Side Effects of Pletal (cilostazol)

Pletal (cilostazol) is a quinolinone derivative used to treat intermittent claudication, a condition caused by narrowing of the arteries that supply the legs with blood. 

Patients with intermittent claudication develop pain when they walk because not enough oxygen-containing blood reaches the active leg muscles. Pletal reduces the pain of intermittent claudication by dilating the arteries, thereby improving the flow of blood and oxygen to the legs. (It does this by decreasing the action of an enzyme, phosphodiesterase III.) It also reduces the ability of blood to clot.

Pletal enables patients with intermittent claudication to walk longer and faster before developing pain. 

Common side effects of Pletal include

• headache,
• abdominal pain,
• diarrhea,
• abnormal stool,
• upper respiratory tract infections,
• runny nose,
• nausea,
• fluid retention,
• dizziness and
• abnormal heartbeats.

Serious side effects of Pletal include

• reduced numbers of white blood cells and platelets and
• severe skin reactions.

Drug interactions of Pletal include erythromycin, omeprazole, and diltiazem, which increase the concentration of Pletal by blocking the action of enzymes that destroy Pletal.

• Though not specifically studied, a similar interaction could occur with ketoconazole, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, and sertraline.
• Diltiazem and omeprazole also increase concentrations of Pletal. Higher concentrations of Pletal could increase the possibility of toxic effects. Therefore, a dose of 50 mg twice daily should be considered when drugs that may increase the concentration of Pletal also are being used.
• Combining Pletal with other drugs that interfere with the blood clotting process may increase the likelihood of bleeding. A high fat meal increases the absorption of Pletal.
• Grapefruit juice could increase the concentration of Pletal and should not be taken by patients on Pletal. 

The use of Pletal in pregnancy has not been adequately studied. Pletal has not been adequately studied in women who are breastfeeding. Consult your doctor before breastfeeding.

The most common adverse effects of cilostazol are:

• headache,
• abdominal pain,
• diarrhea,
• abnormal stool,
• upper respiratory tract infections,
• runny nose,
• nausea,
• fluid retention,
• dizziness and
• abnormal heartbeats.

Other important side effects which have also been reported with cilostazol include a reduction in numbers of white blood cells and platelets. Severe skin reactions also have been reported.

Cilostazol inhibits the enzyme phosphodiesterase III. Other drugs that inhibit this enzyme have caused death in individuals with heart failure. Therefore, individuals with heart failure should not use cilostazol.

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

• Patients with Heart Failure
• Tachycardia
• Left Ventricular Outflow Tract Obstruction
• Hematologic Adverse Reactions
• Hemostatic Disorders or Active Pathologic Bleeding

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• Adverse reactions were assessed in eight placebo-controlled clinical trials involving patients exposed to either 50 or 100 mg twice daily Pletal (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on Pletal and 134 days for patients on placebo.
• The most frequent adverse reaction resulting in discontinuation of therapy in more than 3% of patients treated with Pletal was headache [50 mg twice daily (1.3%), 100 mg twice daily (3.5%) and placebo (0.3%)].
• Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for Pletal (all doses) versus 0.1% for placebo.
• The most common adverse reactions, occurring in at least 2% of patients treated with Pletal 50 or 100 mg twice daily, are shown in Table 1.

Table 1: Most Common Adverse Reactions in Patients on Pletal (PLT) 50 or 100 mg Twice Daily(Incidence at least 2% and Occurring More Frequently (≥ 2%) in the 100 mg Twice Daily Group than on Placebo)

Less frequent clinical significant adverse reactions (less than 2%) that were experienced by patients treated with Pletal 50 mg twice daily or 100 mg twice daily in the eight controlled clinical trials and that occurred at a frequency in the 100 mg twice daily group greater than in the placebo group are listed below.

• Body as a whole: fever, generalized edema, malaise
• Cardiovascular: atrial fibrillation, heart failure, myocardial infarction, nodal arrhythmia, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardia
• Digestive: anorexia, melena
• Hematologic and Lymphatic: anemia
• Metabolic and Nutritional: increased creatinine, hyperuricemia
• Nervous: insomnia
• Respiratory: epistaxis
• Skin and Appendages: urticaria
• Special Senses: conjunctivitis, retinal hemorrhage, tinnitus
• Urogenital: urinary frequency

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Pletal. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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.

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 Pletal.
• Reduce Pletal dose to 50 mg twice daily when coadministered with strong or moderate inhibitors of CYP3A4.

Inhibitors Of CYP2C19

• Coadministration with CYP2C19 inhibitors (e.g., omeprazole) increases systemic exposure of Pletal active metabolites.
• Reduce Pletal dose to 50 mg twice daily when coadministered with strong or moderate inhibitors of CYP2C19.