WHO-Uppsala Monitoring Center (UMC) identified a new drug safety signal-“cardiac arrhythmias-Ginkgo biloba“ from the VigiBase, a global drug safety database maintained by UMC on behalf of WHO for international service and scientific research within the field of pharmacovigilance. In the month of July-2020, WHO-UMC has identified and released two new drug safety signals.

Drug Safety Signal 1: Lack of drug dose titration (Medication error) during treatment with clozapine

Drug Safety Signal 2: cardiac arrhythmias with the use of Ginkgo biloba L (Discussed below)

Ginkgo, the concentrated extracts made from the leaves of Ginkgo biloba tree. This helps in enhancing cognitive function and memory in adults. It also supports peripheral blood circulation in the body. Based on these benefits, it is used in the treatment of cognitive deficiency, intermittent claudication (pain caused due to obstruction of arteries), vertigo and tinnitus of vascular origin. In many countries, this product is marketed as a dietary/food supplement, natural health product, and as an herbal medicinal product.

Cardiac arrhythmias are the heart rhythm disorders which involves abnormalities in heart rate, regularity, or abnormality in the site of origin of the cardiac impulse (like supra ventricular or ventricular), or disturbances in conduction which results in abnormal sequences of activation.

Cardiac symptoms of arrhythmias: Tachycardia (increased heart rate), bradycardia (decreased heart rate), palpitations (irregular heartbeat).

Non-cardiac symptoms of arrhythmias: Dyspnoea (shortness of breath), weakness, dizziness, light-headedness, and syncope (a temporary loss of consciousness).

Some cardiac arrhythmias are asymptomatic (which does not show any symptoms). Cardiac arrhythmias can lead to cardiac arrest and sudden death.

Types of Cardiac arrhythmias:

1. Supraventricular arrhythmias- atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia
2. Ventricular arrhythmias- ventricular tachycardia, ventricular fibrillation, and long QT syndrome.

Causes and risk factors for cardiac arrhythmias:

Electrolyte imbalances or disturbances, congenital channelopathies (disturbed functioning of ion-channel subunits in heart due to genetic variants), hypertension, myocardial infarction, thyroid disease, diabetes, cardiomyopathy, other heart damage and previous heart surgery. Some of the substances like caffeine, nicotine, excess alcohol has potential to cause cardiac arrhythmias.

Signal Detection- Identification of cardiac arrhythmias attributed to the medicinal products containing Ginkgo biloba extracts:

A potential signal identified by a joint signal detection sprint involving the UMC at Sweden and the Netherlands Pharmacovigilance Centre Lareb.  In VigiBase (a global drug safety database), 162 case reports were found with drug-ADR (adverse drug reaction) combination of “cardiac arrhythmias-Ginkgo biloba”. These case reports were originated from 18 countries and most of the case reports were received from Germany and Republic of Korea (contributing 56%), followed by other countries.

Analysis of 162 case reports:

92 cases: ‘Ginkgo biloba’ is reported as the only suspected medicinal product

55 cases: with serious adverse drug reaction(s)

1. 5 fatal cases
2. 4 cases with life-threatening serious ADR.

46 cases: Having De-challenge information with 39 positive de-challenge outcomes.

The outcomes of the serious ADR in these 46 cases followed by drug interruption/suspension/withdrawal (Dechallenge outcomes) listed below:

1. 37 cases: recovered (80%)
2. 2 cases: recovering
3. 1 case: not recovered
4. 6 cases: unknown (13%).

For most of the reports, the specified time to onset of the reactions (temporal relationship) was within days. The most frequently reported cardiac symptoms of arrhythmia (which falls within the Standardized MedDRA Query (SMQ) of ‘cardiac arrhythmia’) are palpitations (n=67), tachycardia (n=24), loss of consciousness (n=14), syncope (n=13) and bradycardia (n=10).

The most frequently reported non-cardiac symptoms of arrhythmia are dizziness (n=22), headache (n=14), nausea (n=13), hyperhidrosis (n=8), paraesthesia (n=8), dyspnoea (n=7), tinnitus (n=7), vomiting (n=7), anxiety (n=6), tremor (n=6).

The most common indications reported for the use of Ginkgo biloba were tinnitus (n=6), cognitive disorder, memory impairment (n=3), perfusion/circulatory disorders (n=3), hearing disorders other than tinnitus, hearing loss (n=3), unspecified prophylaxis (n=3).

The most frequently reported concurrent medications included acetylsalicylic acid (n=11), ascorbic acid (n=11), levothyroxine (n=9), and tocopherol (n=8).

Well established case reports from literature describing cardiac arrhythmia with Ginkgo biloba use:

Case report 1:

“A 35-year-old woman who experienced frequent nocturnal palpitations lasting several minutes after taking a Ginkgo biloba leaf extract (240 mg/day) as a general tonic. The woman had no previous medical history, she had a clear chest X-ray, with no physical abnormalities. Electrocardiographic (ECG) examination showed a sinus rhythm of 80 beats per minute without conduction abnormalities or ST-T changes, and Doppler echocardiography did not reveal any cardiac structural or functional abnormalities. However, a 24-hour Holter ECG monitoring showed four nocturnal episodes of paroxysmal atrial fibrillation. The woman discontinued taking Ginkgo biloba and her symptoms resolved within days. A repeated 24-hour ECG Holter did not show any arrhythmias over the following 12 months”

Case Report 2:

“A healthy 49-year-old man who had been taking Ginkgo biloba (40 mg three times daily) for two weeks to improve his cognitive function. The man described experiencing palpitations and ECG showed sinus rhythm with frequent ventricular premature beats. The palpitations stopped within two days of discontinuing Ginkgo biloba (a positive de-challenge).  He re-started ginkgo treatment two weeks later and experienced palpitations again two days after treatment (a positive re-challenge). ECG again showed frequent ventricular ectopic beats similar to those of the first episode. These resolved within one day of stopping ginkgo (second positive de-challenge).”

Case Report 3:

“A 72-year-old man with ischaemic cardiomyopathy and who had an implantable cardioverter defibrillator (ICD). The man had been taking a standardized Ginkgo biloba extract (120 mg daily) for tinnitus for three weeks and experienced several episodes of dizziness (non-cardiac symptom). His ICD device revealed that he had experienced 1,440 episodes of sustained ventricular tachycardia over the previous four months, with a substantial proportion occurring in the previous ten days. The man discontinued taking Ginkgo biloba and his condition improved markedly within days (positive de-challenge).”

In the 162 case reports, there are cases with alternative causality and other contributing factors for arrhythmia which included patient’s medical history, underlying medical conditions, concomitant medications etc., A clear mechanism of Ginkgo induced cardiac arrhythmias is not fully elucidated. However, based on the significant number and nature of the cases available in the VigiBase and additional published case reports suggest a signal between Ginkgo biloba and cardiac arrhythmias.