Import Alert 54-10

(Note: This import alert represents the Agency's current guidance to FDA field personnel regarding the manufacturer(s) and/or products(s) at issue. It does not create or confer any rights for or on any person, and does not operate to bind FDA or the public).

Import Alert # 54-10
Published Date: 03/21/2018
Type: DWPE

Import Alert Name:

"Detention Without Physical Examination of Bulk/Finished Dietary Supplements Products Containing Aristolochic Acid"

Reason for Alert:

The botanical Aristolochia spp. and other plants in the Aristolochiaceae family are widely used as ingredients in traditional Chinese herbal medicines and other traditional medicines. These products may often be labeled for drug use (e.g., claims that they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases), although there are no approved new drug applications (NDAs). Some products containing botanicals in this family may also be labeled as dietary supplements or may not be labeled in accordance with the requirements for any specific FDA-regulated product.

Plants in the Aristolochiaceae family contain aristolochic acid, which is a substance known to result in serious adverse health effects when taken orally by humans or animals. Several outbreaks of renal failure in recent years have been attributed to the use of Chinese herbal medicines that were later shown to contain aristolochic acid. In each instance, the source of aristolochic acid was determined to be an aristolochia spp. plant that was used in the product for one of two reasons: (1) the plant ingredient that was listed on the label was mis-identified; or (2) the identity of the plant ingredient or product was
confused with an aristolchia-containing ingredient or product because the traditional Chinese names were misinterpreted or similar.

*** Aristolochic acid is a potent carcinogen and nephrotoxin. Its nephrotoxic potential has been demonstrated in animals and humans in case reports and in at least one human clinical study. *** Products that
contain a large amount of aristolochic acid have been documented to result in the rapid onset of acute toxicity symptoms. However, a product containing a small amount of aristolochic acid could be used for years with no apparent adverse effects until serious, irreversible effects, such as renal damage, has occurred. In sum, products containing
aristolochic acid cause renal damage and can cause or contribute to renal failure.

There are analytical methods available to examine suspect raw material and finished product for the presence of aristolochic acid. *** products that contain Aristolochia spp. or other botanicals that contain aristolochic acid should be evaluated in order to establish that the product is free of aristolochic acid. ***

Guidance:

*** Districts may detain without physical examination bulk or finished dietary supplements or drugs, or bulk or finished products of other commodity types that are identified as being composed, in whole or in part, of any Aristolochia spp. and those species of Asarum, Cocculus, and Thottea listed in the below or from the firms identified on the attachment for this alert. ***

Botanicals Known or Suspected to Contain Aristolochic Acid

Botanical Name* Common or Other Names**

Aristolochia spp. Aristolochia
Guan mu tong
Guang mu tong
*** Aristolochiae ***

Aristolochia acuminata Lam. Oval leaf
Syn. Aristolochia tagala Champ. Dutchman's pipe

Aristolochia argentina Griseb. **

Aristolochia baetica Linn. **
Syn. Aristolochia bracteolata Lam.

Aristolochia bracteata Retz. Ukulwe

Aristolochia chilensis Bridges in Lindl. **

Aristolochia cinnabarina C.Y. Cheng & J.L. Wu **

Aristolochia clematitis L. Birthwort
***Aristoloche
clematite Asarabacca ***

Aristolochia contorta Bunge Ma dou ling
*** Madolin ***
Tian xian teng
***Bei ma dou ling ***

*** Aristolochia cucurbitifolia Hayata Gua ye ma dou ling ***

Aristolochia cymbifera Mart. & Zucc. Mil homens

Aristolochia debilis Siebold & Zucc. Ma dou ling
Syn. Aristolochia longa Thunb. *** Madolin ***
Syn. Aristolochia recurvilabra Hance Tian xian teng
Syn. Aristolochia sinarum Lindl. Qing mu xiang
Sei-mokkou (Japanese)
Birthwort
Long birthwort

Aristolochia elegans Mast. **
Syn. Aristolochia hassleriana Chodat

Aristolochia esperanzae Kuntze **

Aristolochia fangchi Y.C. Wu ex L.D. Chow Guang fang ji
& S.M. Hwang Fang ji
Mokuboi (Japanese)
Kwangbanggi (Korean)
Fang chi
Kou-boui (Japanese)

Aristolochia fimbriata Cham. **

*** Aristolochia foveolata Merr. Feng wo ma dou ling ***

Aristolochia indica L. Indian birthwort

Aristolochia kaempferi Willd. ***Yi ye ma dou ling***
Syn. Aristolochia chrysops (Stapf) E.H. Wilson Yellowmouth
ex Rehder Dutchman's pipe
*** Syn. Aristolochia dabieshanensis C.Y. Cheng & W. Yu ***
Syn. Aristolochia feddei H. Lev.
Syn. Aristolochia heterophylla Hemsl.
*** Syn. Aristolochia kaempferi Willd. F. heterophylla (Hemsl.)
S.M. Hwang
Syn. Aristolochia kaempferi Willd. F. mirabilis Hemsl.)
S.M. Hwang ***
Syn. Aristolochia mollis Dunn
*** Syn. Aristolochia neolongifolia J.L. Wu & Z.L. Yamg ***
Syn. Aristolochia setchuenensis Franch.
Syn. Aristolochia shimadai Hayata
Syn. Aristolochia thibetica Franch.
Syn. Isotrema chryspos Stapf
Syn. Isotrema heterophylla (Hemsl.) Stapf
Syn. Isotrema lasiops Stapf

Aristolochia kwangsiensis Chun & F.C. How **
Syn. Aristolochia austroszechuanica C.B. Chien
& C.Y. Cheng

Aristolochia macrophylla Lam. Dutchman's pipe
Syn. Aristolochia sipho L'Her.

Aristolochia manschuriensis Kom. Manchurian birthwort
Syn. Hocquartia manschuriensis (Kom.) Nakai Manchurian Dutchman's
Syn. Isotrema manschuriensis (Kom.) H. Huber pipe
*** Mu tong ma dou ling ***
Guang mu tong
Kan-Mokutsu (Japanese)
Mokuboi (Japanese)
Kwangbanggi (Korean)

Aristolochia maurorum L. **

Aristolochia maxima Jacq. **
Syn. Aristolochia maxima var. angustifolia
Duchartre in DC.
Syn. Howardia hoffmannii Klotzsch

Aristolochia mollissima Hance **

*** Aristolochia odoratissima L. ** ***

Aristolochia pistolochia L. **

*** Aristolochia pubescens Hort. Ex K. Koch ** ***

Aristolochia rigida Duch. **

Aristolochia rotunda Linn. **

Aristolochia serpentaria L. Virginia snakeroot
*** Syn. Aristolochia convolvulacea Small *** Serpentaria
*** Syn. Aristolochia hastata Nutt. *** Virginia serpentary
*** Syn. Aristolochia nashii Kearney ***
Syn. Aristolochia serpentaria var. hastata
(Nutt.) Duchatre

*** Aristolochia trilobata L. ** ***

Aristolochia watsoni Wooton & Standley or **
Aristolochia watsonii Wooton & Standley
Syn. Aristolochia porphyrophylla Pfeifer

Aristolochia westlandii Hemsl. or **
Aristolochia westlandi Hemsl.

Aristolochia zollingerana Miquel **
Syn. Aristolochia kankauensis Sasaki
Syn. Aristolochia roxburghiana subsp. kankauensis
(Sasaki) Kitam.
Syn. Hocquartia kankausensis (Sasaki) Nakai ex Masam
Syn. Aristolochia tagala var. kankauensis
(Sasaki) T. Yamaz.

*** Asarum arifolium Michx **
Syn. Hexastylis arifolia Small var. ruthii (Ashe) H.L. ***

Asarum canadense Linn. Wild ginger
Syn. Asarum acuminatum (Ashe) E.P. Bicknell Indian ginger
Syn. Asarum ambiguum (E.P. Bicknell) Daniels Canada snakeroot
Syn. Asarum canadense var. ambiguum False coltsfoot
(E.P. Bicknell) Farw. Colic root
Syn. Asarum canadense var. reflexum Heart snakeroot
(E.P. Bicknell) B.L. Rob Vermont snakeroot
Syn. Asarum furcatum Raf. Southern snakeroot
Syn. Asarum medium Raf.
Syn. Asarum parvifolium Raf.
Syn. Asarum reflexum E.P. Bicknell
Syn. Asarum rubrocinctum Peattie

*** Asarum caudatum Lindl **
Asarum crispulatum C.Y. Cheng & C.S. Yang **

Asarum debile Franch. **
Asarum forbesii Maximn Batei-saishin
(Japanese)
Asarum fukienense C.Y. Cheng & C.S. Yang **

Asarum heterotropoides F. Schmidt Keirin-saishin
Syn. Asarum heterotropoides F. Schmidt (Japanese)
Syn. Asiasarum heterotropoides (F. Schmidt) Chinese wild ginger
F. Maek Manchurian wild ginger
Bei Xi Xin
Xi xin
His-hsin ***

Asarum himalaicum Hook. f. & Thomson ex Tanyou-saishin
Klotzsch or (Japanese)

*** Asarum ichangense C.Y. Cheng & C.S. Yang **
Asarum maximum Hemsl. **

Asarum sieboldii Miq. Usuba-siashin
(Japanese)
Syn. Asarum sieboldii fo. Seoulense (Nakai) Chinese wild ginger
C.Y. Cheng & C.S. Yang Xi Xin
Syn. Asarum sieboldii var. seoulensis Nakai Hua Xi Xin
Syn. Asarum heterotropoides var. seoulense Manchurian wild ginger
(Nakai) F. Maek. Siebold's wild ginger
Syn. Asiasarum sieboldii (Miq.) F. Maek His-hsin ***

Asarum splendens (F. Maek.) C.Y. Cheng & Do-saishin
C.S. Yang (Japanese)
*** Asarum wagneri K.L.Lu & M.R. Mesler **
Cocculus orbiculatus (L.) DC Moku-boui (Japanese)
Syn. Cocculus cuneatus Benth.
Syn. Cocculus sarmentosus (Lour.) Diels
Syn. Cocculus sarmentosus var. linearis Yamam.
Syn. Cocculus sarmentosus var. pauciflorus Y.C. Wu
Syn. Cocculus sarmentosus var. stenophyllus Merr.
Syn. Cocculus thunbergii DC
Syn. Cocculus trilobus (Thunb.) DC
Syn. Menispermum orbiculatus L.
Syn. Menispermum trilobum Thunb.
Syn. Nephroia sarmentosa Lour.

Thottea siliquosa (Lam.) Apama
Syn. Bragantia Wallichii R. Br. Thottea ***
Syn. Apama siliquosa Lam.

* The Latin binomial name may appear without the author's name.
** Does not indicate the lack of any common name.

*** Chinese products known to contain Aristolochic Acid
Dang Gui Si Ni
Du Hou Ji Sheng Tang (Tuhuo and Loranthus Formula)
Xiao Qing Long Tang (Minor Blue Dragon Formula)
Chuan Xiong Cha Tiao Wan (Cnidium and tea formula)
Da Qin Jiao Tang (Major Gentiana Macrophylla Root formula)
Ling Gan Jiang Wei Xin Xan Ren Tang (Hoelen and Schizandra formula)
Ma Huang Fu Zi Xi Xin Tang (Ephedra and Asarum ofrmula)
San Bi Tang (Tu Huo and Astragalus formula
Jiu Wei Qiang Hou Tang (Notopterygium Nine Herb formula)
Qing Shang Juan Tong Tang (Ophiopogon and Asarum formula)
Ta Huo lo tan (Da hou lo tan)(Chinese old man tea, The Greater Invigorate
Luou Channel Pill)
Tu zhung feng shi wan
Hai long bu wan (Hailung tonic pills)(sea horse, pipe fish nourishing pills)

If product labeling includes claims for the diagnosis, cure,mitigation, treatment, or prevention of disease, use the new drug charge and the misbranding drug charge. If the product labeling does not include disease claims but the district has determined through other means (e.g.,conversation with the importer, letter from the importer, etc.) that the product is intended for disease use, then use the drug misbranding charge. In this instance please contact the Deputy Chief Counsel For Litigation, to further discuss the circumstances and evidence of the importation and whether or not a new drug charge would also be appropriate. In addition, the appropriate food charges (see below) should be included.

If the product does not appear to be a drug, only food adulteration charges should be used. If the products appear to be finished products labeled as dietary supplements, charges under section 402(a)(1), section
402(f)(1)(A), and section 402(f)(1)(D) should be used. If the product is a bulk dietary ingredient (e.g., root, powder, extract) charges under section 402(a)(1) and section 402(f)(1)(A) should be used.

A product labeled as a dietary supplement may be released when a firm is able to provide analytical evidence that it is free of aristolochic acid. Only certificates of analysis or other evidentiary documents that rely on liquid chromatography-mass spectrometry analytical determination of aristolochic acid content should be accepted as a basis to release detained product.

For questions or issues concerning science, science policy, sample collection, analysis, preparation, or analytical methodology, contact the Division of Field Science at 301 796-6600.

All requests for removal from detention without physical examination should be address to DIOP 301-796-0356.

Product Description:

*** Dietary Supplements or Drugs, Bulk or Finished, labeled as containing Aristolochia spp., certain Asarum spp., certain Cocculus spp., and certain Thottea spp. ***

Charge:

"The product is subject to refusal of admission pursuant to Section 801(a)(3) in that it appears to be a dietary supplement or contain a dietary ingredient that presents a significant or unreasonable risk of illness or injury under the conditions of use set out in the labeling or, if none are set out in the labeling, under customary conditions of use [Adulteration, Section 402(f)(1)(A)."

(OASIS Charge Code - UNSFDIETLB)

and/or

“The article is subject to refusal of admission pursuant to Section 801(a)(3) in that it appears to bear or contain a poisonous or deleterious substance which may render the article injurious to health. [Adulteration, Section 402(a)(1)]” Contains:

(OASIS Charge Code - POISONOUS)

and/or

"The product is subject to refusal of admission pursuant to Section 801(a)(3) in that it appears to contain or bear a poisonous or deleterious substance which renders it adulterated under section (a)(1) under conditions of use recommended in or suggested in the labeling [Adulteration, Section 402(f)(1)(D)."

(OASIS Charge Code - UNSFDIETUS)

and/or

"The article is subject to refusal of admission pursuant to 801(a)(3) in that it appears to be a new drug without an approved new drug application [Unapproved new drug, Section 505(a)]."

(OASIS Charge Code - UNAPPROVED)

and/or "The article is subject to refusal of admission pursuant to 801(a)(3) in that it appears to lack adequate directions for use [Misbranded drug, Section 502(f)(1)]."

(OASIS Charge Code - DIRECTIONS)

List of firms and their products subject to Detention without Physical Examination (DWPE) under this Import Alert (a.k.a. Red List)


TAIWAN


Kaiser Pharmaceutical Co.
Date Published : 09/18/2009
No. 9 Huangong Rd. , Yongkang Dist. , Tainan City, TAIWAN
54 F - - 99 Herbals & Botanicals (not Teas), N.E.C.
Date Published: 09/18/2009

Notes: Xi Xin (dietary supplement)