ORIGINAL RESEARCH

Rheum rhaponticum Extract (ERr 731): Postmarketing Data on Safety Surveillance and Consumer Complaints Jyh-Lurn Chang, PhD; Michael B. Montalto, PhD; Peter W. Heger; Eva Thiemann; Reinhard Rettenberger, PhD; Jürgen Wacker, MD, PhD

Abstract Context: Postmarketing surveillance data for a commercially available extract of Rheum rhaponticum (ERr 731) have not been published since the beginning of the reporting in 1993 in Germany about adverse events (AEs) that were believed to be associated with it. The extract is derived from the plant’s roots and is indicated for menopausal relief. In Germany, the extract has been marketed as Phytoestrol N and other related products— Phyto-Strol, Phyto-Strol Loges, and Phyto-Strol compact and as femi-loges. In the United States and Canada and in South Africa, the product had been marketed as Estrovera. Objective: The study’s objective was to summarize the AE reports from Germany from 1993 to June 2014 and also to assess consumers’ complaints in North America and South Africa from the date of the extract’s launch to June 2014. Design: AE reports recorded by 2 German holders of marketing authorizations, Chemisch-Pharmazeutische Fabrik Göppingen, for Phytoestrol N, and Dr. Loges + Co. GmbH, for femi-loges, were collected and analyzed. Consumers’ complaints in North America and South

Jyh-Lurn Chang, PhD, is the manager for medical affairs; and Michael B. Montalto, PhD, is the senior director of medical affairs at Metagenics, Inc, in Gig Harbor, Washington. Peter W. Heger is a director at Health Research Services GmbH in Ubstadt-Weiher, Germany. Eva Thiemann is the qualified person for pharmacovigilance (QPPV) at Dr. Loges + Co. GmbH in Winsen (Luhe), Germany. Reinhard Rettenberger is a director at Chemisch-Pharmazeutische Fabrik Göppingen, Carl Müller, Apotheker, GmbH & Co KG, in Göppingen, Germany. Jürgen Wacker, MD, PhD, is medical director and head of the Department of Obstetrics and Gynecology Bruchsal, Teaching Hospital of the University of Heidelberg in Heidelberg, Germany. Corresponding author: Eva Thiemann E-mail address: [email protected] 34

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Africa that had been captured by the US distributor of Estrovera were also collected and analyzed. Results: From 1993 to June 2014, approximately 140 million daily doses of the extract were placed on the German market, and 124 AE reports were recorded. The most common of those AEs were hypersensitivity, with 74 reactions, and gastrointestinal symptoms, with 47 reactions. From January 2009 to June 2014, approximately 13 million tablets of the supplement were sold in North America, and 79 complaints from consumers associated with a physical response to it had been recorded. The main complaints were gastrointestinal symptoms, with 23 cases, and failure to work as suggested, with 22 cases. From the date of the product’s launch in South Africa in February 2011 to June 2014, no consumer complaints have been reported. Conclusions: The records related to postmarketing surveillance and consumers’ complaints suggest that the extract of R rhaponticum is generally safe for consumption.

A

n extract from the roots of Rheum rhaponticum has been used in Germany since the 1950s as an herbal medicine for the treatment of menopausal symptoms. The composition of the extract has been described previously.1,2 The extract has been marketed as an alternative for women considering a nonhormonal approach to managing menopausal symptoms. A standardized version of the extract, ERr 731, was commercially registered in Germany in July 1993 as Phytoestrol N (Chemisch-Pharmazeutische Fabrik Göppingen, Carl Müller, Apotheker, GmbH & Co KG, Göppingen, Germany). ERr 731 was also launched in Germany in 2011 with the name femi-loges (Dr. Loges + Co. GmbH, Winsen [Luhe], Germany). It was introduced as the dietary supplement Estrovera (Metagenics, Aliso Viejo, CA, USA) in 2009 in the United States, in 2012 in Canada, and in 2011 in South Africa. Experimental studies had demonstrated that both the extract and its individual Chang—ERr 731 Postmarketing Surveillance Data

constituents—rhaponticin and desoxyrhaponticin, with small amounts of aglycones rhapontigenin and desoxyrhapontigenin—have exhibited selective estrogen receptor (ER)-β agonistic activity as well as a lack of ER-α affinity in endometrial and breast tissues.2-5 Safety data from experimental and clinical studies have been published previously. In ovariectomized rats, feeding ERr 731 in doses from 0.1 mg per kg of body weight per day, which is the equivalent of the therapeutic dose in humans, to 100 mg per kg of body weight per day for 72 hours, neither stimulated an uterotrophic response nor modulated the expression of genes associated with proliferation.4 Similarly, uterotrophic effects were not detected when ovariectomized rats were fed ERr 731 for 90 days at up to 1 g per kg of body weight per day, demonstrating its endometrial safety.5 Heger et al’s1 12-week, placebo-controlled, randomized trial with perimenopausal women (N = 109) reported no differences between the extract and a placebo in the gynecological findings (eg, endometrial biopsies and bleeding) and in the laboratory safety parameters. The trial also found that no adverse events (AEs) had been classified as being related to the extract. A second 12-week, placebo-controlled, randomized trial in perimenopausal women (N = 112) reported a similar safety profile and found that no serious AEs had occurred.6 Hasper et al’s7 long-term, observational clinical study that consisted of 81 women who had participated in Heger et al’s1 study, and who received ERr 731 for 96 weeks in the new study, found no changes in gynecological findings or laboratory safety parameters and no AEs that were related to use of the ERr 731. In a 6-month, open-label clinical evaluation conducted at 70 German gynecological practices with 252 menopausal women who were taking ERr 731, only 1 AE was documented. The gynecologist, however, assessed it as not being causally related to the extract.8 In a casecontrol study that examined the use of herbal preparations to alleviate climacteric symptoms and reduce the risk of postmenopausal breast cancer, neither use of Pulsatilla nor of R rhaponticum was associated with an increased risk.9 As per regulations in Germany, marketing authorization holders (MAHs) regularly submit postmarket safety reports on medicinal products, called periodic safety update reports (PSURs), to the Federal Institute for Drugs and Medical Devices (BfArM). Before PSURs are submitted, the cases are recorded in databases and assessed by the MAHs. The MAHs are also obliged to collect and document independently each AE report occurring with their products, whether or not those events have been reported by health care professionals or consumers. Since the official registration of Phytoestrol N in the German market in 1993, when AE report collection began, no postmarketing surveillance data had been published. The current study’s primary objective was to summarize and assess AE reports associated with ERr 731 sold as Phytoestrol N, Phyto-Strol, Phyto-Strol Loges, Chang—ERr 731 Postmarketing Surveillance Data

Phyto-Strol compact, and femi-loges that had been recorded in Germany. In both the United States and Canada in North America, and in South Africa, health authorities do not require submission of AE reports by health care professionals and consumers for events that are suspected to be associated with dietary supplements. However, after health care professionals or consumers have reported suspected AEs to a product’s manufacturer, that company is required to send the report to regulatory authorities.10,11 Consumers’ complaints from North America and South Africa that have been related to the extract sold as Estrovera have been actively recorded by its distributor since the product’s launch. Therefore, information on consumers’ complaints from those regions that was related to any physical response postconsumption has been included in the current study. Methods Procedures The PSURs for Phytoestrol N and other related products—Phyto-Strol, Phyto-Strol Loges, and PhytoStrol compact—were obtained from one MAH, ChemischPharmazeutische Fabrik Göppingen, Carl Müller, Apotheker, GmbH & Co. KG (Göppingen, Germany), and the information on the suspected AEs was analyzed. A second MAH, Dr. Loges + Co. GmbH (Winsen [Luhe], Germany), had also authorized the extract and launched a product in January 2011 with the name femi-loges. Suspected AE cases that had been collected by that MAH were also obtained for analysis. As the minimum information, each collected AE report provided the age or age group of the person experiencing the AE, a description of the reaction, and information on the outcome as well as an assessment of the individual case report. Records for consumers’ complaints related to the extract in North America and South Africa were captured by the distributor when consumers directly used the tollfree product hotline or Web site or when a health care practitioner who had received a user’s complaint informed them. Each record provided a brief description of the complaint. Complaints regarding the quality of the product, such as a broken seal, a defective bottle cap, shipping damage, missing tablets, or smell were excluded as being unrelated to consumption. Only complaints related to a physical response that had occurred after ingestion of the product were relevant and included in the current study. Outcome Measures The research team used the pharmacovigilance guideline E2A from the International Council for Harmonization (ICH) and the guideline from the World Health Organization’s Collaborating Center for International Drug Monitoring to define a suspected AE.12,13 ICH’s guideline E2B (R3) was used to define what constituted a serious AE.14 Integrative Medicine • Vol. 15, No. 3 • June 2016

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The physical reactions were classified as expected (ie, they were mentioned on the Summary of Product Characteristics [SmPC] in the product’s package) or unexpected (ie, they not mentioned in the SmPC). Further, an event more specific or more severe than described in the SmPC was considered “unexpected.” For example, if acute renal failure was a labeled adverse drug reaction, a subsequent new report of interstitial nephritis or hepatitis with a first report of fulminant hepatitis would be considered unexpected. The classification of the category of an adverse reaction was evaluated based on the nature of the AE and all other relevant information (eg, medical investigations, patient checkups). For example, “hypersensitivity reactions of the skin (rash, pruritus, swelling)” is labelled in the SmPC; thus, a reaction reporting rash or pruritus was considered as “hypersensitivity reaction” with the symptoms of rash or pruritus or both. The decision whether a reaction was serious or not was based on the criteria for “seriousness” defined in the ICH guideline E2B (R3). A reaction is considered as serious when the following criteria apply: The reaction (1) results in death, (2) is life-threatening, (3) requires inpatient hospitalization or prolongation of existing hospitalization, (4) results in persistent or significant disability/incapacity, (5) is a congenital anomaly/birth defect, and (6) other medically important condition. The terms life threatening and other medically important condition are defined in the ICH E2A guideline. Because the R rhaponticum extract ERr 731 has a positive risk-benefit profile and the number of reports is very low, at most 2 persons were involved in the evaluation of the case reports. All cases were evaluated and classified by the qualified person for pharmacovigilance. Results In Germany, 4 PSURs involving 55 AEs for products using ERr 731 had been submitted by ChemischPharmazeutische Fabrik Göppingen to BfArM, covering the period from July 1993 to May 2013. The 69 AE reports recorded by Dr. Loges + Co. GmbH covered the period from January 2011 to June 2014. Therefore, from July 1993 to June 2014, 124 AEs had been reported. Sales data from both MAHs, based on a standard daily dose of 1 entericcoated tablet, indicated that approximately 140 million daily doses of the marketed products were placed on the market during the period. On average, 6.7 million doses of products using the extract were sold annually, and 5.9 AE reports per year were recorded. The 124 reports included 215 responses in various organ systems. In some cases, the patient mentioned several responses (Table 1). Eighty-four reactions were classified as expected and were seen as hypersensitivity reactions or intolerance to the extract. The unexpected reactions were either typical menopausal symptoms (eg, headache, intermediate bleeding, hot flashes, sweating, malaise, and other symptoms in the chest) or were gastrointestinal symptoms (eg, nausea, abdominal pain, diarrhea, and indigestion). 36

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The rest were individual cases or randomly occurring reactions that had occurred while taking the marketed products. In most cases, possible alternative causes were present, such as other medications, underlying disease, or diet. The cause attributed to the product was confounded so much in those cases as to be considered unlikely. In many reports, the causality could not be assessed due to a lack of information. All but one case, in which significantly elevated liver enzymes were reported, were classified as not serious according to ICH’s Guideline E2B (R3).14 From January 2009 to June 2014, approximately 13 million tablets of supplements using the extract had been sold in North America, and 79 complaints postconsumption had been recorded. On average, 2.4 million doses of the extract were sold annually, and 14.6 complaints from consumers per year were documented. The main reasons for complaints were gastrointestinal symptoms, in 23 cases; issues with the product not working as suggested, in 22 cases; headache, in 9 cases; and hypersensitivity or rash, in 8 cases (Table 2). One serious case was identified, in which the occurrence of endometrial cancer during the use of the extract had been reported. However, for all cases, insufficient information was available to evaluate whether the complaints were related to the extract’s use. From February 2011 to June 2014, approximately 120 000 tablets of supplements using the extract had been sold in South Africa, and no consumer complaints had been recorded. Discussion As part of complementary and alternative medicine, natural herbal products traditionally have been highly popular in many developing countries. Their use has been growing rapidly in developed countries, including in Germany15 where the herbal medicinal product using ERr 731 required a prescription and were sold only through pharmacies until 2005. It became a nonprescription herbal medicine available only in pharmacies after December 2005 due to its efficacy and to the safety it had demonstrated in clinical trials. The extract is contraindicated for individuals with any known or suspected estrogen-dependent cancer, as stated in the package’s insert.1,6,7 The current investigation of the extract’s postmarketing surveillance data found that 5.9 AEs were reported for every 6.7 million doses sold per year in Germany. In North America, 14.6 complaints were documented for every 2.4 million doses sold annually. Those data suggest that the extract was safe for most users. Hypersensitivity or rash, gastrointestinal symptoms, and symptoms of the nervous system, mainly headache, were the more frequent events in both Germany and North America. A major difference existed regarding complaints about the product not working as suggested, with those complaints representing 27.8% of all cases in North America but only 0.9% in Germany. The current Chang—ERr 731 Postmarketing Surveillance Data

Table 1. Number of Reports of AEs from the R rhaponticum Extract, ERr 731, Recorded in Germany Between July 1993 and June 2014 Organ System (Reactions) No. of Reactions (%) Hypersensitivity or rash: Rash, itching, skin irritation, etc 74 (34.4%) Gastrointestinal symptoms: Diarrhea, nausea, cramps, abdominal pain, bloating, etc 47 (21.9%) Symptoms in nervous system: Headache, confusion, drowsiness, change in taste, etc 23 (10.7%) General symptoms and administration-site conditions: Edema, hot flushes, sweating, 21 (9.8%) chills, weakness, etc Investigations: Increased pulse rate, changes in blood pressure, weight gain, increased liver 13 (6.0%) values, etc Psychiatric symptoms: Sleep disorders, depression, restlessness, anxiety, self-doubt 8 (3.7%) Reproductive system and breast symptoms: Chest pain/discomfort, swollen breasts, spotting, etc 8 (3.7%) Metabolism-related symptoms: Water accumulation, loss of appetite 6 (2.8%) Respiratory symptoms: Allergic cold, impaired respiration 4 (1.9%) Eye symptoms: Itching, swelling, watering eyes 3 (1.4%) Heart symptoms: Palpitations, circulatory disorder 3 (1.4%) No effect 2 (0.9%) Ear and labyrinth symptoms: Tinnitus 1 (0.5%) Vascular symptoms: Thrombosis 1 (0.5%) Musculoskeletal: Connective tissue and bone symptoms—muscle and joint stiffness 1 (0.5%) Total 215 (100%) Abbreviation: AEs, adverse events. Table 2. Consumers’ Complaints Related to Physical Responses in North America Between January 2009 and June 2014 Type of Complaint Gastrointestinal symptoms: Diarrhea, nausea, cramps, abdominal pain, bloating Failure to work as suggested

Cases (%) 23 (29.1%) 22 (27.8%)

Symptoms of the nervous system: Headache, bad taste in mouth Hypersensitivity/rash: Rash, itching, skin irritation Reproductive system and breast symptoms: Bleeding, pelvic congestion, vaginal rash Heart symptoms: Heart or chest palpitation Unexplained Metabolism related symptoms: Swelling in extremities Neoplasms; benign, malignant, and unspecified: Endometrial cancer Respiratory symptoms: Shortness of breath Hair loss Total

9 (11.4%) 8 (10.1%) 7 (8.9%) 4 (5.1%) 2 (2.5%) 1 (1.3%) 1 (1.3%) 1 (1.3%) 1 (1.3%) 79 (100%)

research team concluded that the nature of the databases contributed to that discrepancy. The German data came from reports specifically about AEs, whereas the North American data represented complaints for any reason upon consumption. For instance, one consumer reported that the product was not working as suggested even though she had used the product for only a short period. That example illustrates one of the complicated issues that postmarketing surveillance faces when different reporting methods are used for the same herbal compound. For the common gastrointestinal symptoms, many users suspected that lactose intolerance might have attributed to Chang—ERr 731 Postmarketing Surveillance Data

their symptoms. However, the extract contained only 0.046 g/tablet of lactose, and research has suggested that even those with diagnosed lactose intolerance are able to tolerate foods containing 6 g of lactose.16 Therefore, it remains unclear whether lactose intolerance was the cause. Another explanation, especially for symptoms regarding the stomach, could be the time of ingestion. The tablets with the extract have an enteric coating because the active ingredients can irritate the stomach lining. That protection is pH dependent and works only when no food is in the stomach. The serious case recorded in Germany involved a hospital stay due to a sharp increase in liver enzymes, with Integrative Medicine • Vol. 15, No. 3 • June 2016

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serious toxic parenchymal damage to the liver of the patient. The product was discontinued. Viral hepatitis, autoimmune hepatitis, and alcohol abuse were excluded as potential causes. No other information on the patient was provided to the MAH by the reporting physician. Therefore, the causality for the case was not assessable. A literature search in MEDLINE was performed for comparable cases associated with the extract, R rhaponticum, or its individual components, but no liver toxicity cases were identified. One publication by Raal et al17 reported that extracts of R rhaponticum had exerted hepatoprotective effects in mice that were similar to those of transresveratrol, based on inhibition of the oxidation of the polyunsaturated fatty acids in the liver. The serious case reported in North America involved a 53-year-old woman who was diagnosed with endometrial cancer after taking the extract for less than 1 year. Age is one of the main risk factors for endometrial cancer. That risk increases among those older than 50 years.18 Other risk factors include genetic predisposition, overweight, a high-fat diet, nulliparity, early menarche, or estrogen therapy that was unopposed by progesterone therapy.18 For the case in the current study, the degree to which other risk factors influenced the diagnosis was not known. The benefit/risk ratio of the extract has been continuously monitored, and no comparable cases have been found, neither from spontaneous reporting nor from the scientific literature so far. Given the selective ER-β agonistic activity and the lack of ER-α affinity of the extract in endometrial and breast tissues, a relationship between the development of endometrial cancer and the intake of the extract in the current case seems unlikely. Presumably, other factors have contributed to that reported AE. Spontaneous reporting captures postmarketing safety information that is more diverse than that generated from a clinical trial, which tests a relatively small group of selected participants in a more controlled environment for a fixed duration. However, unlike in clinical trials where all AEs are recorded, underreporting is a well-known limitation of spontaneous reporting.19 Many consumers believe that natural health products such as the extract of R rhaponticum are natural and do not involve risks, thereby failing to identify and report any adverse reactions that occur. Some health care providers consider AE reporting to be burdensome, especially if the symptoms are not serious; lack the awareness or knowledge as to how or where to report; or do not have the resources even to identify suspected AEs. Further, incomplete data gathering makes it difficult to assess causality.20 Missing information on treatment duration in many AE reports also precluded the assessment of the long-term safety of the extract. Often the symptoms that are reported as AEs were ones that are typical for menopause (eg, headache, sleep disturbance, or breast pain) or had nothing to do with either the extract or 38

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menopause. The latter were mostly due to an increased awareness of and attentiveness to body changes during the transitional period of menopause. Another limitation was that the prevalence or incidence rates of AEs could not be precisely calculated because the prescription data and the number of women using the extract had not been reported in Germany. Nevertheless, because very few surveillances of postmarketing safety related to consumption of herbal supplements are published in peer-reviewed literature, the current research team believed that it was valuable as an alternative safety indicator to publish the number of AE reports related to the extract in relationship to the amount sold. Without ongoing postmarketing monitoring, health officials and consumers would not be able to identify any signal that warrants a safety re-evaluation of a marketed natural health product. That monitoring is especially important for the extract of R rhaponticum, a product that is intended to be used by perimenopausal and postmenopausal women, many with chronic health conditions who may consume natural products for an extended period for relief of menopausal symptoms. Conclusions Approximately 140 million daily doses of products using the extract of R rhaponticum, ERr 731, were placed on the German market from July 1993 to June 2014, and within that period, 124 predominantly nonserious AE reports were documented. Approximately 13 million tablets of supplements using the extract had been sold in North America and South Africa from the product’s launch up to June 2014, and 79 complaints from consumers, including 1 serious AE, had been recorded. Thus, the incidence of AEs can be considered to be very low. However, the limitation of underreporting cannot be overlooked and, thus, data should be interpreted with caution. The current study’s analysis of data from postmarketing surveillance and consumers’ complaints have suggested that dietary supplements incorporating the extract of R rhaponticum are safe for consumption.

Author Disclosure Statement

J. Chang and M. B. Montalto are employees of Metagenics, Inc, the distributor of ERr 731 in North America and South Africa. P. W. Heger is director of Health Research Services, a Contract Research Organization providing special services for ERr 731. E. Thiemann is the Qualified Person for Pharmacovigilance of Dr. Loges + Co. GmbH, the marketing authorization holder of femi-loges in Germany. R. Rettenberger is director of Chemisch-Pharmazeutische Fabrik Göppingen, the manufacturer of ERr 731. J. Wacker declares no conflict of interest.

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Chang—ERr 731 Postmarketing Surveillance Data

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