CILOSTAZOL tablet
For Healthcare Providers >

1. Cilostazol Tablets Can Cause Serious Side Effects:
2. What Are Cilostazol Tablets?
3. Do Not Take Cilostazol Tablets If You:
4. Before You Take Cilostazol Tablets, Tell Your Doctor If You:
5. How Should I Take Cilostazol Tablets?
6. Cilostazol Tablets May Cause Serious Side Effects, Including:
7. The Most Common Side Effects Of Cilostazol Tablets Include:
8. How Should I Store Cilostazol Tablets?
9. Active Ingredient:
10. What Are Cilostazol Tablets For?
11. What Is Intermittent Claudication?
12. The Three Main Treatments Available For Intermittent Claudication Are:
13. How Do Cilostazol Tablets Work?
14. Who Should Not Take Cilostazol Tablets?
15. How Should Cilostazol Tablets Be Taken?
16. Can Cilostazol Tablets Be Taken With Other Drugs?
17. What Are The Possible Side Effects Of Cilostazol Tablets?
18. Manufactured In India By:
19. Patient Information
20. Advise The Patient:
21. Manufactured For:
22. Cilostazol Can Cause Serious Side Effects:
23. What Is Cilostazol?
24. How Does Cilostazol Work?
25. Do Not Take Cilostazol If You:
26. Before You Take Cilostazol, Tell Your Doctor If You:
27. How Should I Take Cilostazol?
28. Cilostazol May Cause Serious Side Effects, Including:
29. Inactive Ingredients:

Cilostazol Tablets Can Cause Serious Side Effects: ⮝

• Cilostazol tablets stop 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 nottake 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 increase

your ability to walk further distances.

It is not known if cilostazol tablets are safe and effective for use in children.

Do Not Take Cilostazol Tablets If You: ⮝

• have heart problems (heart failure)
• are allergic to cilostazol or any of the ingredients in 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 tablets causing side effects.
• have any other medical conditions
• are 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 of

medicines that interact with cilostazol tablets. 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 Cilostazol Tablets? ⮝

• Take cilostazol tablets exactly as your doctor tells you to take it.
• Your doctor will tell you how many cilostazol tablets to take and when to take it.
• Your doctor may change your dose if needed.
• Take cilostazol tablets30 minutes beforeyou eator 2 hours afteryou eat.

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.
• 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:
  

hives swelling of your face, lips, mouth, or tongue

trouble breathing or wheezing dizziness

• changes 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: ⮝

headache abnormal stools

diarrhea

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 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 was 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.

Active Ingredient: ⮝

cilostazol, USP

What Are Cilostazol Tablets For? ⮝

Cilostazol tablets may improve the symptoms of patients with a medical condition called intermittent claudication.

What Is Intermittent Claudication? ⮝

Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.

The Three Main Treatments Available For Intermittent Claudication Are: ⮝

• Exercise. Your doctor may advise an exercise program.
• Medication. Your doctor may prescribe a medication such as cilostazol. ()
• Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.

How Do Cilostazol Tablets Work? ⮝

• The exact way that many drugs work is not well understood. Although how cilostazol tablets work is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.
• Cilostazol tablets may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.
• Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.
• Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol tablets have not been shown to work in patients with these problems.

Who Should Not Take Cilostazol Tablets? ⮝

• Patients who have congestive heart failure (CHF) must not take cilostazol.The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.
• Over 1,300 patients took cilostazol tablets in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.

How Should Cilostazol Tablets Be Taken? ⮝

• Follow your doctor s advice about how to take cilostazol tablets.
• You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.
• Do not share cilostazol tablets with anyone else. It was prescribed only for you.
• Keep cilostazol tablets and all drugs out of the reach of children.

Can Cilostazol Tablets Be Taken With Other Drugs? ⮝

Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.

Drugs Interacting with Cilostazol
Generic Name (Brand Name)	Type of Drug
erythromycin (such as E.E.S., Erythrocin)	Antibiotic
ketoconazole (Nizoral), itraconazole (Sporanox)	Antifungal
diltiazem (Cardizem)	Antihypertensive
omeprazole (Prilosec)	Gastric acid reducer

This list does not include every drug that may interact with cilostazol. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol.

What Are The Possible Side Effects Of Cilostazol Tablets? ⮝

Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate, and palpitations.

You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.

This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.

E.E.S.is a registered trademark of Abbott Laboratories Inc.

Erythrocinis a registered trademark of Hospira Inc.

Nizoraland Sporanoxare registered trademarks of Janssen Pharmaceutica Products, L.P.

Cardizemis a registered trademark of Biovail Labs INTL.

Prilosecis a registered trademark of the AstraZeneca group of companies.

Manufactured In India By: ⮝

PIRAMAL HEALTHCARE LIMITED

Pithampur, Madhya Pradesh, India

Patient Information ⮝

Rx only

Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed.This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol tablets when you start taking it and at regular check-ups. You should follow your doctor s advice about when to have check-ups.

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 19454

Rev. O 5/2017

Cilostazol 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 nottake cilostazol if you have heart failure of any kind.

What Is Cilostazol? ⮝

Cilostazol 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 cilostazol is safe and effective for use in children.

How Does Cilostazol Work? ⮝

Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks.

Do Not Take Cilostazol If You: ⮝

have heart problems (heart failure)

are allergic to cilostazol or any of the ingredients in cilostazol.

Before You Take Cilostazol, Tell Your Doctor If You: ⮝

drink grapefruit juice. Taking cilostazol and drinking grapefruit juice can increase the amount of cilostazol causing side effects.

have any other medical conditions

are pregnant or planning to become pregnant. It is not known if cilostazol 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 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 of medicines that interact with cilostazol. 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 Cilostazol? ⮝

Take cilostazol exactly as your doctor tells you to take it.

Your doctor will tell you how much cilostazol to take and when to take it.

Your doctor may change your dose if needed.

Take cilostazol30 minutes beforeyou eator 2 hours afteryou eat.

Cilostazol May Cause Serious Side Effects, Including: ⮝

heart problems.Taking cilostazol may cause you to have heart problems, including a fast heartbeat, palpitations, irregular heartbeat, and low blood pressure.

Store cilostazol at room temperature between 20 C to 25 C (68 F to 77 F). [Store at USP Controlled Room Temperature.]

Keep cilostazol and all medicines out of the reach of children.

General information about the safe and effective use of cilostazol.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use cilostazol for a condition for which it was not prescribed. Do not give cilostazol 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 cilostazol. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about cilostazol that is written for health professionals.

For more information, call 1-800-962-8364.

Inactive Ingredients: ⮝

colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose.

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

Distr. by:West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003054/08

Revised April 2016

1. No Title 1572547992
2. Special Populations:
3. Clinical Studies:
4. Patient Information About Cilostazol (sil-os-tah-zol) Tablets, Usp
5. Package Label Principal Display Panel
6. Contraindication
7. Description
8. Clinical Pharmacology
9. Clinical Studies
10. Indications And Usage
11. Contraindications
12. Precautions
13. Adverse Reactions
14. Overdosage
15. Dosage And Administration
16. How Supplied
17. Principal Display Panel - 100mg
18. 16 How Supplied
19. Package/label Display Panel
20. Warning: Contraindicated In Heart Failure Patientssee Full Prescribing Information For Complete Boxed Warning.
21. Warning: Contraindicated In Heart Failure Patients
22. Principal Display Panel For 50 Mg
23. Principal Display Panel For 100 Mg
24. Highlights Of Prescribing Information
25. Warning: Contraindicated In Heart Failure Patients
26. See Full Prescribing Information For Complete Boxed Warning.
27. Dosage Forms And Strengths
28. Warnings And Precautions
29. Drug Interactions
30. 16 How Supplied/storage And Handling
31. Cilostazol
32. 1 Indications And Usage
33. 2 Dosage And Administration
34. 3 Dosage Forms And Strengths
35. 4 Contraindications
36. 5 Warnings And Precautions
37. 6 Adverse Reactions
38. 7 Drug Interactions
39. 8 Use In Specific Populations
40. 10 Overdosage
41. 11 Description
42. 12 Clinical Pharmacology
43. 13 Nonclinical Toxicology
44. 14 Clinical Studies
45. Cilstazol
46. Cilostazol Tablets50 Mg And 100 Mgrx Only
47. Distribution:
48. Inhibitors Of Cyp3a4
49. Repackaging Information
50. Package/label Principal Display Panel
51. No Title 1572453857
52. Principal Display Panel
53. Storage
54. Principal Display
55. Principal Display Panel - 100mg
56. Recent Major Changes
57. Warning: Contraindicated In Heart Failure Patients
58. 1 Indications And Usage
59. 2 Dosage And Administration
60. 3 Dosage Forms And Strengths
61. 4 Contraindications
62. 5 Warnings And Precautions
63. 6 Adverse Reactions
64. 7 Drug Interactions
65. 8 Use In Specific Populations
66. 10 Overdosage
67. 11 Description
68. 12 Clinical Pharmacology
69. 13 Nonclinical Toxicology
70. 14 Clinical Studies
71. 16 How Supplied/storage And Handling

No Title 1572547992 ⮝

PATIENT INFORMATION

Cilostazol (sil-OS-tah-zol) Tablets USP, for oral use

Read this Patient Information leaflet before you start taking cilostazol tablets 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 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 increase your 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 conditions
  
• are 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 of medicines that interact with cilostazol tablets. 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 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:
  o hives
  o swelling of your face, lips, mouth, or tongue
  o trouble breathing or wheezing
  o dizziness
  
• changes 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:

• headache
  
• abnormal stools
  
• diarrhea

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 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 1-888-341-9214

What are the ingredients in cilostazol tablets USP?

Active ingredient: cilostazol, USP

Inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, 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 Slate Run Pharmaceuticals, LLC.

Manufactured By:

Frontida Biopharm, Inc.

Philadelphia, PA 19124

Distributed By:

Slate Run Pharmaceuticals, LLC

Columbus, OH 43215

10000098/01

Rev. 00, 10/2017

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 and/or gender across a 50-to-80-year-old age range.

Smokers

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

Hepatic Impairment

The pharmacokinetics of cilostazol and its metabolites were similar 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 normal subjects. Severe renal impairment increases metabolite levels and alters protein bindingof the parent and metabolites. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of patent 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 to 98%).

Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions:
Cilostazol could have pharmacodynamic interactions with other inhibitors of platelet function and pharmacokinetic interactions because of effects of other drugs on its metabolism by CYP3A4 or CYP2C19. A reduced dose of Cilostazol Tablets, USP should be considered when taken concomitantly with CYP3A4 or CYP2C19 inhibitors. Cilostazol does not appear to inhibit CYP3A4 (see Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions, Lovastatin ).

Aspirin

Short-term ( 4 days) coadministration of aspirin with Cilostazol Tablets, USP increased the inhibition of arachidonic acid-induced ex vivoplatelet aggregation by 20% compared to Cilostazol Tablets, USP alone and by 48% compared to aspirin alone. However, short-term coadministration of aspirin with Cilostazol Tablets, USP 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 wer 75 to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increases in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.

Warfarin

The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2, and CYP2C19, and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effecr of concomitant multiple dosing of warfarin and Cilostozol Tablets, USP on the pharmacokinetics and pharmacodynamics of both drugs is unknown.

Clopidogrel

Mulitiple doses of clopidogrel do not significantly increase steadystate plasma concentrations of cilostzol.

INHIBITORS OF CYP3A4

Strong Inhibitors of CYP3A4:
A priming dose of ketoconazole 400 mg (a strong inhibitor of CYP3A4), was given one day prior to coadminstration 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 intraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, and sertraline, would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION ).

Moderate Inhibitors of CYP3A4:
1. Erythromycin and other macrolide antibiotics: Erythromycin is a moderately strong inhibitor of CYP3A4. Coadministration of erythromycin 500 mg q 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%. Other macrolide antibiotics (e.g., clarithromycin), but not all (e.g. azithromycin), would be expected to have a similar efect (see DOSAGE AND ADMINISTRATION ).
2. Diltiazem: Diltiazem 180 mg decreased the clearance of cilostazol by ~30% and AUC increased ~40% (see DOSAGE AND ADMINITRATION ).
3. Grapefruit Juice: Grapefruit juice increased the Cmax of cilostazol by ~50%, but had not 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).

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 AUC, by 15%. There is also a decrease, although nonsignificant, in cilostazole metaboite concentrations. Coadministration of cilostazole with lovastatin increased lovastatin and -hydroxi lovastatin AUC approximately 70%. This is most likely clinically insignificant.

Clinical Studies: ⮝

The ability of Cilostazol Tablets, USP to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (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 Cilostazol Tablets, USP 50 or 100 mg b.i.d. 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 Cilostazol Tablets, USP on walking distance was seen as early as the first on-therapy observation point of two or four weeks.

The following figure depicts the percent mean improvement in maximal walking distance at study end for each of the eight studies.

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 Cilostazol Tablets, USP
100 mg b.i.d., expressed as the percent mean 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 Cilostazol Tablets, USP 100 mg b.i.d. or 50 mg b.i.d. 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 of calcium channel blockers. Cilostazol Tablets, USP 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 the 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 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 s the a priori study hypothesis.

Patient Information About Cilostazol (sil-os-tah-zol) Tablets, Usp ⮝

Cilostazol Tablets 50 mg and 100 mg

Please read this leaflet before you start taking cilostazol and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor s advice about when to have check-ups.

What is Cilostazol Tablets, USP for?

Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.

What is intermittent claudication?

Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.

What treatments are available for intermittent claudication?

The three main treatments available for intermittent claudication are:

• Exercise. Your doctor may advise an exercise program.
• Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol?)
• Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.

How does Cilostazol Tablets, USP work?

• The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting
• Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.
• Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol after 12 weeks you and your doctor may wish to discuss other forms of treatment.
• Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.

Who should not take Cilostazol Tablets, USP?

• Patients who have congestive heart failure (CHF) must not take cilostazol.
  The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms.
• Patients who have bleeding problems, such as a bleeding peptic ulcer, must not take cilostazol.
  Cilostazol decreases the ability of blood particles, called platelets, to stick together and this can increase the risk of bleeding.
  It is important that you discuss with your doctor whether you have CHF or bleeding problems.
• Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.

How should Cilostazol Tablets, USP be taken?

• Follow your doctor"s advice about how to take cilostazol.
• You should take cilostazol twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol at about the same times each day.
• Do not share cilostazol with anyone else. It was prescribed only for you.
• Keep cilostazol and all drugs out of the reach of children.

Can Cilostazol Tablets, USP be taken with other drugs?

Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.

Drugs Interacting With Cilostazol
Generic Name (Brand Name)	Type of Drug
erythromycin (such as E.E.S. , Erythrocin )	Antibiotic
ketoconazole (Nizoral ), itraconazole (Sporanox )	Antifungal
diltiazem (Cardizem )	Antihypertensive
omeprazole (Prilosec )	Gastric acid reducer

This list does not include every drug that may interact with cilostazol. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol.

What are the possible side effects of CIlostazol Tablets, USP?

Cilostazol may cause side effects including headache, diarrhea, abnormal stools, increased heart rate, and palpitations.

You should discuss possible side effects with your doctor before taking cilostazol and any time you think you are having a side effect.

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

This provides only a summary of information about cilostazol. If you have any questions about cilostazol, talk to your doctor.

Rev. October, 2009
MF # 334-04

Manufactured and Distributed by:
Corepharma LLC
Middlesex, NJ 08846

Package Label Principal Display Panel ⮝

Cilostazol Tablets, USP 100mg

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:54868-5411(NDC:64720-159) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 100 mg

Inactive Ingredients Ingredient Name Strength CARBOXYMETHYLCELLULOSE CALCIUM (UNII: UTY7PDF93L) STARCH, CORN (UNII: O8232NY3SJ) HYPROMELLOSES (UNII: 3NXW29V3WO) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)

Product Characteristics Color white (White) Score no score Shape ROUND (round) Size 10mm Flavor Imprint Code cor;159 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:54868-5411-0 60 in 1 BOTTLE, PLASTIC 2 NDC:54868-5411-1 30 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077022 09/09/2005

Labeler - Physicians Total Care, Inc. (194123980)

Establishment
Name	Address	ID/FEI	Business Operations
Physicians Total Care, Inc.		194123980	relabel, repack

Revised: 11/2010 Document Id: 22f68cbf-a96c-442a-a124-082f276cd6c3 34391-3 Set id: 151d1497-7655-44ce-8e97-dd1cd91f686a Version: 2 Effective Time: 20101115 Physicians Total Care, Inc.

Contraindication ⮝

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 congestive heart failure. Cilostazol is contraindicated in patients with congestive heart failure of any severity.

Description ⮝

Cilostazol, USP is a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase III). Cilostazol, USP is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.

The structural formula is:

C20H27N5O2 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, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, and starch.

Meets USP Dissolution Test 3.

Clinical Pharmacology ⮝

Mechanism of Action

The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant 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. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL ( 10%).

Cardiovascular Effects

Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogenous 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 cynomolgous 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 b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained ventricular tachycardia events than did placebo-treated patients; the increases were not dose-related.

Pharmacokinetics

Cilostazol 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 cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-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 normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).

The mean SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below:

Distribution

Plasma Protein and Erythrocyte Binding

Cilostazol is 95 to 98% protein bound, predominantly to albumin. The mean percent 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 normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.

Metabolism and Excretion

Cilostazol is eliminated predominately 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 to 7 times as active as cilostazol), and 4% was 4'-trans-hydroxy-cilostazol (one fifth as active as cilostazol). 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 the 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 and/or gender across a 50- to 80-year-old age range.

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 normal subjects. Severe renal impairment increases metabolite levels and alters protein binding of the parent and metabolites. 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 to 98%).

Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions

Cilostazol could have pharmacodynamic interactions with other inhibitors of platelet function and pharmacokinetic interactions because of effects of other drugs on its metabolism by CYP3A4 or CYP2C19. A reduced dose of cilostazol should be considered when taken concomitantly with CYP3A4 or CYP2C19 inhibitors. Cilostazol does not appear to inhibit CYP3A4 (see Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions, Lovastatin).

Aspirin

Short-term ( 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 ( 4 days) coadministration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo 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 201 patients. 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 incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.

Warfarin

The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2, and CYP2C19, and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or 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 the pharmacokinetics and pharmacodynamics of both drugs is unknown.

Clopidogrel

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

Inhibitors of CYP3A4

Strong inhibitors of CY3A4

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, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, and sertraline, would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION).

Moderate inhibitors of CYP3A4

1. Erythromycin and other macrolide antibiotics: Erythromycin is a moderately strong inhibitor of CYP3A4. Coadministration of erythromycin 500 mg q8h 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%. Other macrolide antibiotics (e.g., clarithromycin), but not all (e.g., azithromycin), would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION).
2. Diltiazem: Diltiazem 180 mg decreased the clearance of cilostazol by ~ 30%. Cilostazol Cmax increased ~ 30% and AUC increased ~ 40% (see DOSAGE AND ADMINISTRATION).
3. 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).

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 AUC by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatin increases lovastatin and -hydroxi lovastatin AUC approximately 70%. This is most likely clinically insignificant.

Clinical Studies ⮝

The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks' duration using dosages of 50 mg b.i.d. (n = 303), 100 mg b.i.d. (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 cilostazol 50 or 100 mg b.i.d. 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 cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.

The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.

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 cilostazol 100 mg b.i.d., expressed as the percent mean 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 cilostazol 100 mg b.i.d. or 50 mg b.i.d. 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. 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 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% Cl of 2.8 to 8.4 %) on cilostazol and 6.8% (95% Cl 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.

Indications And Usage ⮝

Cilostazol tablets are a phosphodiesterase III inhibitor (PDE III inhibitor) indicated for the reduction of symptoms of intermittent claudication, as demonstrated by an increased walking distance ( 1)

Contraindications ⮝

• Heart failure of any severity ( 4)
• Hypersensitivity to cilostazol or any components of cilostazol tablets ( 4)

Precautions ⮝

Hematologic Adverse Reactions

Rare cases have been reported of thrombocytopenia or leukopenia progressing to agranulocytosis when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.

Use With Clopidogrel

There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and clopidogrel, a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and clopidogrel, caution is advised for checking bleeding times during coadministration.

Information for Patients

Please refer to the patient package insert.

Patients should be advised:

• to read the patient package insert for cilostazol tablets carefully before starting therapy and to reread it each time therapy is renewed in case the information has changed.
• to take cilostazol tablets at least one-half hour before or two hours after food.
• that the beneficial effects of cilostazol tablets 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.

Hepatic Impairment

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

Special caution is advised when cilostazol is used in such patients.

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%).

Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance < 25 mL/min.

Drug Interactions

Since cilostazol is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when cilostazol is coadministered with inhibitors of CYP3A4 such as ketoconazole and erythromycin or inhibitors of CYP2C19 such as omeprazole. Pharmacokinetic studies have demonstrated that omeprazole and erythromycin significantly increased the systemic exposure of cilostazol and/or its major metabolites. Population pharmacokinetic studies showed higher concentrations of cilostazol among patients concurrently treated with diltiazem, an inhibitor of CYP3A4 (see CLINICAL PHARMACOLOGY, Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions). Cilostazol does not, however, appear to cause increased blood levels of drugs metabolized by CYP3A4, as it had no effect on lovastatin, a drug with metabolism very sensitive to CYP3A4 inhibition.

Use With Other Antiplatelet Agents

Cilostazol inhibits platelet aggregation but in a reversible manner. Caution is advised in patients at risk of bleeding from surgery or pathologic processes. Platelet aggregability returns to normal within 96 hours of stopping cilostazol. Caution is advised in patients receiving both cilostazol and any other antiplatelet agent, or in patients with thrombocytopenia.

Cardiovascular Toxicity

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 b.i.d. 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.

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.

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.

Pregnancy

Teratogenic Effects

Pregnancy category C

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).

There are no adequate and well-controlled studies in pregnant women.

Nursing Mothers

Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol.

Pediatric Use

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

Geriatric Use

Of the total number of subjects (n = 2274) in clinical studies of cilostazol, 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 ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of cilostazol and its metabolites.

Adverse Reactions ⮝

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, abnormal stools, and palpitation ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safety@tevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Overdosage ⮝

Information on acute overdosage with cilostazol 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 > 5.0 g/kg in mice and rats and > 2.0 g/kg in dogs.

Dosage And Administration ⮝

• 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 ( 2.1)
• Reduce the dose to 50 mg twice daily when coadministered with CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, and diltiazem, or CYP2C19 inhibitors such as ticlopidine, fluconazole, and omeprazole ( 2.2)

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 blisterpacks of 30.

100 mg - white to off-white, round tablets, debossed with TEVA on one side and 7231 on the other, available in blisterpacks of 30.

Principal Display Panel - 100mg ⮝

NDC 71610-037 Cilostazol 100mg - Rx Only

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71610-037(NDC:0185-0223) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 100 mg

Inactive Ingredients Ingredient Name Strength CARBOXYMETHYLCELLULOSE CALCIUM (UNII: UTY7PDF93L) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) STARCH, CORN (UNII: O8232NY3SJ) METHYLCELLULOSE (15 MPA.S) (UNII: NPU9M2E6L8)

Product Characteristics Color WHITE Score no score Shape ROUND Size 9mm Flavor Imprint Code E;223 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71610-037-53 60 in 1 BOTTLE; Type 0: Not a Combination Product 02/02/2018 2 NDC:71610-037-60 90 in 1 BOTTLE; Type 0: Not a Combination Product 02/02/2018 3 NDC:71610-037-80 180 in 1 BOTTLE; Type 0: Not a Combination Product 02/02/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077021 11/23/2004

Labeler - Aphena Pharma Solutions - Tennessee, LLC (128385585)

Establishment
Name	Address	ID/FEI	Business Operations
Aphena Pharma Solutions - Tennessee, LLC		128385585	REPACK(71610-037)

Revised: 2/2018 Document Id: 64560280-1d4e-47ff-a839-3a3bef49e760 34391-3 Set id: 55ae41fb-6c59-4f41-bdc6-db7f75e98e00 Version: 1 Effective Time: 20180220 Aphena Pharma Solutions - Tennessee, LLC

16 How Supplied ⮝

NDC 68071-4125-6 Bottles of 60

16.1 How Supplied

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 68071-4125)

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.

Package/label Display Panel ⮝

Cilostazol Tablets USP 50 mg 60s Label Text

NDC 0093 -2065-06

Cilostazol
Tablets USP
50 mg

PHARMACIST: PLEASE DISPENSE WITH
ATTACHED PATIENT INFORMATION LEAFLET

Rx only

60 TABLETS

TEVA

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68071-2052(NDC:0093-2065) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 50 mg

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

Product Characteristics Color white (white to off-white) Score no score Shape SQUARE (pillow-shaped) Size 6mm Flavor Imprint Code TEVA;7230 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68071-2052-3 30 in 1 BOTTLE; Type 0: Not a Combination Product 01/24/2017

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077027 04/24/2012

Labeler - NuCare Pharmaceuticals, Inc. (010632300)

Establishment
Name	Address	ID/FEI	Business Operations
NuCare Pharmaceuticals, Inc.		010632300	repack(68071-2052)

Revised: 1/2017 Document Id: 46e0afbd-4b3e-4b8b-e054-00144ff88e88 34391-3 Set id: 46e0afbd-4b3d-4b8b-e054-00144ff88e88 Version: 1 Effective Time: 20170124 NuCare Pharmaceuticals, Inc.

Warning: Contraindicated In Heart Failure Patientssee Full Prescribing Information For Complete Boxed Warning.  ⮝

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

Warning: Contraindicated In Heart Failure Patients  ⮝

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 [see Contraindications (4)].

Principal Display Panel For 50 Mg ⮝

Representative sample of labeling (see HOW SUPPLIED section of complete listing): APOTEX CORP. NDC 60505-2521-1 Cilostazol Tablets, USP 50 mg Rx 60 count

Principal Display Panel For 100 Mg ⮝

Representative sample of labeling (see HOW SUPPLIED section of complete listing): APOTEX CORP. NDC 60505-2522-1 Cilostazol Tablets, USP 100 mg Rx 60 count

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-2521 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cilostazol (UNII: N7Z035406B) (cilostazol - UNII:N7Z035406B) cilostazol 50 mg

Inactive Ingredients Ingredient Name Strength starch, corn (UNII: O8232NY3SJ) croscarmellose sodium (UNII: M28OL1HH48) magnesium stearate (UNII: 70097M6I30) silicon dioxide (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score no score Shape ROUND Size 7mm Flavor Imprint Code APO;CIL;50 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-2521-3 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/18/2011 2 NDC:60505-2521-1 60 in 1 BOTTLE; Type 0: Not a Combination Product 10/18/2011 3 NDC:60505-2521-8 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/18/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077030 10/18/2011

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-2522 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cilostazol (UNII: N7Z035406B) (cilostazol - UNII:N7Z035406B) cilostazol 100 mg

Inactive Ingredients Ingredient Name Strength starch, corn (UNII: O8232NY3SJ) croscarmellose sodium (UNII: M28OL1HH48) magnesium stearate (UNII: 70097M6I30) silicon dioxide (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score no score Shape ROUND Size 9mm Flavor Imprint Code APO;CIL;100 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-2522-3 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/18/2011 2 NDC:60505-2522-1 60 in 1 BOTTLE; Type 0: Not a Combination Product 10/18/2011 3 NDC:60505-2522-8 1000 in 1 BOTTLE; Type 0: Not a Combination Product 10/18/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077030 10/18/2011

Labeler - Apotex Corp. (845263701)

Registrant - Apotex Inc. (209429182)

Establishment
Name	Address	ID/FEI	Business Operations
Apotex Inc.		209429182	analysis(60505-2521, 60505-2522) , manufacture(60505-2521, 60505-2522)

Revised: 11/2018 Document Id: ed9d7023-9c8e-fb3f-388e-36bdb0d0bf06 34391-3 Set id: ceac1ae3-c343-28ca-c083-b748d21a15e6 Version: 7 Effective Time: 20181123 Apotex Corp.

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use CILOSTAZOL TABLETS safely and effectively. See full prescribing information for CILOSTAZOL TABLETS.

CILOSTAZOL tablets, for oral use

Initial U.S. Approval: 1999

Warning: Contraindicated In Heart Failure Patients  ⮝

Cilostazol 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 Full Prescribing Information For Complete Boxed Warning. ⮝

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

Dosage Forms And Strengths ⮝

• Tablets: 50 mg and 100 mg ( 3)

Warnings And Precautions ⮝

• Risks of tachycardia, palpitation, tachyarrhythmia or hypotension. Risks of exacerbations of angina pectoris or myocardial infarction in patients with a history of ischemic heart disease ( 5.1)
• Risks of thrombocytopenia or leukopenia progressing to agranulocytosis--monitor platelets and white blood cell counts ( 5.2)
• Avoid use in patients with hemostatic disorders or active pathologic bleeding ( 5.3)

Drug Interactions ⮝

• Strong and moderate CYP3A4 and CYP2C19 inhibitors: Increase exposure to cilostazol. Reduce cilostazol dose ( 2.2, 7.1)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 6/2016

16 How Supplied/storage And Handling  ⮝

Product: 50090-3509

NDC: 50090-3509-0 30 TABLET in a BOTTLE

Cilostazol ⮝

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-3509(NDC:0054-0028) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 50 mg

Inactive Ingredients Ingredient Name Strength HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code 54;521 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-3509-0 30 in 1 BOTTLE; Type 0: Not a Combination Product 07/25/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077024 05/17/2005

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-3509) , REPACK(50090-3509)

Revised: 7/2018 Document Id: 61333b63-da2a-4114-bca1-67e784b8e999 34391-3 Set id: 81b5b4f1-4324-416b-9b65-ea476017d7e6 Version: 1 Effective Time: 20180725 A-S Medication Solutions

1 Indications And Usage  ⮝

Cilostazol tablets are 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 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, and

omeprazole) [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 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 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 and

white blood cell counts periodically.

5.3 Hemostatic Disorders or Active Pathologic Bleeding

Cilostazol inhibits platelet aggregation in a reversible manner. Cilostazol has not been studied in patients with hemostatic

disorders 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)]

- Hematologic Adverse Reactions [see Warnings and Precautions (5.2)]

- Hemostatic Disorders or Active Pathologic Bleeding [see Warnings and Precautions (5.3)]

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 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 with

cilostazol 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 Reactions	Placebo (N = 973)	Cilostazol 50 mg twice daily (N = 303)	Cilostazol 100 mg twice daily (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 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 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.

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

Coadministration of strong (e.g., ketoconazole) and moderate (e.g., erythromycin, diltiazem and grapefruit juice) CYP3A4

inhibitors can increase exposure to cilostazol. Reduce cilostazol 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 cilostazol active

metabolites. Reduce cilostazol 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.

Cilostazol 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-dehydrocilostazol 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 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, 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.

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 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 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 LD 50

of 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 Clinical Pharmacology  ⮝

12.1 Mechanism of Action

Cilostazol 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.

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 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 cilostazol. After 12 weeks, as compared to

placebo, 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 Interactions

Aspirin

Short-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 201

patients. 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.

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 cilostazol on the

pharmacodynamics of both drugs is unknown.

12.3 Pharmacokinetics

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

in 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 III

inhibition) activity after administration of cilostazol.

Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination

half-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 SEM plasma concentration-time profile at steady state after multiple dosing of

cilostazol 100 mg twice daily.

Distribution

Cilostazol is 95 to 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

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 to 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-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 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 to 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

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 C max 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 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 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 C ss, max and AUC by 15%. There is also a

decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatin

increases lovastatin and -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.

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.

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 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 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 cilostazol 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 cilostazol 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.

Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol

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 cilostazol 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. 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 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.

Cilstazol ⮝

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68151-3844(NDC:0054-0028) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 50 mg

Inactive Ingredients Ingredient Name Strength HYPROMELLOSES (UNII: 3NXW29V3WO) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code 54;521 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68151-3844-2 1 in 1 PACKAGE; Type 0: Not a Combination Product 05/17/2005

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077024 05/17/2005

Labeler - Carilion Materials Management (079239644)

Establishment
Name	Address	ID/FEI	Business Operations
Carilion Materials Management		079239644	REPACK(68151-3844)

Revised: 8/2016 Document Id: 211b3b29-35eb-460c-962b-eba72c1b070a 34391-3 Set id: eb510ad0-dce7-4714-afc6-7959a151ad28 Version: 3 Effective Time: 20160806 Carilion Materials Management

Cilostazol Tablets50 Mg And 100 Mgrx Only ⮝

CONTRAINDICATION
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 congestive heart failure. Cilostazol is contraindicated in patients with congestive heart failure of any severity.

DESCRIPTION
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.

Cilostazol tablets for oral administration are available as 50 mg or 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: carboxymethylcellulose calcium, corn starch, hypromellose, magnesium stearate and microcrystalline cellulose.

Distribution: ⮝

Plasma Protein and Erythrocyte Binding: Cilostazol is 95%-98% protein bound, predominantly to albumin. The mean percent 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 normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.

Metabolism and Excretion:
Cilostazol is eliminated predominately 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 (one fifth as active as cilostazol). 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.

Inhibitors Of Cyp3a4 ⮝

Strong Inhibitors of CYP3A4: 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, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, and sertraline, would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION).

Moderate Inhibitors of CYP3A4 :

1. Erythromycin and other macrolide antibiotics: Erythromycin is a moderately strong inhibitor of CYP3A4. Coadministration of erythromycin 500 mg q 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%. Other macrolide antibiotics (e.g., clarithromycin), but not all (e.g., azithromycin), would be expected to have a similar effect (see DOSAGE AND ADMINISTRATION).
2. Diltiazem: Diltiazem 180 mg decreased the clearance of cilostazol by 30%. Cilostazol Cmax increased 30% and AUC increased 40% (see DOSAGE AND ADMINISTRATION).
3. 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 of 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole's potent inhibition of CYP2C19 (see DOSAGE AND ADMINISTRATION).

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 AUC by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatin increases lovastatin and -hydroxi lovastatin AUC approximately 70%. This is most likely clinically insignificant.

Repackaging Information ⮝

Please reference the How Supplied section listed above for a description of individual tablets. This drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:

Count	100 mg
60	71610-037-53
90	71610-037-60
180	71610-037-80

Store between 20 -25 C (68 -77 F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.

Repackaged by:

Cookeville, TN 38506

20180220DKJ

Package/label Principal Display Panel  ⮝

Cilostazol Tablets USP, 100 mg

0054-0044-21

Rx only

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0054-0028 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 50 mg

Inactive Ingredients Ingredient Name Strength HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code 54;521 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0054-0028-21 60 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2005

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077024 05/17/2005

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0054-0044 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 100 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)

Product Characteristics Color WHITE Score no score Shape ROUND Size 7mm Flavor Imprint Code 54;757 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0054-0044-21 60 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2005 2 NDC:0054-0044-29 500 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2005

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077024 05/17/2005

Labeler - West-Ward Pharmaceuticals Corp. (080189610)

Establishment
Name	Address	ID/FEI	Business Operations
West-Ward Columbus Inc.		058839929	MANUFACTURE(0054-0028, 0054-0044)

Revised: 7/2017 Document Id: 22e44fc6-35df-4e96-96b6-31054e157a9a 34391-3 Set id: 9ffdb1e8-fdc8-44d4-b558-210954138b2f Version: 14 Effective Time: 20170714 West-Ward Pharmaceuticals Corp.

No Title 1572453857 ⮝

PATIENT INFORMATION

Cilostazol (sil-OS-tah-zol) Tablets USP, for oral use

Read this Patient Information leaflet before you start taking cilostazol tablets 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 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 increase your 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 conditions
  
• are 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 of medicines that interact with cilostazol tablets. 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 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:
  o hives
  o swelling of your face, lips, mouth, or tongue
  o trouble breathing or wheezing
  o dizziness
  
• changes 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:

• headache
  
• abnormal stools
  
• diarrhea

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 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 1-888-341-9214

What are the ingredients in cilostazol tablets USP?

Active ingredient: cilostazol, USP

Inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, 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 Slate Run Pharmaceuticals, LLC.

Manufactured By:

Frontida Biopharm, Inc.

Philadelphia, PA 19124

Distributed By:

Slate Run Pharmaceuticals, LLC

Columbus, OH 43215

10000098/01

Rev. 00, 10/2017

Principal Display Panel ⮝

NDC 70436-051-06
Cilostazol
Tablets USP
100 mg
60 Tablets
Rx Only

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70436-050 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 50 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (UNII: 2S7830E561) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE (UNII: FZ989GH94E)

Product Characteristics Color WHITE Score no score Shape ROUND Size 9mm Flavor Imprint Code MP;474 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:70436-050-06 60 in 1 BOTTLE; Type 0: Not a Combination Product 01/01/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077208 01/01/2018

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70436-051 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 100 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (UNII: 2S7830E561) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE (UNII: FZ989GH94E)

Product Characteristics Color WHITE Score no score Shape ROUND Size 10mm Flavor Imprint Code MP;475 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:70436-051-06 60 in 1 BOTTLE; Type 0: Not a Combination Product 01/01/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077208 01/01/2018

Labeler - Slate Run Pharmaceuticals (039452765)

Revised: 10/2017 Document Id: b036e172-9bd4-4430-814a-aa12cf1a67be 34391-3 Set id: 93063635-6785-4847-a6ae-66eaec851831 Version: 1 Effective Time: 20171001 Slate Run Pharmaceuticals

Storage ⮝

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.

Manufactured In India By:

PIRAMAL ENTERPRISES LIMITED

Pithampur, Madhya Pradesh, India

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. K 6/2012

Principal Display ⮝

Cilostazol Tablets, USP

100 mg

Contains Approximately 12060 Tablets

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55154-6671(NDC:60505-2522) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cilostazol (UNII: N7Z035406B) (cilostazol - UNII:N7Z035406B) cilostazol 100 mg

Inactive Ingredients Ingredient Name Strength starch, corn (UNII: O8232NY3SJ) croscarmellose sodium (UNII: M28OL1HH48) magnesium stearate (UNII: 70097M6I30) silicon dioxide (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score no score Shape ROUND Size 9mm Flavor Imprint Code APO;CIL;100 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55154-6671-8 12060 in 1 BOTTLE; Type 0: Not a Combination Product 10/18/2011

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077030 10/18/2011

Labeler - Cardinal Health (188557102)

Registrant - Apotex Inc. (209429182)

Establishment
Name	Address	ID/FEI	Business Operations
Cardinal Health		188557102	REPACK(55154-6671)

Revised: 1/2018 Document Id: acc19269-1a54-4a0d-92dd-e4e7a69ed7b0 34391-3 Set id: 85fc5079-ec88-450e-9c0b-bca7340cad4f Version: 3 Effective Time: 20180105 Cardinal Health

Principal Display Panel - 100mg ⮝

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0615-7747(NDC:0093-2064) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 100 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSPOVIDONE (UNII: 68401960MK) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POVIDONES (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ)

Product Characteristics Color WHITE (white to off-white) Score no score Shape ROUND Size 8mm Flavor Imprint Code TEVA;7231 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0615-7747-39 30 in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077027 03/23/2012

CILOSTAZOL cilostazol tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0615-7716(NDC:0093-2065) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CILOSTAZOL (UNII: N7Z035406B) (CILOSTAZOL - UNII:N7Z035406B) CILOSTAZOL 50 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSPOVIDONE (UNII: 68401960MK) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POVIDONES (UNII: FZ989GH94E) STARCH, CORN (UNII: O8232NY3SJ)

Product Characteristics Color WHITE (white to off-white) Score no score Shape SQUARE (pillow-shaped) Size 6mm Flavor Imprint Code TEVA;7230 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0615-7716-39 30 in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077027 06/26/2012

Labeler - NCS HealthCare of KY, Inc dba Vangard Labs (050052943)

Establishment
Name	Address	ID/FEI	Business Operations
NCS HealthCare of KY, Inc dba Vangard Labs		050052943	RELABEL(0615-7747, 0615-7716) , REPACK(0615-7747, 0615-7716)

Revised: 10/2013 Document Id: 84fd20f2-c938-45d9-8550-20c350d3f631 34391-3 Set id: 66e0ed7b-e29a-45ee-82bb-3db6142c2697 Version: 6 Effective Time: 20131009 NCS HealthCare of KY, Inc dba Vangard Labs

Recent Major Changes ⮝

Warnings and Precautions, Left Ventricular Outflow Obstruction ( 5.2) 05/2017

Warning: Contraindicated In Heart Failure Patients ⮝

Cilostazol 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 ⮝

Cilostazol tablets are 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 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, and

omeprazole) [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 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.

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 and

white 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 hemostatic

disorders 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 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 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 with

cilostazol 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 Reactions	Placebo (N = 973)	Cilostazol 50 mg twice daily (N = 303)	Cilostazol 100 mg twice daily (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 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 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.

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

Coadministration of strong (e.g., ketoconazole) and moderate (e.g., erythromycin, diltiazem and grapefruit juice) CYP3A4

inhibitors can increase exposure to cilostazol. Reduce cilostazol 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 cilostazol active

metabolites. Reduce cilostazol 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.

Cilostazol 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-dehydrocilostazol 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 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, 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.

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 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 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 LD 50

of 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 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Cilostazol 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.

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 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 cilostazol. After 12 weeks, as compared to

placebo, 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 Interactions

Aspirin

Short-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 201

patients. 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.

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 cilostazol on the

pharmacodynamics of both drugs is unknown.

12.3 Pharmacokinetics

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

in 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 III

inhibition) activity after administration of cilostazol.

Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination

half-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.

Distribution

Cilostazol is 95 to 98% protein bound, predominantly to albumin. The binding for 3,4-dehydrocilostazol 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

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-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 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-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 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 to 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

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 C max 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 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 CYP2C19

Omeprazole: 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 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 C ss, max and AUC by 15%. There is also a

decrease, although nonsignificant, in cilostazol metabolite concentrations. Coadministration of cilostazol with lovastatin

increases lovastatin and -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.

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 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 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 cilostazol 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 cilostazol 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.

Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol

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 cilostazol 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. 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 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

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 30 (NDC 68071-2052-3).

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.