NDC 70518-2200 Cilostazol

Cilostazol

NDC Product Code 70518-2200

NDC Code: 70518-2200

Proprietary Name: Cilostazol What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Cilostazol What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE TO OFF-WHITE)
Shape: ROUND (C48348)
Size(s):
8 MM
Imprint(s):
TEVA;7231
Score: 1

NDC Code Structure

  • 70518 - Remedyrepack Inc.
    • 70518-2200 - Cilostazol

NDC 70518-2200-0

Package Description: 90 TABLET in 1 BOTTLE, PLASTIC

NDC Product Information

Cilostazol with NDC 70518-2200 is a a human prescription drug product labeled by Remedyrepack Inc.. The generic name of Cilostazol is cilostazol. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Remedyrepack Inc.

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Cilostazol Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • CILOSTAZOL 100 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • POVIDONE K30 (UNII: U725QWY32X)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Phosphodiesterase 3 Inhibitor - [EPC] (Established Pharmacologic Class)
  • Phosphodiesterase 3 Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Remedyrepack Inc.
Labeler Code: 70518
FDA Application Number: ANDA077027 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 07-10-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Cilostazol Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Contraindicated In Heart Failure Patients

Cilostazol is contraindicated in patients with heart failure of any severity. Cilostazol and several of itsmetabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have causeddecreased survival compared to placebo in patients with class III-IV heart failure


[see Contraindications (


4)]


.

1 Indications And Usage

Cilostazol tablets are indicated for the reduction of symptoms of intermittent claudication, as demonstrated by an increased walking distance.

The recommended dosage of cilostazol tablets 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 cilostazol tablets.

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, andomeprazole)


[see Drug Interactions (7.1)]


.

3 Dosage Forms And Strengths

Cilostazol tablets USP are available as 50 mg pillow-shaped and 100 mg round, white to off-white, debossed tablets.

4 Contraindications

  • Cilostazol tablets are 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 cilostazol tablets (e.g., anaphylaxis, angioedema)

5.1 Tachycardia

Cilostazol may induce tachycardia, palpitation, tachyarrhythmia or hypotension. The increase in heart rate associated withcilostazol is approximately 5 to 7 bpm. Patients with a history of ischemic heart disease may be at risk for exacerbationsof 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.

5.3 Hematologic Adverse Reactions

Cases of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued have been reported. Agranulocytosis is reversible on discontinuation of cilostazol. Monitor platelets andwhite blood cell counts periodically.

5.4 Hemostatic Disorders Or Active Pathologic Bleeding

Cilostazol inhibits platelet aggregation in a reversible manner. Cilostazol has not been studied in patients with hemostaticdisorders or active pathologic bleeding. Avoid use of cilostazol 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 trialsof a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observedin practice.Adverse reactions were assessed in eight placebo-controlled clinical trials involving patients exposed to either 50 or 100 mg twice daily cilostazol (n = 1301) or placebo (n = 973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.The most frequent adverse reaction resulting in discontinuation of therapy in more than 3% of patients treated withcilostazol 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 cilostazol (all doses) versus 0.1% for placebo.The most common adverse reactions, occurring in at least 2% of patients treated with cilostazol 50 or 100 mg twice daily,are shown in


Table 1.


Table 1: Most Common Adverse Reactions in Patients on Cilostazol 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 ReactionsPlacebo(N = 973)Cilostazol 50 mg twice daily(N = 303)Cilostazol 100 mg twice daily(N = 998)Headache14%27%34%Diarrhea7%12%19%Abnormal stools4%12%15%Palpitation1%5%10%Dizziness6%9%10%Pharyngitis7%7%10%Infection8%14%10%Peripheral edema4%9%7%Rhinitis5%12%7%Dyspepsia4%6%6%Abdominal pain3%4%5%Tachycardia1%4%4%Less frequent clinical significant adverse reactions (less than 2%) that were experienced by patients treated with cilostazol


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 cilostazol. Because these reactions arereported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure.Blood and lymphatic system disorders:Aplastic anemia, granulocytopenia, pancytopenia, bleeding tendencyCardiac 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, nauseaGeneral disorders and administration site conditions:Pain, chest pain, hot flushesHepatobiliary disorders:Hepatic dysfunction/abnormal liver function tests, jaundiceImmune system disorders:Anaphylaxis, angioedema, and hypersensitivityInvestigations:Blood glucose increased, blood uric acid increased, increase in BUN (blood urea increased), blood pressure increaseNervous system disorders:Intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident, extradural hematoma and subdural hematomaRenal and urinary disorders:HematuriaRespiratory, thoracic and mediastinal disorders:Pulmonary hemorrhage, interstitial pneumoniaSkin and subcutaneous tissue disorders:Hemorrhage subcutaneous, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa), rashVascular disorders:Subacute stent thrombosis, hypertension.

7.1 Inhibitors Of Cyp3a4 Or Cyp2c19

Inhibitors of CYP3A4Coadministration of strong (e.g., ketoconazole) and moderate (e.g., erythromycin, diltiazem and grapefruit juice) CYP3A4inhibitors can increase exposure to cilostazol. Reduce cilostazol dose to 50 mg twice daily when coadministered withstrong or moderate inhibitors of CYP3A4


[see Dosage and Administration (2.2) and Clinical Pharmacology (


12.3)].


Inhibitors of CYP2C19Coadministration with CYP2C19 inhibitors (e.g., omeprazole) increases systemic exposure of cilostazol activemetabolites. Reduce cilostazol dose to 50 mg twice daily when coadministered with strong or moderate inhibitors ofCYP2C19


[see Dosage and Administration (2.2) and Clinical Pharmacology (


12.3)].

8.1 Pregnancy

Teratogenic EffectsPregnancy Category C.


Cilostazol has been shown to be teratogenic in rats at doses that are greater than 5-times the human MRHD on a bodysurface 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 decreasedfetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch andsubclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). At this dose, systemic exposureto unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increasedincidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD ona systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossificationof the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure tounbound cilostazol was considerably lower than that seen in humans given the MRHD, and exposure to 3,4-dehydrocilostazol was barely detectable.When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn anddecreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposurebasis).

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the total number of subjects (n = 2,274) in clinical studies of cilostazol, 56 percent were 65 years old and over, while16 percent were 75 years old and over. No overall differences in safety or effectiveness were observed between thesesubjects and younger subjects, and other reported clinical experience has not identified differences in responses betweenthe elderly and younger patients, but greater sensitivity of some older individuals cannot be excluded. Pharmacokineticstudies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination ofcilostazol and its metabolites.

8.6 Hepatic Impairment

No dose adjustment is required in patients with mild hepatic impairment. Patients with moderate or severe hepaticimpairment have not been studied in clinical trials and dosing recommendations cannot be provided


[see ClinicalPharmacology (


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 to 98%)


[see Clinical Pharmacology (12.3)].

10 Overdosage

Information on acute overdosage with cilostazol in humans is limited. The signs and symptoms of an acute overdose canbe anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, andpossibly cardiac arrhythmias. The patient should be carefully observed and given supportive treatment. Since cilostazol ishighly protein-bound, it is unlikely that it can be efficiently removed by hemodialysis or peritoneal dialysis. The oral LD


50of cilostazol is greater than 5 g per kg in mice and rats and greater than 2 g per kg in dogs.

11 Description

Cilostazol, USP is a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase III). Cilostazol, USP is 6-[4-(1-cyclohexyl-1


H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1


H)-quinolinone, CAS-73963-72-1.


The structural formula is:C


20H


27N


5O


2 M.W. 369.46


Cilostazol, USP 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.Cilostazol tablets USP for oral administration are available in 50 mg pillow-shaped and 100 mg round, white to off-white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: colloidal silicon dioxide, corn starch, crospovidone, magnesium stearate, microcrystalline cellulose, and povidone.Meets USP Dissolution Test 3.

12.1 Mechanism Of Action

Cilostazol and several of its metabolites inhibit phosphodiesterase III activity and suppress cAMP degradation with aresultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation,respectively.Cilostazol 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 notresponsive to the effects of cilostazol.In dogs or cynomolgus monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow aswell as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increasedat doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in adose-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 ofcerebral thrombosis, cerebral embolism, transient ischemic attack, or cerebral arteriosclerosis over a range of doses from50 mg every day to 100 mg three times a day. Cilostazol significantly inhibited platelet aggregation in a dose-dependentmanner. 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 48hours after withdrawal and returned to baseline by 96 hours with no rebound effect. A cilostazol dosage of 100 mg twicedaily 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 cilostazol. After 12 weeks, as compared toplacebo, cilostazol 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 InteractionsAspirinShort-term (less than or equal to 4 days) coadministration of aspirin with cilostazol increased the inhibition of ADP- induced


ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (less than or equal to 4 days) coadministration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced


exvivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short- term coadministration of aspirin with cilostazol 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 201patients. The most frequent doses and mean durations of aspirin therapy were 75 to 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.WarfarinCilostazol 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 cilostazol on thepharmacodynamics of both drugs is unknown.

12.3 Pharmacokinetics

Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increasein C


max 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 IIIinhibition) activity after administration of cilostazol.Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent eliminationhalf-lives of about 11 to 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


cilostazol 100 mg twice daily.DistributionCilostazol is 95 to 98% protein bound, predominantly to albumin. The binding for 3,4-dehydrocilostazol is 97.4% and for4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazolwas 27% higher in subjects with renal impairment than in healthy volunteers. The displacement of cilostazol from plasmaproteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.MetabolismCilostazol is eliminated predominantly by metabolism and subsequent urinary excretion of metabolites. Based on


in vitrostudies, the primary isoenzymes involved in cilostazol’s metabolism are CYP3A4 and, to a lesser extent, CYP2C19. Theenzyme responsible for metabolism of 3,4-dehydrocilostazol, 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-dehydrocilostazol (4 to 7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (20% as active ascilostazol).EliminationThe primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurableamount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydrocilostazol. 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 PopulationsAge and GenderThe total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantlydifferent with respect to age (50 to 80 years) or gender.SmokersPopulation pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.Hepatic ImpairmentThe pharmacokinetics of cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared tohealthy subjects.Patients with moderate or severe hepatic impairment have not been studied.Renal ImpairmentThe total pharmacologic activity of cilostazol and its metabolites was similar in subjects with mild to moderate renalimpairment and in healthy subjects. Severe renal impairment increases metabolite levels and alters protein binding of theparent. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibitingpotency of parent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but, it isunlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95 to 98%).Drug InteractionsCilostazol does not appear to inhibit CYP3A4.WarfarinCilostazol did not inhibit the metabolism of R- and S-warfarin after a single 25-mg dose of warfarin.ClopidogrelMultiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.Strong Inhibitors of CYP3A4A priming dose of ketoconazole 400 mg (a strong inhibitor of CYP3A4), was given one day prior to coadministration ofsingle doses of ketoconazole 400 mg and cilostazol 100 mg. This regimen increased cilostazol C


max by 94% and AUC by


117%. Other strong inhibitors of CYP3A4, such as itraconazole, voriconazole, clarithromycin, ritonavir, saquinavir, andnefazodone would be expected to have a similar effect


[see Dosage and Administration (


2.2), Drug Interactions (


7.1)]


.


Moderate Inhibitors of CYP3A4Erythromycin 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 C


max 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 C


max of cilostazol by ~50%, but had no effect on AUC.


Inhibitors of CYP2C19Omeprazole: Coadministration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic


exposure to 3,4-dehydrocilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition ofCYP2C19


[see


Dosage and Administration (2.2)


].


QuinidineConcomitant administration of quinidine with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.LovastatinThe concomitant administration of lovastatin with cilostazol decreases cilostazol C


ss, max and AUC


τ by 15%. There is also a


decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatinincreases lovastatin and β-hydroxylovastatin AUC approximately 70% and is not expected to be clinically significant.

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/dayin rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered inboth 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


invivo 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. Atthis dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males, and about 5 times infemales, the exposure in humans at the MRHD.

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 13weeks, 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 ofthe smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery, and coronary arteritis andperiarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) tounbound cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mgtwice 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 13weeks of administration of cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unboundcilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at theMRHD. Cardiovascular lesions were also not seen in rats following 52 weeks of administration of cilostazol at doses up to150 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were about 0.5 and 5 times (male andfemale rats, respectively) the exposure in humans at the MRHD. In female rats, cilostazol AUCs were similar at 150 and1500 mg/kg/day. Cardiovascular lesions were also not observed in monkeys after oral administration of cilostazol for 13weeks at doses up to 1800 mg/kg/day. While this dose of cilostazol produced pharmacologic effects in monkeys, plasmacilostazol levels were less than those seen in humans given the MRHD, and those seen in dogs given doses associatedwith cardiovascular lesions.

14 Clinical Studies

The ability of cilostazol 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 of50 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 standardizedexercise treadmill tests.Compared to patients treated with placebo, patients treated with cilostazol 50 or 100 mg twice daily experiencedstatistically significant improvements in walking distances both for the distance before the onset of claudication pain andthe distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol onwalking 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.


Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol100 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 atherapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100mg twice daily or 50 mg twice daily reported improvements in their walking speed and walking distance as compared toplacebo. Improvements in walking performance were seen in the various subpopulations evaluated, including thosedefined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use ofbeta blockers or calcium channel blockers. Cilostazol 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 ofcilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. Thetrial 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 monthswas 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 besufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the


a priori study hypothesis.

16.1 How Supplied

Cilostazol tablets USP are available as follows:50 mg - white to off-white, pillow-shaped tablets, debossed with “TEVA” on one side and “7230” on the other, available in bottles of 60 (NDC 0093-2065-06).100 mg - white to off-white, round tablets, debossed with “TEVA” on one side and “7231” on the other, available in bottles of 60 (NDC 0093-2064-06) and 5000 (NDC 0093-2064-50).

16.2 Storage And Handling

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

17 Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Patient Information)Advise the patient:to take cilostazol 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 cilostazol 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 cilostazol if symptoms do not improve after 3 months.Manufactured For:Teva Pharmaceuticals USA, Inc.North Wales, PA 19454Rev. O 5/2017

Patient Information

  • Cilostazol (sil-OS-tah-zol) Tablets USP, for oral useRead this Patient Information leaflet before you start taking cilostazol tablets and each time you get a refill. There maybe 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 cilostazol tablets?Cilostazol tablets can cause serious side effects: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 cilostazol tablets if you have heart failure of any kind.
  • What are cilostazol tablets?Cilostazol tablets are a prescription medicine used to reduce the symptoms of intermittent claudication and can increaseyour ability to walk further distances.It is not known if cilostazol tablets are safe and effective for use in children.How do cilostazol tablets work?Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks.Who should not take cilostazol tablets?Do not take cilostazol tablets if you:have heart problems (heart failure)are allergic to cilostazol or any of the ingredients in cilostazol tablets. See the end of this leaflet for a complete list of ingredients in cilostazol tablets.Tell your doctor before taking this medicine if you have any of these conditions.What should I tell my doctor before taking cilostazol tablets?Before you take cilostazol tablets, tell your doctor if you:drink grapefruit juice. Taking cilostazol tablets and drinking grapefruit juice can increase the amount of cilostazol causing side effects.have any other medical conditionsare pregnant or planning to become pregnant. It is not known if cilostazol tablets will harm your unborn baby.are breastfeeding or planning to breastfeed. It is not known if cilostazol passes into your breast milk. You and your doctor should decide if you will take cilostazol tablets or breastfeed. You should not do both.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 ofmedicines that interact with cilostazol tablets. Know the medicines you take. Keep a list of them to show to your doctorand pharmacist when you get a new medicine.How should I take cilostazol tablets?Take cilostazol tablets exactly as your doctor tells you to take them.Your doctor will tell you how many cilostazol tablets to take and when to take them.Your doctor may change your dose if needed.Take cilostazol tablets
  • 30 minutes before you eat
  • Or 2 hours after you eat.
  • What are the possible side effects of cilostazol tablets?Cilostazol tablets may cause serious side effects, including:heart problems. Taking cilostazol tablets 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 cilostazol tablets?”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:
  • Hivesswelling of your face, lips, mouth, or tonguetrouble breathing or wheezingdizzinesschanges in your blood cell counts (thrombocytopenia or leukopenia). Your doctor should do blood tests to check your blood cell counts while you take cilostazol tablets.
  • The most common side effects of cilostazol tablets include:headacheabnormal stoolsdiarrheaTell your doctor if you have any side effect that bothers you or does not go away. These are not all the possibleside effects of cilostazol tablets. 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 cilostazol tablets?Store cilostazol tablets at 68° to 77°F (20° to 25°C).Keep cilostazol tablets and all medicines out of the reach of children.General information about the safe and effective use of cilostazol tablets.Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use cilostazol tablets for a condition for which they were not prescribed. Do not give cilostazol tablets to other people, even if they have the same symptoms that you have. They may harm them.This Patient Information summarizes the most important information about cilostazol tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about cilostazol tablets that is written for health professionals.For more information, call 1-888-838-2872.What are the ingredients in cilostazol tablets USP?Active ingredient: cilostazol, USP
  • Inactive ingredients: colloidal silicon dioxide, corn starch, crospovidone, magnesium stearate, microcrystalline cellulose, and povidone.
  • This Patient Information has been approved by the U.S. Food and Drug Administration.All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA, Inc.Manufactured For:Teva Pharmaceuticals USA, Inc.North Wales, PA 19454Rev. G 5/2017

* Please review the disclaimer below.

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