Consultation: Proposed changes to the Permissible Ingredients Determination: low-negligible risk changes 2020-21

High doses of magnesium from dietary supplements and medicines have been shown to result in diarrhoea, which can be accompanied by nausea and abdominal cramping. The diarrhoea and laxative effects of magnesium salts are due to the osmotic activity of unabsorbed salts in the intestine and colon, and the stimulation of gastric motility^[1]. The TGA holds concerns that the risk of these effects from common self-selected listed medicines is not apparent for consumers.

The TGA is proposing new restrictions for listed medicines, not indicated for laxative use, where those medicines contain higher doses of easily-dissociable magnesium salts.

Background

In 2014, the Australian National Health and Medical Research Council (NHMRC) published recommendations for upper levels of supplemental magnesium intake in different population groups. Based on the available human studies, the NHMRC found that doses of 250 mg elemental magnesium per day was well tolerated in men and women (including during pregnancy and lactation) and diarrhoea was observed at doses of 360 mg elemental magnesium per day and greater. An upper level for magnesium supplements was specified by the NHMRC at:

• 350 mg elemental magnesium per day for adults and children over 9 years of age;
• 110 mg elemental magnesium per day for children 4-8 years of age;
• 65 mg elemental magnesium per day for children 1-3 years of age; and
• not established for infants 0-12 months of age, as magnesium intake should be sourced from dietary sources only^[2].

In 2019, the US Food and Nutrition Board Institute of Medicine (IOM) established dietary reference intakes for magnesium^[3] through a dose-response assessment of magnesium studies from non-food sources, using diarrhoea as the most sensitive effect. Diarrhoea was reported in doses ranging from 360-470 mg elemental magnesium per day.

The European Scientific Committee on Food (SCF) analysed data from studies on magnesium supplementation^[4] with doses ranging from 180 to 1095 mg elemental magnesium per day. The SCF concluded that mild diarrhoea was an established effect in studies of adult patients at oral doses of around 360-365 mg elemental magnesium per day. No laxative effects were reported in adults, including during pregnancy and lactation in women, at doses of up to 250 mg elemental magnesium per day, or in children aged 4-12 years at up to 245 mg elemental magnesium per day.

The Norwegian Scientific Committee for Food Safety (VKM) conducted a risk assessment of magnesium supplementation in 2016^[5]. In consideration of the findings by the SCF and IOM, the VKM set an upper level for adults of 350 mg elemental magnesium per day, with adjusted ULs for children based on recommended intakes by age group.

The TGA sought advice from the Advisory Committee on Complementary Medicines (ACCM) on the laxative effects of easily dissociable magnesium salts at the 24th ACCM meeting. The TGA sought the committee's views on whether a label warning and maximum daily dose was necessary for medicines containing 250 mg or more elemental magnesium per maximum recommended daily dose for children and adults greater than 4 years of age, and 150 mg elemental magnesium per maximum recommended daily dose for children aged 1-3 years of age. The committee noted that the upper limit differed between agencies with respect to age thresholds. Daily dosages of 250 mg elemental magnesium per day in adults was advised to be a more appropriate level to mandate warning statements, as it aligns with the dose where diarrhoea was not observed as an adverse effect in human studies. This more conservative level was also considered due to the large number of magnesium-containing supplements and medications, which may be taken simultaneously. The committee noted that the existing restrictions for magnesium salts are not consistent in the Therapeutic Goods (Permissible Ingredients) Determination.

The committee advised that the TGA should consider a requirement for listed medicines containing more than 250 mg elemental magnesium per day of easily-dissociable forms of magnesium to carry a label statement for potential laxative effects, and measures to not exceed the maximum daily dose. The committee noted that products indicated for use as a laxative would not require a warning regarding the risk of laxative effects. The committee also noted that a daily dose of 150 mg elemental magnesium in listed medicines may be too high for children aged 1-3 years of age. In consideration of this advice, the TGA amended the proposed levels for mandated laxative warning statements for products indicated for use in children between 1 and 8 years of age; and, reduced the proposed levels to the upper limits specified for these age groups by the NHMRC. The TGA does not propose to consider an appropriate maximum recommended daily or single dose of all magnesium salts in listed medicines at this time.

Current requirements

The Therapeutic Goods (Permissible Ingredients) Determination (No. 3) 2020 specifies:

• magnesium hydroxide must include a laxative warning, when the medicine is not promoted or marketed as a laxative and magnesium hydroxide is present at greater than 2 g magnesium hydroxide per maximum recommended daily dose, based on the established therapeutic dosage of 2-5 g of magnesium hydroxide as a laxative.
• magnesium sulfate salts are restricted to 1.5 g magnesium sulfate (approximately 300 mg elemental magnesium) per maximum recommended daily dose. This requirement reflects the inclusion of magnesium sulfate in Schedule 3 of the Poisons Standard. The osmotic effect of magnesium sulfate is greater than other magnesium salts due to the additional osmotic effect of the sulfate ion^[6].
• magnesium pyruvate must not contain more than 7 grams magnesium pyruvate per maximum recommended daily dose, due to the risk of gastrointestinal disturbances from pyruvate.
• bittern, an ingredient which was recently evaluated and made available for use during the TGA's consideration of the laxative effect of magnesium, carries similar requirements to those proposed below.
• no requirements relating to maximum recommended daily dose or warning statements for other forms of magnesium.

The Therapeutic Goods (Permissible Indications) Determination (No. 2) 2019 specifies indications that are related to having a laxative effect:

• Open/relax bowels
• Decrease/reduce/relieve constipation
• Aperient/laxative
• Helps reduce occurrence of constipation
• Promote/increase bowel evacuation
• Stimulant laxative
• Enhance/improve/promote/increase bowel regularity
• Maintain/support bowel regularity
• Enhance/improve/promote/increase bowel waste elimination

These indications each have the same requirements, as follows:

• Label statement: If symptoms persist, talk to your health professional.
• Label statement: Drink plenty of water (or words to that effect).
• Label statement for stimulant laxatives: Prolonged use may cause serious bowel problems.
• Label statement: Do not use when abdominal pain, nausea or vomiting are present or if you develop diarrhoea. If you are pregnant or breastfeeding - seek the advice of a healthcare professional before taking this product (or words to that effect).
• Product presentation must not refer to or imply weight loss.

Consultation

The TGA is seeking consultation on an amendment to the requirements for all easily-dissociable forms of magnesium salts in the Therapeutic Goods (Permissible Ingredients) Determination.

The osmotic laxative effect of orally ingested magnesium is well-established, with such effects being observed consistently at doses of 360 mg elemental magnesium per day. Only doses of up to 250 mg elemental magnesium per day have been consistently well tolerated in human studies. As such, the TGA proposes a warning statement to alert consumers to the risk of laxative-effect from products containing easily dissociable magnesium salts that provide more than 250 mg of elemental magnesium from the maximum recommended daily dose.

Indications specified by the Permissible Indications Determination that are related to laxative effects are not impacted by this proposal, as consumers are informed of the effects by these indications and products with these indications are required to carry relevant warning statements:

• 'If symptoms persist, talk to your health professional'
• 'Do not use when abdominal pain, nausea or vomiting are present or if you develop diarrhoea. If you are pregnant or breastfeeding - seek the advice of a healthcare professional before taking this product (or words to that effect).'

These requirements are proposed to apply to the existing warning statement requirement for magnesium hydroxide and bittern; and be in addition to the existing limits for magnesium sulfate salts and magnesium pyruvate. The proposed specific requirements will provide a consistent approach to address the risks of diarrhoea for listed medicines, which do not currently alert consumers to this effect.

Following consideration of comments received for this consultation, and subject to any revisions of the proposals and consideration by the Delegate of the Minister, sponsors of existing listed medicines containing easily-dissociable forms of magnesium salts will have until the end of the transition period to amend medicine labels in line with any new specific requirements.

Easily-dissociable forms of magnesium in the Therapeutic Goods (Permissible Ingredients) Determination

• ALUMINIUM MAGNESIUM SILICATE
• BITTERN
• DIBASIC MAGNESIUM CITRATE TETRAHYDRATE
• DIBASIC MAGNESIUM PHOSPHATE TRIHYDRATE
• DRIED MAGNESIUM SULFATE
• HEAVY MAGNESIUM OXIDE
• LEVOCARNITINE MAGNESIUM CITRATE
• LIGHT MAGNESIUM OXIDE
• MAGNESIUM AMINO ACID CHELATE
• MAGNESIUM ASCORBATE
• MAGNESIUM ASCORBATE MONOHYDRATE
• MAGNESIUM ASPARTATE
• MAGNESIUM ASPARTATE DIHYDRATE
• MAGNESIUM ASPARTATE TETRAHYDRATE
• MAGNESIUM CARBONATE HYDRATE
• MAGNESIUM CHLORIDE 4.5-HYDRATE
• MAGNESIUM CHLORIDE HEXAHYDRATE
• MAGNESIUM CITRATE
• MAGNESIUM CITRATE NONAHYDRATE
• MAGNESIUM CITRATE TETRADECAHYDRATE
• MAGNESIUM DIGLUTAMATE
• MAGNESIUM GLUCONATE
• MAGNESIUM GLYCEROPHOSPHATE
• MAGNESIUM GLYCINATE
• MAGNESIUM GLYCINATE DIHYDRATE
• MAGNESIUM HYDROGEN PHOSPHATE
• MAGNESIUM HYDROXIDE
• MAGNESIUM LYSINATE
• MAGNESIUM METHIONINATE
• MAGNESIUM OROTATE
• MAGNESIUM OROTATE DIHYDRATE
• MAGNESIUM OXIDE
• MAGNESIUM PHOSPHATE PENTAHYDRATE
• MAGNESIUM PHOSPHATE TRIBASIC
• MAGNESIUM PYRUVATE
• MAGNESIUM STEARATE
• MAGNESIUM SULFATE DIHYDRATE
• MAGNESIUM SULFATE HEPTAHYDRATE
• MAGNESIUM SULFATE MONOHYDRATE
• MAGNESIUM SULFATE TRIHYDRATE
• MAGNESIUM TRISILICATE

Proposed specific requirements

Magnesium is a mandatory component of this ingredient.

When used in medicines:

1. with an oral route of administration;
2. not indicated for laxative (or related) use; and
3. the maximum recommended daily dose for:
   1. children aged between 1 and 3 years (inclusive) provides 65 mg or more total magnesium;
   2. children aged between 4 and 8 years (inclusive) provides 110 mg or more total magnesium; or
   3. individuals aged 9 years or older provides 250 mg or more total magnesium;

the following warning statements are required on the label:

• 'This product may have a laxative effect. Discontinue use if you develop diarrhoea (or words to that effect)'.

When used in medicines with an oral route of administration, the following warning statement is required on the label:

• 'Not suitable for infants under the age of twelve months' (or words to that effect).'

References

[1] Swain R, Kaplan-Machlis B. Magnesium for the next millennium. South Med J. 1999;92(11):1040-1047. doi: 10.1097/00007611-199911000-0000
[2] National Health and Medical Research Council (NHMRC). Magnesium - Nutrient Reference Values for Australia and New Zealand 2014. Available from: https://www.nrv.gov.au/nutrients/magnesium.
[3] Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. 6. Magnesium Washington (DC): National Academies Press; 1997. Available from: https://www.ncbi.nlm.nih.gov/books/NBK109816/#ch6.s73
[4] European Food Safety Authority. Tolerable Upper Intake Levels for Vitamins and Minerals - Magnesium 2006 [107-16]. Available from: http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf
[5] The Norwegian Scientific Committee for Food and Environment (VKM). Risk assessment of magnesium in food supplements 2016. Available from: https://vkm.no/english/riskassessments/allpublications/riskassessmentofmagnesiuminfoodsupplements.4.2375207615dac0245aee5130.html
[6] SC Sweetman. Magnesium Hydroxide, in Martindale: The Complete Drug Reference 2008.

Andrographis paniculata is a herb commonly used in Indian and Chinese medicine. It is also known as kalmegh (King of bitters) or green chiretta in Ayurvedic medicine, and as chuan xin lian in traditional Chinese medicine. Andrographis paniculata is traditionally used mostly for a variety of acute conditions, including to reduce symptoms of respiratory infections and gastro-intestinal complaints^[1].

Andrographis paniculata is currently permitted for use in listed medicines as an active or homoeopathic ingredient with a warning statement on the label: 'Andrographis may cause allergic reactions in some people. If you have a severe reaction (such as anaphylaxis), stop use and seek immediate medical attention (or words to that effect).' The TGA has released a separate web statement in October 2015 concerning Andrographis paniculata-related allergic reactions. Andrographis paniculata is an active ingredient in 82 listed medicines as of 18 August 2020.

The TGA has considered evidence that indicates an association between Andrographis paniculata and loss of taste/taste disturbance. A web statement was released in May 2020 to advise consumers and health professionals of this risk.

Background

In 2017, the TGA had received four reports of loss of taste/taste disturbance associated with a product containing Andrographis paniculata. A subsequent investigation did not identify a causal association. A major obstacle was the nature of the product as a cold relief medication; as it could not be confirmed whether the adverse events were caused by the product or by upper respiratory tract infections (URTIs) which can sometimes disrupt the senses of smell and taste.

By 7 May 2020, the TGA had received 88 reports of taste disturbance related to products containing Andrographis paniculata. This increase in available data allowed for a more thorough investigation. Andrographis paniculata was identified as the most likely cause of the symptoms based on clinical trial data^[2],[3],[4], and analysis of the other ingredients in the identified products. URTIs were excluded as a suspected cause due to a number of reports from individuals who reported that they had no concurrent URTI, and were using the product for general wellness when they developed loss of taste/taste disturbance.

The issue was considered by the Advisory Committee on Complementary Medicines (ACCM) at their 25th meeting on 16 July 2020, which considered adverse events reports up to 30 June 2020. At the time the committee considered that the evidence supported a correlation between ArmaForce products and taste-related adverse events. However, the evidence for a causal association for the ingredient Andrographis paniculata was less clear, and ACCM recommended continued monitoring. The TGA has continued to receive reports for products containing Andrographis paniculata including an additional 11 reports between 30 June 2020 and 30 July 2020 for products other than ArmaForce.

By 30 July 2020, the TGA had received 226 reports of ageusia (loss of taste), dysgeusia (taste distortion), hypogeusia (decreased sense of taste) and/or taste disorder related to products containing Andrographis paniculata.

Investigation summary

Active ingredients

A review of the active ingredients common to the medicines involved in the adverse events did not identify evidence of a causal association for any ingredient other than Andrographis paniculata. Limited evidence was identified to suggest that the active constituent, andrographolide, may be responsible for these effects.

Andrographis paniculata/andrographolide clinical trials

Three clinical trials were identified that reported loss of taste or taste disturbance after treatment with Andrographis paniculata or purified andrographolide^[2],[3],[4]. The rates of taste loss/taste disturbance (2%-24%) in the treatment arms of the trials suggest that the incidence may be as high as common or very common^[5]. However, establishing a rate of occurrence with any certainty is limited by the small number of participants in the treatment arms (17-149). Notwithstanding, these trials provide evidence that there is a plausible causal association between the ingredient Andrographis paniculata and/or its active constituent andrographolide, and taste loss/taste disturbance.

Other clinical trials of Andrographis paniculata have not reported effects on the sense of taste. However, only limited information regarding the methodology was published, and as such the level of safety monitoring was not clear, and the preparation of Andrographis paniculata used was not frequently described.

Zinc

Taste disturbance associated with zinc has been observed in clinical trials, however only when administered as zinc lozenges or liquids, mostly reporting metallic or 'bad taste', with no cases of taste loss reported^[6],[7]. These effects appear to result from direct contact between the oral mucosa and zinc, which can have a distinctly unpleasant taste. While the suspected Andrographis paniculata containing products involved in the adverse events also contained zinc, none were lozenges or liquids. Therefore, zinc was not considered to play a causative role in the taste loss/taste disturbance reported in the analysed cases.

Adverse events

The majority (91%) of the cases were associated with ArmaForce products. However, 20/226 (9%) cases involved a total of nine different products which also contain Andrographis paniculata. While a small proportion of the total cases, the receipt of 20 reports of taste loss/taste disturbance is considered a significant signal for listed medicines and would have led to an investigation even in the absence of ArmaForce reports.

Confounding factors

Adverse event reports were reviewed for confounding factors, resulting in 62 reports being excluded from further analysis. This included six reports associated with four products other than ArmaForce. The remaining 164 reports (150 associated with ArmaForce products and 14 associated with nine other Andrographis paniculata-containing products) were analysed for trends relating to dosage and duration of use.

Confounding factors included the use of concomitant medicines that can cause taste disturbance, or symptoms of URTI. While URTIs can be a cause of loss of taste/taste distortion, they could also lead to under-reporting whereby consumers may attribute loss of taste to the URTI rather than the product containing Andrographis paniculata. Sudden onset of loss of taste or altered taste is also a symptom of COVID-19. This raises the question of whether consumers may have been infected with COVID-19, which caused loss of taste. While COVID-19 prevention was mentioned as a reason for use in many cases (see below), none of the analysed cases reported reason for use as treatment of COVID-19. Further, 24 of the analysed cases reported negative results from COVID-19 testing, while a further six cases reported COVID-19 testing, but did not provide results. As such, COVID-19 was not considered to be a confounding feature in the analysed cases, and was specifically excluded as a contributing factor in 24 cases. Moreover, any cases that reported symptoms of active URTI were excluded from further analysis.

It should also be noted that for the majority of cases that were excluded from analysis due to concomitant medicines associated with taste disturbance, the concomitant medicines were not suspected in the reaction. A possible reason for this is that medicines had been taken for some time without affecting taste, whereas the onset of taste loss/taste disturbance appeared related to the introduction of the product containing Andrographis paniculata. Therefore, it is possible that Andrographis paniculata played a causative role in excluded cases.

Reason for use

A reason for use was not reported in 77/164 cases, while the remaining 87 listed various reasons for use that related to immune support, cold/flu prevention and general wellness. COVID-19 prevention was reported as the reason for use in 24 cases.

Dose and time to onset

A correlation was observed with respect to dose and duration of use/time to onset. Cases that included data on both dose and time to onset (n=115) showed that 100/115 (87%) of cases involved a dose of two or more dosage units per day and/or a time to onset of two weeks or longer. There were 15/115 (13%) reports that involved a duration of use than less than two weeks, with a dose of one dosage unit per day. Of the 115 cases with dose and latency data, the equivalent quantity of Andrographis paniculata herb per dosage unit ranged from 2.25g-13.9g (mean = 2.8g), in the form of concentrated extracts with an extract ratio of 14:1 or greater (i.e. 14 parts raw material [dry herb] to 1 part final extract). The quantity of the active constituent andrographolide per dosage unit (where known [n=114]) ranged from 41.67mg to 62.5mg (mean = 62mg).

Traditionally, Andrographis paniculata is not recommended to be taken long term or in 'too a high a dose'^[8]. The traditional literature does not report toxic side effects when taken as a decoction or a traditional pill, but does report unspecified toxicity from pharmaceutical preparations of tablets^[8]. Further, traditional use involves powdered dried plant material, aqueous based decoctions/infusions or dilute ethanolic extracts (tinctures)^[9], which are likely to contain lower quantities of andrographolide than in concentrated extracts, such as those involved in the adverse event reports, and in the majority of Andrographis paniculata products on the Australian Register of Therapeutic Goods (ARTG). Andrographis paniculata is included in the National List of Essential Medicines (NLEM) in Thailand. Published analysis of Thai pharmacovigilance data did not identify taste-related adverse events for Andrographis paniculata^[10]. However, the NLEM recommends Andrographis paniculata be used for no more than three days in the treatment of respiratory tract infections. This duration of use may limit the occurrence of taste loss/taste disturbance as an adverse effect.

Thus, the modern preparations of Andrographis paniculata associated with adverse effects on taste appear to mostly involve a longer exposure period to higher doses of Andrographis paniculata and andrographolide than traditional preparation types and duration of use. In addition, the use of indications such as immune support, differ from most traditional indications and are more likely to be associated with a prolonged duration of use.

Doses administered in the clinical trials with reported adverse effects on taste ranged from 1200-2400mg/day Andrographis paniculata extract^[3],[4] and 1050mg-2100mg/day andrographolide. Clinical trial doses of andrographolide were considerably higher than doses consumed in the adverse events reported to the TGA. Unfortunately, the Andrographis paniculata extracts were not adequately characterised in the clinical trials to enable dosage comparison with those in the adverse events reported to the TGA. The time to onset of taste related adverse events in the trials was also not well described, however were observed during weeks 1-9 in one trial^[2], through to week 12 in another^[3].

Time to resolution

The typical time for resolution is unknown, with symptoms ongoing at the time of reporting in 70% (114/164) analysed cases. Of these, 28 cases reported some degree of improvement. Symptoms had persisted for several weeks in many cases, while 18% of cases (20/114) had ongoing symptoms that had persisted for one month or longer, up to three months after ceasing the product in two cases. In two of these 20 cases, the cessation date of the suspect product was not reported, therefore the duration of the adverse event was based on the date of symptom onset. For the other 18 cases, the adverse event had persisted for over a month after ceasing the suspect product. Only 7% (11/164) of cases included confirmation that symptoms had resolved, with time to recovery ranging from 21-47 days after symptom onset. Case analysis indicates that in most cases, loss of taste persists after discontinuation of the product, and can take up to several months to resolve.

Severity and impact

Taste disturbance or loss of taste, which persists after cessation of the suspect product, is a serious adverse event^[11] with potentially significant sequelae, including weight loss and malnutrition^[12]. Complete loss of taste (ageusia) was reported in 73% (119/164) cases, with weight loss reported in 5% (8/164) of cases, while a further 7% (11/164) cases reported nausea while eating, decreased appetite, trouble eating and/or not feeling like eating.

In 50 reports, patients reported consultation with their general practitioner following the adverse reaction, while 27 cases went on to have further investigations (blood tests, MRI, X-ray, CT scan and/or specialist consultation). As previously mentioned, COVID-19 testing was also reported in 30 cases. Many cases also reported significant distress and anxiety. Loss of taste and taste disturbance can be symptoms of certain serious conditions, therefore it is important that medical advice is sought if these symptoms are experienced.

Together these reports highlight the seriousness of these adverse events and their impact on the health system as well as persistent disruption to normal body function and quality of life.

International adverse event reports

No international reports, other than those from Australia, could be located for Andrographis paniculata and taste loss/taste disturbance in The Uppsala Monitoring Centre's adverse reaction reporting database VigiLyze.

Consultation

The TGA is seeking consultation on a proposed amendment to the requirements for Andrographis paniculata in the Therapeutic Goods (Permissible Ingredients) Determination. The proposed requirements are intended to address the risk of taste loss/taste disturbance effects associated with the use of Andrographis paniculata. The TGA notes that some sponsors have already implemented voluntarily, or indicated to the TGA their intention to implement, warning statements consistent with the proposed specific requirements below.

Following consideration of comments received for this consultation, and subject to any revisions of the proposals and consideration by the Delegate of the Minister, sponsors of existing listed medicines containing Andrographis paniculata will have until the end of the transition period to amend medicine labels in line with any new specific requirements.

Proposed specific requirements

References

[1] Okhuarobo A, et al. Harnessing the medicinal properties of Andrographis paniculata for diseases and beyond: a review of its phytochemistry and pharmacology. 2014. Asian Pacific Journal of Tropical Disease, Vol. 4, pp. 213-222.
[2] Calabrese C, et al. A phase I trial of andrographolide in HIV positive patients and normal volunteers. Phytotherapy Research. 2000. 4(5):333-8.
[3] Sandborn WJ, et al. Andrographis paniculata extract (HMPL-004) for active ulcerative colitis. The American journal of gastroenterology. 2013;108: 90-98.
[4] Liu R. A Phase III Trial of HMPL-004 in Patients with Mild to Moderate Active Ulcerative Colitis. ClinicalTrials.gov Identifier: NCT01805791 Available at: https://clinicaltrials.gov/ct2/show/results/NCT01805791?view=results Accessed 14 August 2020
[5] Council for International Organizations of Medical Sciences. Guidelines for Preparing Core Clinical-Safety Information on Drugs. 1999. Switzerland.
[6] Science M, et al. Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. 2012. Canadian Medical Association Journal. Jul 10;184(10):E551-61.
[7] Natural Medicines Database - Zinc. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-…
[8] Bensky D, Clavey S & Stoger E. Chinese Herbal Medicine Materia Medica. 3rd Edition. Eastland Press. 2004. P. 181-183.
[9] Zhongzhen Z. An illustrated Chinese Materia Medica in Hong Kong. School of Chinese Medicine. 2004. Hong Kong.
[10] Suwankesawong W, et al. Characterization of hypersensitivity reactions reported among Andrographis paniculata users in Thailand using Health Product Vigilance Center (HPVC) database. 2014. BMC Complementary and Alternative Medicine. 14, 515.
[11] Therapeutic Goods Administration. Pharmacovigilance responsibilities of medicine sponsors - Serious adverse reactions. 2018. Available from: https://www.tga.gov.au/publication/pharmacovigilance-responsibilities-medicine-sponsors#adverse-serious
[12] Bromley SM. Smell and Taste Disorders: A Primary Care Approach. 2000. American Family Physician.Jan 15;61(2):427-436.