Drug Interaction Report

This report displays the potential drug interactions for the following 4 drugs:
clopidogrel
cilostazol
bisoprolol
insulin aspart

Interactions between your drugs

Moderate
bisoprolol  insulin aspart
Applies to: bisoprolol, insulin aspart
MONITOR: Beta-blockers may inhibit some of the normal physiologic response to hypoglycemia. Symptoms
of hypoglycemia such as tremor and tachycardia may be absent, making it more difficult for patients to
recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported,
usually with the noncardioselective beta-blockers (e.g., propranolol, pindolol, timolol) but occasionally also
with relatively beta-1 selective agents (e.g., atenolol, metoprolol, nebivolol). Specifically, inhibition of
catecholamine-mediated glycogenolysis and glucose mobilization in association with beta-blockade can
potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels.
Prolonged and severe hypoglycemia may occur, although these events have rarely been reported.
Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics
treated with insulin and beta-blockers due to antagonism of epinephrine's effect on beta-2 adrenergic
receptors, which leads to unopposed alpha-adrenergic effects including vasoconstriction. Other effects
reported with various beta-blockers include decreased glucose tolerance and decreased glucose-induced
insulin secretion.

MANAGEMENT: In general, cardioselective beta-blockers are considered safer than noncardioselective

agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to
patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin
secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose
some of the same risks as nonselective agents. Patients should be advised of the need for regular blood
glucose monitoring and be aware that certain symptoms of hypoglycemia such as tremor and tachycardia
may be masked. However, other symptoms such as headache, dizziness, drowsiness, confusion, nausea,
hunger, weakness, and perspiration may be unaffected. The same precautions are applicable in diabetic
patients treated with ophthalmic beta-blockers.

References
1. Sinclair AJ, Davies IB, Warrington SJ "Betaxolol and glucose-insulin relationships: studies in normal subjects taking glibenclamide or metformin." Br J Clin
Pharmacol 30 (1990): 699-702

2. Zaman R, Kendall MJ, Biggs PI "The effect of acebutolol and propranolol on the hypoglycaemic action of glibenclamide." Br J Clin Pharmacol 13 (1982): 507-
12

3. Viberti GC, Keen H, Bloom SR "Beta blockade and diabetes mellitus: effect of oxprenolol and metoprolol on the metabolic, cardiovascular, and hormonal
response to insulin-induced hypoglycemia in normal subjects." Metabolism 29 (1980): 866-72

View all 16 references

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Moderate clopidogrel  cilostazol

Applies to: clopidogrel, cilostazol
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.

References
1. "Product Information. Pletal (cilostazol)." Otsuka American Pharmaceuticals, Rockville, MD.

2. Wilhite DB, Comerota AJ, Schmieder FA, Throm RC, Gaughan JP, Rao AK "Managing PAD with multiple platelet inhibitors: the effect of combination therapy
on bleeding time." J Vasc Surg 38 (2003): 710-3

3. Mallikaarjun S, Forbes WP, Bramer SL "Interaction potential and tolerability of the coadministration of cilostazol and aspirin." Clin Pharmacokinet 37 (1999):
87-93

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No other interactions were found between your selected drugs. This does not necessarily mean no other
interactions exist. Always consult your healthcare provider.

Drug and food interactions

Moderate
cilostazol  food
Applies to: cilostazol
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.

References
1. "Product Information. Pletal (cilostazol)." Otsuka American Pharmaceuticals, Rockville, MD.

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the
recommended therapeutic duplication maximum.

Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific
individual is difficult to determine. Always consult your healthcare provider before starting or stopping
any medication.

Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the
benefit.

Moderate Moderately clinically significant. Usually avoid combinations; use it only under special
circumstances.
 Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative
drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.

Unknown No interaction information available.

Further information
Always consult your healthcare provider to ensure the information displayed on this page applies to your
personal circumstances.