Cilostazol (Page 4 of 4)

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

Cilostazol tablets, USP 100 mg tablets are white, round, flat-faced, bevelled-edge tablets, engraved “APO” on one side and “CIL” over “100” on the other side. They are supplied as follows:

NDC: 70518-2714-00

PACKAGING: 90 in 1 BOTTLE PLASTIC

16.2 Storage and handling

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

Repackaged and Distributed By:

Remedy Repack, Inc.

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

17 PATIENT COUNSELING INFORMATION

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

  • to take cilostazol tablets 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 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. Discontinue cilostazol tablets if symptoms do not improve after 3 months.

Repackaged By / Distributed By:

RemedyRepack Inc.

625 Kolter Drive, Indiana, PA 15701

(724) 465-8762

PATIENT INFORMATION

Cilostazol Tablets, USP
(sye loe’ sta zol)
for oral use
50 mg and 100 mg

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 tablets 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 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 tablets is safe and effective for use in children.

How does 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 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 tablets 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 much cilostazol tablets to take and when to take it.
  • 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:
    • 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 room temperature between 68°F to 77°F (20°C 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 it was not prescribed. Do not give cilostazol tablets 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 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 Apotex Corp. at 1-800-706-5575.

    What are the ingredients in cilostazol tablets?

    Active ingredient: cilostazol
    Inactive ingredients: corn starch, croscarmellose sodium, magnesium stearate, and silicon dioxide

    This Patient Information has been approved by the U.S. Food and Drug Administration.
    CILOSTAZOL TABLETS, USP 50 mg and 100 mg.

    Repackaged and Distributed By:

    Remedy Repack, Inc.

    625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

DRUG: cilostazol

GENERIC: cilostazol

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 70518-2714-0

COLOR: white

SHAPE: ROUND

SCORE: No score

SIZE: 9 mm

IMPRINT: APO;CIL;100

PACKAGING: 90 in 1 BOTTLE, PLASTIC

ACTIVE INGREDIENT(S):

  • cilostazol 100mg in 1

INACTIVE INGREDIENT(S):

  • starch, corn
  • croscarmellose sodium
  • magnesium stearate
  • silicon dioxide
MM1
(click image for full-size original)
CILOSTAZOL cilostazol tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70518-2714(NDC:60505-2522)
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
CILOSTAZOL (CILOSTAZOL) CILOSTAZOL 100 mg
Inactive Ingredients
Ingredient Name Strength
STARCH, CORN
CROSCARMELLOSE SODIUM
MAGNESIUM STEARATE
SILICON DIOXIDE
Product Characteristics
Color white Score no score
Shape ROUND Size 9mm
Flavor Imprint Code APO;CIL;100
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:70518-2714-0 90 TABLET in 1 BOTTLE, PLASTIC None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077030 04/29/2020
Labeler — REMEDYREPACK INC. (829572556)

Revised: 10/2021 REMEDYREPACK INC.

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