Drug Interaction Report

MONITOR: Coadministration of cilostazol with other antiplatelet agents may produce additive pharmacodynamic effects resulting in increased inhibition of platelet function. In 12 healthy male volunteers, coadministration of cilostazol (100 mg twice a day for 10 days) and aspirin (325 mg once a day for the last 5 days of cilostazol administration) resulted in a 23% to 35% increase in inhibition of adenosine diphosphate (ADP)-induced ex vivo platelet aggregation compared to aspirin plus placebo. However, there was no additive or synergistic effect on arachidonic acid-induced platelet aggregation. Cilostazol, with or without aspirin, caused no changes in PT, aPTT, or bleeding time. Drug-related adverse events were generally mild, the most frequent being headache. Another study involving 21 patients with peripheral arterial disease also found no increase in bleeding time when cilostazol (100 mg twice a day) was added to clopidogrel (75 mg once a day), aspirin (325 mg once a day), or clopidogrel and aspirin combined, each for two weeks. The investigators concluded that cilostazol may be used with other platelet inhibitors. However, effects of long-term coadministration in the general population are unknown. During clinical trials, there was no apparent increase in the incidence of hemorrhagic adverse effects in 201 patients who received cilostazol with aspirin (75 to 325 mg daily for up to 137 days) compared to those who received placebo and equivalent doses of aspirin.

MANAGEMENT: Because of theoretical concerns regarding increased inhibition of platelet aggregation, cilostazol should be used cautiously with other antiplatelet agents.

ADJUST DOSING INTERVAL: Caffeine and other xanthine derivatives (e.g., theophylline) are nonspecific, competitive antagonists of adenosine receptors. As such, they may interfere with the vasodilating effect of dipyridamole, an adenosine receptor agonist. In studies of healthy volunteers, caffeine has been shown to reduce the hemodynamic response (i.e., heart rate increases, vasodilation, blood pressure changes) to dipyridamole infusions, and both caffeine and theophylline have been reported to cause false-negative results in myocardial scintigraphy tests using dipyridamole.

MANAGEMENT: Patients should avoid consumption of caffeine-containing products for at least 24 hours prior to administration of dipyridamole for myocardial perfusion imaging.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of cilostazol. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Until more information is available, the manufacturer recommends avoiding consumption of grapefruit juice during cilostazol therapy. Orange juice is not expected to interact with cilostazol.

ADJUST DOSING INTERVAL: Methylxanthines (e.g., caffeine, theophylline) are nonspecific, competitive antagonists of adenosine receptors. As such, they may interfere with the pharmacologic effects of adenosine and other adenosine receptor agonists such as dipyridamole and regadenoson. There have been case reports of patients receiving theophylline who required higher than normal dosages of adenosine for the treatment of paroxysmal supraventricular tachycardia. In studies of healthy volunteers, caffeine and theophylline have been shown to reduce the cardiovascular response to adenosine infusions (i.e., heart rate increases, vasodilation, blood pressure changes), and theophylline has also been shown to attenuate adenosine-induced respiratory effects and chest pain/discomfort. Similarly, caffeine has been found to reduce the hemodynamic response to dipyridamole, and both caffeine and theophylline have been reported to cause false-negative results in myocardial scintigraphy tests using dipyridamole. In a placebo-controlled study that assessed the effects of oral caffeine on regadenoson-induced increase in coronary flow reserve (CFR), healthy subjects who took caffeine 200 mg orally two hours prior to regadenoson administration exhibited a median CFR that was 92% that of subjects who took placebo. The study was done using positron emission tomography with radiolabeled water.

MANAGEMENT: Clinicians should be aware that adenosine and other adenosine receptor agonists may be less effective in the presence of methylxanthines. Methylxanthines including caffeine should be withheld for 12 to 24 hours (or five half-lives) prior to administration of adenosine receptor agonists for myocardial perfusion imaging. However, parenteral aminophylline should be readily available for treating severe or persistent adverse reactions to adenosine receptor agonists such as bronchospasm or chest pain.

The recommended maximum number of medicines in the 'phosphodiesterase inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'phosphodiesterase inhibitors' category:

• cilostazol
• dipyridamole

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.