Ginkgo biloba has been associated with platelet, bleeding and clotting disorders, and there are

isolated reports of serious adverse reactions after its concurrent use with antiplatelet drugs such
as aspirin, clopidogrel and ticlopidine.

Clinical evidence
A study in 10 healthy subjects found no significant increase in the antiplatelet effects of single
doses of clopidogrel 75 mg or cilostazol 100 mg when a single dose of ginkgo 120 mg was
added. However, the bleeding time was significantly increased when cilostazol was combined
with ginkgo, although none of the subjects developed any significant adverse effects.1 Another
study2 in 8 healthy subjects found that ginkgo 40 mg three times daily had no significant effect
on the pharmacokinetics of a single 250-mg dose of ticlopidine taken on day 4. A randomised,
double-blind study in 55 patients with established peripheral artery disease (PAD), or with risk
factors for developing PAD, found that the addition of ginkgo 300mg (standardised extract EGb
761) in divided doses to aspirin 325 mg daily did not have a significant effect on platelet
aggregation. Five of the patients taking combined therapy reported nosebleeds or minor
bleeding; however, 4 patients from the aspirin-only group also reported minor bleeding.3
Similarly, a study in 41 healthy subjects found that 120-mg ginkgocoated tablets (EGb 761)
twice daily had no effect on the antiplatelet activity of aspirin 500 mg daily given for 7 days.

Minor bleeding
was seen in a few subjects but this was attributed to the use of aspirin.4 In an analysis of
supplement use, 23% of 123 patients were currently taking supplements, and 4 patients were
found to be taking ginkgo and aspirin. However, no problems from this use were found on
review of the patients’ notes.5 Nevertheless, a number of cases of clinically significant bleeding
have been reported. A 70-year-old man developed spontaneous bleeding from the iris into the
anterior chamber of his eye within one week of starting to take a ginkgo supplement (Ginkoba)
tablet twice daily. He experienced recurrent episodes of blurred vision in one eye lasting about
15 minutes, during which he could see a red discoloration through his cornea. Each tablet
contained 40 mg of concentrated (50:1) extract of ginkgo. He was also taking aspirin 325 mg
daily, which he had taken uneventfully for 3 years since having coronary bypass surgery. He
stopped taking the ginkgo but continued with the aspirin, and 3 months later had experienced no
recurrence of the bleeding.6 Another case reports persistent postoperative bleeding from a hip
arthroplasty wound, which continued despite stopping aspirin. On closer questioning, the
patient had continued to take ginkgo extract 120 mg daily postoperatively. The oozing from the
wound gradually reduced when the ginkgo was stopped.

A search of Health Canada’s database of spontaneous adverse reactions for the period January
1999 to June 2003 found 21 reports of suspected adverse reactions associated with ginkgo. Most
of these involved platelet, bleeding and clotting disorders. One report of a fatal gastrointestinal
haemorrhage was associated with ticlopidine and ginkgo, both taken over 2 years along with
other medications. Another report was of a stroke in a patient taking multiple drugs, including
clopidogrel, aspirin and a herbal product containing ginkgo.

Experimental evidence
Ginkgo (EGb 761) 40 mg/kg daily had no effect on the antiplatelet activity of ticlopidine 50
mg/kg daily when given to rats for 3 days. However, when both were given for 5 days, the
inhibition of platelet aggregation was double that of ticlopidine given alone and the bleeding
time was increased by about 60%. Also, when given for 9 days, the combination was twice as
effective at inhibiting thrombus formation when compared with the same dose of ticlopidine
alone.8

Mechanism
The reason for the bleeding is not known, but ginkgo extract contains ginkgolide B, which is a
potent inhibitor of plateletactivating factor in vitro; this is needed for arachidonate-independent
platelet aggregation. However, in one controlled study in healthy subjects, taking a ginkgo
preparation alone for 2 weeks had no effect on platelet function.9 Nevertheless, there are case
reports of ginkgo supplements, on their own, being associated with prolonged bleeding times,10
12 left and bilateral subdural haematomas,10,13 a right parietal haematoma,14 a retrobulbar
haemorrhage,15 postlaparoscopic cholecystectomy bleeding16 and subarachnoid haemorrhage.
11 It seems that the effects of ginkgo and conventional antiplatelet drugs can be additive, leading
to bleeding complications on rare occasions.
Importance and management
The evidence from these case reports is too slim to advise patients taking aspirin, clopidogrel or
ticlopidine to avoid ginkgo, but some do recommend caution,7 which seems prudent, especially
as this is generally advised with most combinations of conventional antiplatelet drugs. There
may also be a theoretical risk of increased bleeding if ginkgo is taken with other antiplatelet
drugs and anticoagulants; interactions have been reported with NSAIDs, some of which have
antiplatelet effects, and with warfarin. Consider also Ginkgo + NSAIDs, page 214 and Ginkgo +
Warfarin and related drugs, page 217.

Sumber :
Aruna D, Naidu MUR. Pharmacodynamic interaction studies of Ginkgo biloba with
cilostazol and clopidogrel in healthy human subjects. Br J Clin Pharmacol (2007) 63,
333–8.