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not
responsive to the effects of cilostazol.

In dogs or cynomolgus monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as
well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased
at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a
dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg twice daily,
respectively.

12.2 Pharmacodynamics
Cilostazol's effects on platelet aggregation were evaluated in both healthy subjects and in patients with stable symptoms of
cerebral thrombosis, cerebral embolism, transient ischemic attack, or cerebral arteriosclerosis over a range of doses from
50 mg every day to 100 mg three times a day. Cilostazol significantly inhibited platelet aggregation in a dose-dependent
manner. The effects were observed as early as 3 hours post-dose and lasted up to 12 hours following a single dose.
Following chronic administration and withdrawal of cilostazol, the effects on platelet aggregation began to subside 48
hours after withdrawal and returned to baseline by 96 hours with no rebound effect. A cilostazol dosage of 100 mg twice
daily consistently inhibited platelet aggregation induced with arachidonic acid, collagen and adenosine diphosphate
(ADP). Bleeding time was not affected by cilostazol administration.

Effects on circulating plasma lipids have been examined in patients taking PLETAL. After 12 weeks, as compared to
placebo, PLETAL 100 mg twice daily produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-
cholesterol of 4.0 mg/dL (≅ 10%).

Drug Interactions

Aspirin

Short-term (less than or equal to 4 days) coadministration of aspirin with PLETAL increased the inhibition of ADP-
induced ex vivo platelet aggregation by 22% - 37% when compared to either aspirin or PLETAL alone. Short-term (less
than or equal to 4 days) coadministration of aspirin with PLETAL increased the inhibition of arachidonic acid-induced ex
vivo platelet aggregation by 20% compared to PLETAL alone and by 48% compared to aspirin alone. However, short-
term coadministration of aspirin with PLETAL had no clinically significant impact on PT, aPTT, or bleeding time
compared to aspirin alone. Effects of long-term coadministration in the general population are unknown.

In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was coadministered with cilostazol to 201
patients. The most frequent doses and mean durations of aspirin therapy were 75-81 mg daily for 137 days (107 patients)
and 325 mg daily for 54 days (85 patients). There was no apparent increase in frequency of hemorrhagic adverse effects in
patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.

Reference ID: 4099638

 Warfarin

Cilostazol did not inhibit the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-
warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and PLETAL on the
pharmacodynamics of both drugs is unknown.

12.3 Pharmacokinetics
PLETAL is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase
in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by
hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine.
Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III
inhibition) activity after administration of PLETAL.

Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination
half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration
and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active
metabolites were similar in healthy subjects and patients with intermittent claudication due to peripheral arterial disease
(PAD). Figure 1 shows the mean plasma concentration-time profile at steady state after multiple dosing of PLETAL 100
mg twice daily.

Figure 1: Mean Plasma Concentration-time Profile at Steady State after Multiple Dosing of PLETAL 100
mg Twice Daily

1800

1600 Cilostazol
3,4-dehydrocilostazol
4'-trans-hydroxycilostazol
1400
Plasma Conce ntration (ng/mL)

1200

1000

800

600

400

200

0 4 8 12 16 20 24

Time (hrs)

Distribution

Cilostazol is 95 - 98% protein bound, predominantly to albumin. The binding for 3,4-dehydro-cilostazol is 97.4% and for
4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol
was 27% higher in subjects with renal impairment than in healthy volunteers. The displacement of cilostazol from plasma
proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.

Metabolism

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 Cilostazol is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. Based on in vitro
studies, the primary isoenzymes involved in cilostazol’s metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The
enzyme responsible for metabolism of 3,4-dehydro-cilostazol, the most active of the metabolites, is unknown.

Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15%
was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (20% as active as
cilostazol).

Elimination

The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable
amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro­
cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as
other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.

Special Populations

Age and Gender

The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly
different with respect to age (50 to 80 years) or gender.

Smokers

Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.

Hepatic Impairment

The pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to
healthy subjects.

Patients with moderate or severe hepatic impairment have not been studied.

Renal Impairment

The total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renal
impairment and in healthy subjects. Severe renal impairment increases metabolite levels and alters protein binding of the
parent. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting
potency of parent drug and metabolites, appeared little changed. 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%).

Drug Interactions

Cilostazol does not appear to inhibit CYP3A4.

Warfarin

Cilostazol did not inhibit the metabolism of R- and S-warfarin after a single 25-mg dose of warfarin.

Clopidogrel

Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.

Strong Inhibitors of CYP3A4

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 A priming dose of ketoconazole 400 mg (a strong inhibitor of CYP3A4), was given one day prior to coadministration of
single doses of ketoconazole 400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by
117%. Other strong inhibitors of CYP3A4, such as itraconazole, voriconazole, clarithromycin, ritonavir, saquinavir, and
nefazodone would be expected to have a similar effect [see Dosage and Administration (2.2), Drug Interactions (7.1)].

Moderate Inhibitors of CYP3A4

Erythromycin and other macrolide antibiotics: Erythromycin is a moderately strong inhibitor of CYP3A4.
Coadministration of erythromycin 500 mg every 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by
47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy­
cilostazol by 141% [see Dosage and Administration (2.2)].

Diltiazem:

Diltiazem 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased
~40% [see Dosage and Administration (2.2)].

Grapefruit Juice:

Grapefruit juice increased the Cmax of cilostazol by ~50%, but had no effect on AUC.

Inhibitors of CYP2C19

Omeprazole: Coadministration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic
exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of
CYP2C19 [see Dosage and Administration (2.2)].

Quinidine

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

Lovastatin

The concomitant administration of lovastatin with cilostazol decreases cilostazol Css, max and AUCτ by 15%. There is also a
decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatin
increases lovastatin and ß-hydroxylovastatin AUC approximately 70% and is not expected to be clinically significant.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day
in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in
both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug.
Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in
vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal
aberrations in the in vitro Chinese Hamster Ovary Cell assay.

In female mice, cilostazol caused a reversible contraceptive effect at a dose (300 mg/kg) that was approximately 7.4-fold
greater than the Maximum Recommended Human Dose (MRHD) on a body surface area basis. These findings have not
been demonstrated in other animal species.

Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At
this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males, and about 5 times in
females, the exposure in humans at the MRHD.
Reference ID: 4099638
 13.2 Animal Toxicology and/or Pharmacology
Repeated oral administration of cilostazol to dogs (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13
weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial hemorrhage,
hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of
the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery, and coronary arteritis and
periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) to
unbound cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg
twice daily. Similar lesions have been reported in dogs following the administration of other positive inotropic agents
(including PDE III inhibitors) and/or vasodilating agents. No cardiovascular lesions were seen in rats following 5 or 13
weeks of administration of cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound
cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the
MRHD. Cardiovascular lesions were also not seen in rats following 52 weeks of administration of cilostazol at doses up to
150 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were about 0.5 and 5 times (male and
female rats, respectively) the exposure in humans at the MRHD. In female rats, cilostazol AUCs were similar at 150 and
1500 mg/kg/day. Cardiovascular lesions were also not observed in monkeys after oral administration of cilostazol for 13
weeks at doses up to 1800 mg/kg/day. While this dose of cilostazol produced pharmacologic effects in monkeys, plasma
cilostazol levels were less than those seen in humans given the MRHD, and those seen in dogs given doses associated
with cardiovascular lesions.

14 CLINICAL STUDIES

The ability of PLETAL to improve walking distance in patients with stable intermittent claudication was studied in eight,
randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration involving 2,274 patients using dosages of
50 mg twice daily (n=303), 100 mg twice daily (n=998), and placebo (n=973). Efficacy was determined primarily by the
change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized
exercise treadmill tests.

Compared to patients treated with placebo, patients treated with PLETAL 50 or 100 mg twice daily experienced
statistically significant improvements in walking distances both for the distance before the onset of claudication pain and
the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of PLETAL on
walking distance was seen as early as the first on-therapy observation point of two or four weeks.

Figure 2 depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.

Reference ID: 4099638

 Figure 2: Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight
Randomized, Double-Blind, Placebo-Controlled Clinical Trials

Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with PLETAL
100 mg twice daily, expressed as the change from baseline, was 28% to 100%.

The corresponding changes in the placebo group were –10% to 41%.

The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a
therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either PLETAL 100
mg twice daily or 50 mg twice daily 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. PLETAL has not been studied in patients with rapidly progressing claudication
or in patients with leg pain at rest, ischemic leg ulcers, or gangrene. Its long-term effects on limb preservation and
hospitalization have not been evaluated.

A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of
cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The
trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality,
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 cilostazol and 6.8% (95% CI of 1.9 to 11.5 %) on placebo. These data appear to be
sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How supplied

PLETAL is supplied as 50 mg and 100 mg tablets.

The 50 mg tablets are white, triangular, debossed with PLETAL 50, and provided in bottles of 60 tablets (NDC 59148­
003-16).

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 The 100 mg tablets are white, round, debossed with PLETAL 100, and provided in bottles of 60 tablets (NDC 59148-002­
16).

16.2 Storage and handling

Store PLETAL tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room
Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information)

Advise the patient:

• to take PLETAL at least one-half hour before or two hours after food.
• to discuss with their doctor before taking any CYP3A4 or CYP2C19 inhibitors (e.g., omeprazole).
• that the beneficial effects of PLETAL on the symptoms of intermittent claudication may not be immediate. Although
the patient may experience benefit in 2 to 4 weeks after initiation of therapy, treatment for up to 12 weeks may be
required before a beneficial effect is experienced. Discontinue PLETAL if symptoms do not improve after 3 months.

Manufactured for

OTSUKA AMERICA PHARMACEUTICAL, INC.

Rockville, MD 20850

Manufactured by

OTSUKA PHARMACEUTICAL CO., LTD.

Tokushima 771-0182, Japan

May 2017

Reference ID: 4099638

 PATIENT INFORMATION

PLETAL® (PLAY-tal)

(cilostazol)

Tablets, for oral use

Read this Patient Information leaflet before you start taking PLETAL and each time you get a refill. There may
be new information. This information does not take the place of talking to your doctor about your medical
condition or your treatment.

What is the most important information I should know about PLETAL?

PLETAL can cause serious side effects:

• PLETAL (cilostazol) stops a protein called phosphodiesterase III from working. Other similar drugs which
affect this protein may cause death if you already have heart problems, called class 3 to 4 (III-IV) heart
failure. Do not take PLETAL if you have heart failure of any kind.

What is PLETAL?
PLETAL is a prescription medicine used to reduce the symptoms of intermittent claudication and can increase
your ability to walk further distances.
It is not known if PLETAL is safe and effective for use in children.
How does PLETAL work?
Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks.

Who should not take PLETAL?

Do not take PLETAL if you:

• have heart problems (heart failure)

• are allergic to cilostazol or any of the ingredients in PLETAL. See the end of this leaflet for a complete list
of ingredients in PLETAL.
Tell your doctor before taking this medicine if you have any of these conditions.

What should I tell my doctor before taking PLETAL?

Before you take PLETAL, tell your doctor if you:

• drink grapefruit juice. Taking PLETAL and drinking grapefruit juice can increase the amount of PLETAL
causing side effects.
• have any other medical conditions
• are pregnant or planning to become pregnant. It is not known if PLETAL will harm your unborn baby.
• are breastfeeding or planning to breastfeed. It is not known if PLETAL passes into your breast milk. You
and your doctor should decide if you will take PLETAL or breastfeed. You should not do both.

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 Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines,
vitamins and herbal supplements.
Ask your doctor for a list of these medicines if you are not sure. You can ask your pharmacist for a list of
medicines that interact with PLETAL. Know the medicines you take. Keep a list of them to show to your doctor
and pharmacist when you get a new medicine.

How should I take PLETAL?

• Take PLETAL exactly as your doctor tells you to take it.
• Your doctor will tell you how much PLETAL to take and when to take it.
• Your doctor may change your dose if needed.
• Take PLETAL 30 minutes before you eat or 2 hours after you eat.

What are the possible side effects of PLETAL?

PLETAL may cause serious side effects, including:
• heart problems. Taking PLETAL may cause you to have heart problems, including a fast heart beat,
palpitations, irregular heartbeat, and low blood pressure.
• See “What is the most important information I should know about PLETAL?”
• severe allergic reactions (anaphylaxis, angioedema). Call your doctor or go to the nearest emergency
room right away if you have any of the following signs or symptoms of a severe allergic reaction:
o hives o trouble breathing or wheezing
o swelling of your face, lips, mouth, or
o dizziness
tongue

• changes in your blood cell counts (thrombocytopenia or leukopenia). Your doctor should do blood
tests to check your blood cell counts while you take PLETAL.

The most common side effects of PLETAL include:

• headache • diarrhea
• abnormal stools
Tell your doctor if you have any side effect that bothers you or does not go away. These are not all the possible
side effects of PLETAL. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store PLETAL?

Store PLETAL at room temperature between 68OF to 77OF (20OC to 25OC).
Keep PLETAL and all medicines out of the reach of children.

General information about the safe and effective use of PLETAL.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do
not use PLETAL for a condition for which it was not prescribed. Do not give PLETAL to other people, even if
they have the same symptoms that you have. It may harm them.
This Patient Information summarizes the most important information about PLETAL. If you would like more
information, talk with your doctor. You can ask your pharmacist or doctor for information about PLETAL that is
written for health professionals.

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 For more information, go to www.otsuka-us.com or call 1-800-441-6763.

What are the ingredients in PLETAL?

Active ingredient: cilostazol
Inactive ingredients: carboxymethylcellulose calcium, corn starch, hydroxypropyl methylcellulose 2910,
magnesium stearate, microcrystalline cellulose

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for
OTSUKA AMERICA PHARMACEUTICAL, INC.
Rockville, MD 20850

Manufactured by
OTSUKA PHARMACEUTICAL CO., LTD.
Tokushima 771-0182, Japan

Revised: July/2015

Reference ID: 4099638