Cilostazol was approved by the Food and Drug Administration (FDA) in January 1999 for reduction of the symptoms of intermittent claudication, a chronic, sometimes debilitating, non-life-threatening disorder that causes pain, ache, cramping, numbness or sense of fatigue in the leg muscles during exercise that is relieved with rest. The drug was approved despite the fact that it adds very little to the benefits of exercise alone and is associated with decreased survival in certain patients with...
Cilostazol was approved by the Food and Drug Administration (FDA) in January 1999 for reduction of the symptoms of intermittent claudication, a chronic, sometimes debilitating, non-life-threatening disorder that causes pain, ache, cramping, numbness or sense of fatigue in the leg muscles during exercise that is relieved with rest. The drug was approved despite the fact that it adds very little to the benefits of exercise alone and is associated with decreased survival in certain patients with heart failure.
Cilostazol is not a new drug. It has been sold in Japan since 1988 and is also available in Korea, Thailand, the Philippines, the People’s Republic of China, Argentina and Indonesia.
Prior to cilostazol’s approval, Public Citizen’s Health Research Group wrote the FDA on two occasions to urge strongly that it not be approved., Cilostazol works by inhibiting an enzyme known as phosphodiesterase III. Other drugs that affect this enzyme and are used to treat conditions such as congestive heart failure have been associated with increased risk of death. In fact, one of these, flosequinan (MANOPLAX), was withdrawn from the market in 1993 for just this reason. Also, a pooled safety analysis of clinical trials submitted to the FDA by Otsuka found a higher mortality rate at 30 days after treatment in patients taking cilostazol than in those taking placebo. This difference was not statistically significant.
Among the adverse events that have been reported worldwide since the launch of cilostazol in the U.S. are the following: pain, hot flushes, bleeding in the brain, angina (chest pain due to inadequate blood flow to the heart), low blood pressure, liver damage, vomiting, low platelet and white blood cell levels, bleeding into the lungs,itching, and serious skin reactions including Stevens-Johnson syndrome (a blistering rash with peeling skin; this condition is a medical emergency that is similar to experiencing severe burns and usually requires hospitalization).
Cilostazol works by inhibiting the clumping of platelets in the blood. Because clumping of platelets is one of the body’s first defenses against bleeding, cilostazol’s effect on platelets has raised concerns about its use together with clopidogrel (PLAVIX), a drug that also inhibits platelets and is used to reduce the risk of heart attack and stroke in patients with atherosclerosis (documented by a recent stroke or heart attack) or peripheral arterial disease.
A study published in the August 18, 1998, issue of the journal Circulation compared cilostazol with a placebo in patients with intermittent claudication. At the beginning of this 12-week study, the patients in the placebo group could walk, on average, 184 yards and those in the cilostazol group could walk 155 yards before having to stop because of their symptoms. At the end of the 12 weeks, the distance that could be walked by placebo patients had dropped to an average of 166 yards, while cilostazol patients increased their maximum walking distance to 253 yards. The placebo group could walk an average of 18 yards less, and the cilostazol patients could walk 98 yards farther. Overall, there was no statistically significant difference between cilostazol and placebo at the end of the study.
Otsuka submitted to the FDA eight large clinical trials comparing cilostazol with placebo to support its application for the drug’s approval. On average, cilostazol patients could walk only 65 yards farther than those patients taking a placebo after 12 to 24 weeks of treatment.
Two studies also were provided to the FDA comparing cilostazol with pentoxifylline (TRENTAL), the only other drug approved for the treatment of intermittent claudication in the U.S. In the first of these studies the patients taking cilostazol were able to walk about 108 yards farther than those receiving pentoxifylline. In the second, walking distance was improved by only 41 yards in those taking cilostazol compared to the pentoxifylline group. Because of these conflicting results the FDA denied Otsuka America’s request to allow it to claim that cilostazol is superior to pentoxifylline in the treatment of intermittent claudication.
We have listed pentoxifylline as a Do Not Use drug since the first edition of Worst Pills, Best Pills (1988) because of its lack of significant effectiveness. Swedish drug regulatory authorities had refused to approve pentoxifylline in 1995.
Cilostazol has shown only a small effect in increasing walking distance in patients with intermittent claudication. There are unanswered and very worrisome questions about its safety, and combined with the increased risk of death that has been seen with other phosphodiesterase III–inhibiting drugs, cilostazol should be avoided.
In 2010, the FDA issued safety-labeling changes stating that using cilostazol with esomeprazole or omeprazole is expected to increase the levels of cilostazol in the body.
In 2013, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) issued information concerning changes to the recommended use of cilostazol. The agency stated that cilostazol should be used only in patients with intermittent claudication when lifestyle changes have not led to an improvement in the symptoms of the patient’s condition. The information leading to this decision showed that the benefit of using cilostazol was greater than the risk (specifically heart problems and bleeding) of using it only in a limited subgroup of patients.
In 2013, the Medicines and Healthcare Products Regulatory Agency a government agency in the U.K. issued drug safety advice that due to bleeding and cardiovascular risk, cilostazol is restricted to second-line treatment in patients with claudication and is contraindicated in patients with certain cardiovascular problems as well as those on certain anticoagulation and antiplatelet drugs.
In 2015, the FDA updated the cilostazol drug label to indicate that the drug may cause a rapid heart rate or a drop in blood pressure. In patients with a history of heart disease, these effects may cause angina orf a heart attack.