ADVERSE DRUG REACTIONS, HERBAL ADVERSE EVENT REPORTS, AND ADVERSE EVENTS REPORTING SYSTEMS

Several operational definitions exist regarding what constitutes adverse drug reactions (ADRs) of varying severity. According to the World Health Organization (WHO), an ADR is defined as “Any response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function.”⁹ For reporting purposes, the FDA categorizes a serious adverse event as one in which “the patient outcome is death, life-threatening (real risk of dying), hospitalization (initial or prolonged), disability (significant, persistent, or permanent), congenital anomaly, or required intervention to prevent permanent impairment or damage.”¹⁰ The American Society of Health-System Pharmacists (ASHP) defines a significant ADR as any unexpected, unintended, undesired, or excessive response to a drug that:

Consistent with this definition, allergic and idiosyncratic reactions are also considered ADRs.¹¹ Not technically classified as ADRs are side effects, which are defined by ASHP as “an expected, well-known reaction resulting in little or no change in patient management (e.g., drowsiness or dry mouth due to administration of certain antihistamines or nausea associated with the use of antineoplastics)” and that has “a predictable frequency and an effect whose intensity and occurrence are related to the size of the dose.” Also not categorized as ADRs are “drug withdrawal, drug-abuse syndromes, accidental poisoning, and drug-overdose complications.”¹¹

Following the thalidomide disaster of the 1950s, WHO established and has maintained an international adverse drug events reporting system. Since 1978, the WHO International Drug Monitoring Program (IDMP) has collected ADR reports from 60 participating nations, and now includes both pharmaceutical and botanical medicine information. Of the more than 2.5 million reports in their International Drug Information System (INTDIS) database, approximately 10,000 relate to herbal medicines, primarily involving multiple ingredients.¹² This demonstrates a remarkably low incidence of serious ADRs resulting from herbal products, especially when compared with that of pharmaceutical drugs and the much larger worldwide consumption of botanicals compared with conventional medications. Many of the reports were associated with negative interactions with conventional medications and most side effects were reported for people 60 to 69 years of age.

A retrospective review of adverse effects reports (AERs) due to herbal medicines made to the National Poisons Unit of the United Kingdom was conducted in 1991. Between 1983 and 1989 a total of 1070 inquiries were made. Twenty-five percent of reports were of subjects with acute symptoms. Most confirmed adverse events were due to herbal sedatives.¹³ Ernst conducted a survey of complementary and alternative medicine users in the United Kingdom. Of those who had reported use of herbal medicines, 8% reported having observed adverse effects, none of which were considered serious.¹³

Adverse events associated with dietary supplements are not effectively monitored in the United States.¹⁴ The main AER systems are local and national poison control centers and the FDA’s MedWatch program, all of which have serious limitations. Most reporting systems, including these, are passive systems with no criteria for submission, no verification of the authenticity or accuracy of reports, and no effective follow-up or investigation. In order to be meaningful, AERs must be critically reviewed and products analyzed. Yet, neither a systematic review of the patient or event is conducted, nor is the product involved in an event typically analyzed, making it impossible to establish a causal relationship between an event and an herb/herbal product. Further, recording practices are highly variable between systems and between centers within the same reporting system and there is often selection bias.¹⁴

A relatively recent survey of data from US poison control centers evaluated the incidence of AERs for all dietary supplements.¹⁴ In a 10-month period, 1466 reports of potential events due to ingestion of supplements were made. More than one-third of these (534) were unintentional ingestions; 471 reported no symptoms. Half (741) of the total reports produced symptoms. The reviewers reported that 66% (489) were associated with dietary supplement exposure with varying degrees of confidence and 27% (132) were considered to be either definitely or probably related, whereas 34% (166) were reported as definitely or probably unrelated. The balance of reports (39%; 190) represented a 50% chance for the event to be correlated to supplement use. Ninety of the subjects used supplements in an attempted suicide, whereas the others used supplements for various reasons, ranging from the treatment of specific conditions (35%) to enhanced athletic performance (10%) and dieting (14%), among others. Botanicals most frequently associated with adverse events included ma huang (Ephedra sinensis), St. John’s wort (Hypericum perforatum), guarana (Paullinia cupana), and ginseng (species not identified). Of a total of 401 calls specifically related to adverse events of dietary supplements, 286 events were classified as mild, 89 as moderate, and 22 as severe, with a total of four deaths. Subjects experiencing symptoms were taking as many as 44 ingredients concurrently and had more serious adverse events than did those taking fewer supplements long-term. However, 89% of these adverse events were considered mild (57%) or moderate (32%); 11% were reported as severe or resulted in death. Most acute reports (95%) were considered mild (77%) or moderate (18%), and 4% severe or death. Many of these reports suffer from the same limitations of not being subjected to critical review or product characterization. Of all the supplement adverse events reported, only 12 products were retrieved for analysis. In comparison, a total of 61,229 calls regarding adverse events due to other consumed substances, mostly pharmaceuticals, were made in the same time period.

CATEGORIES OF COMMON HERBAL ADVERSE EFFECTS

The Toxicologic Medical Unit of Guy’s and St. Thomas Hospital in London conducted a 5-year toxicologic review of adverse events caused by herbal drugs based on reports made to the National Poison Control Center.¹⁵ Drowsiness and dizziness followed by vomiting, diarrhea, abdominal pain, and nausea were the most commonly reported side effects. Other events of note included agitation and irritability, cardiac arrhythmias, psychological disturbances, and facial flushing. Interaction of botanical and conventional anticoagulants has resulted in reports of abnormal bleeding, and effects of interactions with herbs that rely on the cytochrome P450 enzyme system have resulted in elevations or decreases in serum drug concentrations affecting clearance times, efficacy, and toxicity. Reports of liver abnormalities were most commonly associated with Chinese herbal medicines.

Botanical Quality Standards and Reactions Caused by Contamination and Adulteration of Herbs

The safety of any medicinal product is partly dependent on the manner in which the product is produced. Although individuals, organizations, industry, and government are actively working to establish national quality control (QC) standards, current standards are not a guarantee for herbal products in the United States, or those imported from countries such as China and India. European herbal product standards are generally stricter than most other countries, including the United States; thus, European herbal products have a greater likelihood of safety and quality. The most important aspects of QC include the accurate identification, relative purity, and relative quality of raw material used in herbal products (Tables 4-3 and 4-4).

TABLE 4-3 Potential Toxic Plant Adulterations Causing Safety Concerns

TABLE 4-4 Potential Contaminants of Herbal Products

* Current law prohibits the presence of toxic microorganisms in herbal products. Contaminated products can be removed from the market. To date, there have been no published reports of herbal products toxicity from such microorganisms.

** Although some of these pesticides have been banned in the United States for decades, they may still be in use in other countries. Conversely, some pesticides may be approved for use in common foods but lack approval for use on herbal products.

† These sterilization processes, although approved for use in certain foods, are not approved for use on herbal products.

‡ Heavy metals in food and water is a problem worldwide but have been specifically noted to occur in numerous herbal medicine products manufactured in China.

§ It is prohibited to combine conventional drugs in products marketed as dietary supplements.

The safety of plants may also be affected by the presence of contaminants not naturally occurring in the plants, including heavy metals (taken up from the soil naturally, resulting from pollution, or their addition as part of traditional formulation or processing, as may be the case with TCM or Ayurvedic preparations and prescriptions), microbial contamination (owing to animal feces or poor handling under unhygienic conditions), or processes that are applied to the plant (e.g., sterilization with ethylene oxide gas, pesticides, fungicide, or gamma irradiation). By law, herbal products that enter the market must be safe for consumption as a food and be free of toxic microbial contamination. Similarly, certain treatments, such as with pesticides and irradiation, are not permitted on herbal products unless expressly approved. Nonetheless, because herbs are obtained from a variety of sources worldwide, many of which routinely use such treatments, herbal products may contain one or more of these contaminants.

Most herbs and botanical products are not tested before importation into the United States. It is impossible for consumers and health professionals to determine if such contaminations are present without subjecting the product to extensive testing. Again, any presence of a known pathogen (e.g., Escherichia coliform) or prohibited treatment (certain pesticides or gamma irradiation) renders a product adulterated and subject to removal from the market by the FDA. However, regulatory oversight in this area is almost nonexistent. The best way for practitioners to avoid potentially contaminated or adulterated products is to become knowledgeable of the practices of suppliers and manufacturers, and identify those with high quality standards (see Identifying Quality Botanical Medicine Products). Companies that are run by or employ qualified herbalists on their staff and that serve the needs of health professionals are often the most reliable, but this in itself is not a guarantee of quality.²⁰

Traditional Chinese Herbal Medicines Mixed with Conventional Pharmaceutical Drugs

It is not uncommon for Chinese herbal products made in Asia, including those sold in the United States, to be adulterated with conventional pharmaceutical drugs.²¹ Adulterants have included caffeine, paracetamol, indomethacin, hydrochlorothiazide, prednisolone, barbiturates, and corticosteroids.²² The purpose for the inclusion of pharmaceutical drugs in botanical products is presumed increased efficacy. However, inclusion of such substances is not consistent with principles of traditional Chinese medicines. In a survey evaluating herbal products used in hospitals in Taiwan, approximately 24% of 2406 herbal drugs tested contained pharmaceuticals.

Significantly, in most cases the pharmaceutical adulterants are not disclosed on the product label or packaging. Herbal products adulterated with conventional medications have been found to be manufactured in Mainland China, Hong Kong, and Taiwan.²¹ In the United States, under dietary supplement regulations, such products are considered to be adulterated and are subject to removal from the market. Thus far, there have been no reports of the addition of pharmaceuticals in domestically made Chinese herbal products. Although there are undoubtedly high-quality herbal products manufactured in Asia, it is currently almost impossible for consumers and most health professionals (even trained TCM practitioners) to differentiate between adulterated and nonadulterated products. Thus, patients using some traditional Chinese herbal medicine products in combination with conventional medications may be also be unknowingly subjected to unexpected drug–drug interactions via a pharmaceutical adulterant.

Ayurvedic Herbs and Heavy Metal Contamination