Melilot – Meliloti herba (Melilotus officinalis (L.) Lam.)
|Latin name of the genus:||Meliloti herba|
|Latin name of herbal substance:||Melilotus officinalis (l.) lam.|
|Botanical name of plant:||Herbalref.com|
|English common name of herbal substance:||Melilot|
Latin name of the genus: Meliloti herba
Botanical name of plant: Melilotus officinalis (L.) Lam.
English common name of herbal substance: Melilot
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Melilotus officinalis (L.) Lam., herba1, 2
The European Pharmacopoeia provides the following definition for melilot (Meliloti herba): Whole or cut, dried aerial parts of Melilotus officinalis (L.) Lam. Content: minimum 0.3 per cent of coumarin (C9H6O2; Mr 146.1) (dried herbal substance).
The definition formerly given by the Pharmacopée Française was as follows: “melilot consists of the dried flowering tops of Melilotus officinalis Desr.” was changed in 2005 to the above mentioned definition of the European Pharmacopoeia. Similarly, the former German DAB and DAC definitions of melilot were replaced by the current European Pharmacopoeia melilot monograph.
The main characteristic constituents of melilot are cinnamic acid/coumarin derivates (HagerROM, 2014). Coumarin is contained in the herbal substance in quantities of
Dicoumarol and the antifungal isoflavonoid medicarpin, can be formed in melilot due to fungal infection and spoilage (Bradley, 2006).
1According to Guideline on quality of herbal medicinal products (CPMP/QWP/2819/00 Rev. 2)
2According to Guideline on specifications: test procedures and acceptance criteria for herbal preparations and herbal medicinal products/traditional herbal medicinal products (CHMP/QWP/2820/00 Rev. 2)
a)Comminuted herbal substance
b)Powdered herbal substance
c)Liquid extract, ratio of herbal substance to extraction solvent 1:3, extraction solvents: ethanol 70% (V/V) and rapeseed oil.
The preparation methodology of the liquid extract c) was described in monograph Emplastrum Meliloti in Farmakopea Polska III (1954) and in, Farmakopea Polska IV, Vol 2 (1970). According to the description Herba Meliloti is wetted with ethanol 70% (V/V) (2 parts of ethanol to 10 parts of herbal substance, = 16% of wetted herbal substance). After 2 hours rapeseed oil is added and the mixture is heated on a water bath for 2‒3 hours. Then the oil extract is pressed and filtered through paper filter. The filtrate is used to prepare cutaneous patches.
•Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
Meliloti herba and preparations thereof are often used in combinations with other herbal substances/ herbal preparations or various chemically defined substances. Although bibliographic data on combinations were discussed in the former assessment report from 2008, the current monograph refers exclusively to Meliloti herba.
1.2. Search and assessment methodology
In 2008 the assessment report reviewed the scientific data available for Meliloti herba and had taken into account the literature presented by the ESCOP to the monograph “Meliloti herba”, the French Avis aux fabricants and the German list of traditional medicinal products according to § 109 a AMG. Previous search for methodology was based on keywords “Melilotus” and ‘human” from 1900 in all text fields, melilot, coumarin, melilotoside, melilotin,
After review of newly available data this revised assessment report is focused on data on melilot preparations and safety. It takes into account compounds contained in melilot herb which are important for safety of the herbal substance or its preparations assessed.3, 4
Search engines used: Google, Google Scholar
Scientific databases: SciFinder, SCOPUS, ScienceDirect
Medical databases: PubMed, Medline
Toxicological databases: TOXLINE
3Data on human use of medicinal products, containing individual substances derived from Melilotus officinalis, herba (like coumarin), or their combinations with other substances, which were contained in the assessment report from 2008, does not fulfill criteria for herbal medicinal products and they are not included in this assessment report.
4 One herbal combination product present on EU market contains 20 mg dry extract from Hippocastani semen and 30 mg dry extract from Meliloti herba and have to regarded as fixed combination of both extracts.
Pharmacovigilance resources: WHO Global ICSR database, VigiBase. Drugs searched: Melilot, Melilotus spp. Status 01.2017
Data from EU and
Other resources: Bibliography collected in 20085
2. Data on medicinal use
2.1. Information about products on the market
2.1.1. Information about products on the market in the EU/EEA Member States
Information on medicinal products marketed in the EU/EEA
Table 2: Overview of data obtained from marketed medicinal products
5 Bibliographic sources from 2008 not included in this revised assessment report, can be found in Addendum I to the List of references.
This overview is not exhaustive. It is provided for information only and reflects the situation at the time when it was established.
The following preparations listed in the HMPC monograph published in 2008 were found not to be on the EU market: dry extract
Information on relevant combination medicinal products marketed in the EU/EEA
In Belgium there are two combination herbal medicinal products containing Melilotus officinalis herb:
Cnicus benedictus, herb, 0.03 mg/g
Frangula, cortex, extract 0.05 mg/g
Foeniculus, fruit, essential oil 0.03 mg/g
Mallow, flower 0.01 mg/g
Melilotus officinalis, (flowering stems) 0.08 mg/g
Pimpinella anisum, fruit 0.03 mg/g
Peppermint, leaf 0.27 mg/g
Senna, leaf, 0.35 mg/g
Rosmarinus, leaf, Tincture 0.04 mg/g
Tilia sylvestris/cordata, flower, Dry Extract 0.04 mg/g
Althaeae Flos/Radix 0.06 mg/g
Calendula officinalis, flower 0.01 mg/g
Indication: for gastric juice and bile secretion stimulation
On the market since 1962 to 2013;
2. Eyes drops, solution
Centaurea cyanus, flower, 0.05 ml/ml
Melilotus officinalis, (flowering stems), 0.05 ml/ml Rosa, flowers, fluid extract 0.1 ml/ml
Procaine 1.0 mg/ml Oxychinoli Sulfas 0.02 mg/ml Boric acid 4.2 mg/ml Amylocaine 0.5 mg/ml
Zinc sulfate (Heptahydrate) 2.0 mg/ml Indication, Posology: No data
On the market since 1961 to 1997.
In France there are two combination products containing Melilotus officinalis extracts:
1.Cream, containing Ruscus aculeatus dry extract, extraction solvent: water, DER unknown and Melilotus officinalis liquid extract, extraction solvent: ethanol 30% (V/V). Content of extracts in the cream 2 g/100 g. The product has been on the market since 1974.
2.Hard capsules, containing: Crataegus (Crataegi folium cum flore, powder) 120 g, Eschscholzia californica (herba, powder) 120 mg, Melilotus officinalis (herba, powder) 120 mg; traditionally used in the “symptomatic treatment of neurotonic conditions of adults and adolescents, notably in cases of mild disorders of sleep”. The product has been on the market since 1992.
In Germany, there is one combination product containing extract of Melilotus officinalis, herba: Capsules, soft, containing:
20 mg dry extract from Hippocastani semen
30 mg dry extract from Meliloti herba
Posology: 1 capsule, soft 2‒3 times daily
On the market since 1976, Traditional Use Registration 30.07.2013.
There is one combination product on the market:
1 tablet contains:
150 mg Crataegi folium cum flore, powdered, 150 mg
Crataegi fructus, powdered, 30 mg
Leonuri cardiacae herba, powdered 100 mg
Meliloti herba, powdered, 40 mg
Indication: as additional treatment of functional disorders of heart function and blood system
The product has been on the market since 1999.
One combination product is on the market (the same as in Latvia). One tablet contains 0.02‒0.5 mg of coumarin. The product has been on the market since 20.03.1992.
Two combination herbal teas were used in Belgium, where Meliloti herba was a minor component. One of them has been used in gastrointestinal complaints (in combination with Sennae folium, Frangulae cortex, Anisi fructus, Foeniculi fructus, Cnici benedicti herba and others) but it seems not to be a key component. The second combination product in form of eye drops, where Meliloti herba was one minor additive to combination of boric acid, zinc sulphate, procaine and amylocaine (4.2 mg/ml + 2 mg/ml + 1 mg/ml 0.5 mg/ml) was used in eye irritation or discomfort due to various causes (smoky atmospheres, sustained visual effort, swimming in the sea or swimming pools). A herbal cream, containing extracts of Ruscus aculeatus rhizome and the Melilotus officinalis herb extracts has been on the French market since 1974. It is used for mild venous insufficiency. The concentration of extracts is not known.
One combination product, containing 120 mg of Crataegi folium cum flore (powdered), Eschscholziae californicae herba (powdered 120 mg) and Meliloti herba (powdered 120 mg), has been on the market in France since 1992. It was traditionally used in symptomatic treatment of “neurotonic conditions” and sleep disorders. Another combination product, containing: Crataegi folium cum flore (powdered, 150 mg); Cratagi fructus (powdered, 30 mg); Leonuri cardiacae herba (powdered, 100 mg) and Meliloti herba (powdered, 40 mg), has been on the market in Poland and Latvia since 1992. It is used in the indication: supporting the heart and circulatory system. The quality of melilot herb in the product indicates that it is not a key component.
Information on other products marketed in the EU/EEA (where relevant)
There are combination products, manufactured and sold by pharmacies, that contain liquid extracts of Melilotus officinalis but there are no details available about the extracts. The products are used for the treatment of venous insufficiency.
2.1.2. Information on products on the market outside the EU/EEA
A herbal preparation made of Melilotus officinalis flowering herb, was developed in Iran for use as a supplement to treat diabetic food ulcers (Abdollahi et al. 2008, Farzamfar et al. 2008, Heshmat et al. 2008, Bahrami et al. 2008, Larijani et al. 2008).
2.2. Information on documented medicinal use and historical data from literature
According to Madaus, Hippokrates had used melilot flowers externally for septic ulcers and Bock (1551) summarized the use of melilot extracts as constricting, softening and analgetic agent externally for ulcers of the eyes, earache, “hardening and swelling of uterus” (Madaus, 1938). Traditional formulas under the name of Emplastrum Meliloti, were used in many European countries in the 18th century. They were for example listed in Dispensatorium fuldense tripartitum (von Schlereth FA, 1787); Pharmacopoea Rossica (1799) or Pharmacopoea Gandavensis (1786) (Emplastrum e Meliloto five Emolliens). The Emplastrum was contained in many dispensatorias and manuals until the 20th century (Madaus, 1938). There were two kinds of of melilot plasters, the monocomponent, containing as only active component a preparation of the flowering herb of melilot (Pharmacopoea Gandavensis, 1786; Pharmacopoea Hispana, Editio tertia, 1803; Pharmacopoea Rossica, 1799); and combination products described mostly in manuals, containing, apart from Herba Meliloti, also additional components like Flores Chamomillae, Baccae Lauri and others. Emplastrum Meliloti and Emplastrum Meliloti comp. were mentioned first in “Neues Pharmazeutisches Manual” dated 1904 (Dieterich, 1924). Herba Meliloti and Emplastrum Meliloti were also included in the “Deutsche Arzneitaxe” from 1936 and Herba Meliloti in the (DAB 6, 1926, 1957). The example of the Emplastrum Meliloti, combination type, was mentioned in Madaus manual, 1938. This combination melilot plaster was used in arthritis and rheumatoidal swelling (Madaus, 1976). Emplastrum Meliloti has been used externally in skin ulcers, varices, skin inflammations, superficial burns, as
Roeske (1955) mentions use of 10% infusions of Meliloti herba, taken
Hagers Handbuch der Pharmazeutischen Praxis (1938, 1949, 1976), lists the medical and folk uses of melilot herb including varices, hemorrhoids, ulcer cruris, edemas, brachalgias, thrombophlebitis, in thrombosis prophylaxis, as a diureticum and as deodorant. Also, the traditional use of herbal pillows in swelling, ulcers and rheumatism is mentioned as well use as antispasmodic and carminative remedies. There are no data on preparations used in the mentioned indications and on their posologies.
Madaus (1938, 1976) lists the topical use of melilot herb for ulcers and even tumors as an agent “softening” tissues around, promoting purulence and in arthritis, rheumatoidal swelling (in a form of preparations like Emplastrum Meliloti). Topically melilot herb was used in inflamed breasts of breastfeeding women; in the case of earaches such as otitis and otorrhoea (in combination with Flos Malvae arboreae, Folium Altheae, Flos Chamomillae and Semen Lini for preparation of “earmuffs” form for ear evaporation). In combination products it’s being used in oesophageal ulcers (Species Emollientes contained: Folium Althaeae, Folium Malvae, Herba Meliloti, Flos Chamomillae, Semen Lini). The author also mentioned the use of the herb in insomnia and in a form of herbal pillows in swellings. The monograph of German Kommission E: Steinkleekraut (published March 13 1986; revised March 13 1990) contained following indications for internal use:
1.Problems arising from chronic venous insufficiency, such as heaviness in legs, night cramps in the legs, itching and swelling,
2.For the supportive treatment of thrombophlebitis,
3.For external use: Contusions, sprains, and superficial effusion of blood (Monographie: Meliloti herba (Steinkleekraut), 1986, 1990).
In the ESCOP monograph are assigned for Meliloti herba following indications: Symptomatic treatment of problems related to varicose veins, such as painful and heavy legs, nocturnal cramps in the legs, itching and swelling (ESCOP, 2003).
The British Herbal Compendium lists following indications for internal use: for the treatment of complaints arising from chronic venous insufficiency in the legs, such as varicose veins and associated pains, swelling, nocturnal cramp, itching and feeling of heaviness. Also oral uses mentioned are: treatment of lyphoedema arising from various causes of cutaneous capillary fragility, such as ecchymoses or petechiae; haemorrhoids; phlebitis; indigestion and flatulence; minor sleep disorders; rheumatic pains; and burns, based on experience and tradition as well as external use in bruises and superficial bleeding, were regarded by the author to be based only on experience and tradition (Bradley, 2006).
Melilot monopreparations for oral use are licensed in Poland and Spain. One cutaneous patch preparation for topical use, Emplastrum Meliloti, is present on the Polish market (see in 2.1.1).
The 2008 HMPC monograph included a number of melilot extracts: dry extract DER
6 Bibliography for the combination products containing isolated herbal substances not included in this revised assessment report can be found in Addendum I to the List of references.
Table 3: Overview of historical data
Based on the available literature, herbal monographs and the use in EU Member States, the following indications are proposed for the HMPC monograph for traditional use:
Traditional herbal medicinal product to relieve symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances.
•Traditional herbal medicinal product to relieve symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances.
•Traditional herbal medicinal product used for the treatment of minor inflammations of the skin
The traditional use in ulcers was not endorsed by the HMPC, because this may require medical supervision.
The tradition to use infusions in complaints of chronic venous insufficiences is documented (Wichtl, 1984)
The traditional use in hemorrhoids is mentioned by Hagers (1976), however, the information on preparations is incomplete. Wichtl (1984) mentions the use of cataplasms prepared of comminuted melilot herb for ulcers and hemorrhoids, but the details of the preparations are lacking. In the Commission E monograph for Melilotus officinalis two preparations are mentioned: infusion for oral use or other preparations in quantities corresponding to
Single bibliographical sources mention the use of melilot tee, infusion, in insomnia, neuralgia, migraine, digestive disorders, cough and cold but the use of these preparations could not be confirmed with other bibliography.
2.3. Overall conclusions on medicinal use
The traditional use of melilot preparations is plausible by the consistent and
There are no authorised medicinal products on the market for longer than 10 years in the EU for melilot mono preparations that are suitable for
Table 4: Overview of evidence on period of medicinal use
The tradition to use infusions in complaints of chronic venous insufficiences is documented (Wichtl, 1984). However the daily dose given by the author (up to 6 teaspoons) exceeds the level of coumarin once recommended by the Commission E (30 mg a day) and also the tolerable daily intake for coumarin from food as established by EFSA (see section 5.1). For safety reasons the oral dose of melilot herb may therefore be reduced to 2.0‒2.4 g (corresponding to two level teaspoons a day and 10 mg of coumarin a day).
The proposed indications for melilot preparations are:
For oral use: in symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances.
The justification of the traditional use of herbal teas in this indication is based on bibliography and former national regulations. It was accepted in 2008 by HMPC as indication for Melilotus officinalis based of its use in EU countries.
For topical use:
•in symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances
•for the treatment of minor inflammations of the skin
Although the duration of topical use of melilot oil extract had never been limited traditionally, in the opinion of the HMPC it is reasonable to limit the use of the product to one week. If a product does not prove to be effective enough, it is advised to consult a doctor.
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
3.1.1. Primary pharmacodynamics
Constituents responsible for therapeutic activity of the melilot preparations are not known. Historically, antioedematous activity of melilot preparation was attributed to its coumarin content (Pabst & Klemm, 1960).
Melilot extract (details of the extract unknown) was administered to rats at a dose of 2.5 g/kg, intraperitoneally or subcutaneously, 4 hours before the thermal injury. The effect of intraperitoneal injection of melilot extract on the rate of swelling was compared to that of saline. Both methods of administration of melilot extract gave significant differences with saline control, diminishing swelling rate, i.p. gave more intensive effect on swelling. In another experiment the extract was administered immediately after applying the burns and after 2 hours and 4 hours, by single and multiple injections. Both single and multiple injections of melilot extract (2.5 g/kg), immediately, 2 hours after, 4 hours after thermal injury gave statistical reduction of swelling rate (Nishikawa et al., 1983). The histological observation of massive infiltration of neutrophils and macrophages 6 to 24 hours after the subcutaneous injection of Melilotus officinalis extract suggested its reducing effect on thermal injuries and rat model experiment indicate that lymphatic circulation is not involved in this effect. The observed effect was similar to the effects of coumarin in experimental oedemas (see below).
Coumarin possesses weak
The antiedematous activity of coumarin was studied by Piller &
Scopoletin contained in melilot may also contribute to the
3.1.2. Secondary pharmacodynamics
Some coumarin derivatives present in melilot extract were recorded to possess antiprotozoal activities. Melilotoside
In contrast to the coumarin and its simple derivatives, naturally occurring in Meliloti herba, which are devoid of effect on coagulation,
3.1.3. Safety pharmacology
The data are not available.
3.1.4. Pharmacodynamic interactions
There are no data.
There are only limited data on pharmacodynamic properties of melilot
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
There are no data on pharmacokinetic properties of melilot preparations. There is one study on human skin absorption of coumarin from cutaneous patches containing melilot extract, applied on skin of volunteers and human skin permeation (ex vivo), see part. 4.1.2.
A combination product containing coumarin and rutin has been used in pharmacokinetic studies in humans, but only the kinetic behaviour of coumarin has been studied (the product is not regarded as herbal medicinal product).
Coumarin in animals undergoes a very extensive metabolism along two major pathways, 7- hydroxylation and
Distribution of coumarin in rats, after single intraperitoneal injections, was studied by Piller (1977). Coumarin binds readily with serum albumins and after injection the level of free compound is greatly reduced what delays its excretion and metabolism. About 40% of coumarin is eliminated in the feaces and the remainder excreted in the urine. The major hydroxy derivative in rats was found 3- hydroxycoumarin, followed by
In primates, coumarin and its principal metabolite
Percutaneous absorption and distribution of
The relative contribution of the two major metabolic pathways, which are catalysed by different P450 enzymes, is highly variable between species. The
The frequency of CYP2A6 poor metabolizer phenotype due to a loss of functional enzyme in the Caucasian population is below 1%. The frequency is much more common in Orientals, up to 25% of the Japanese, Korean or Chinese population (Nakajima et al., 2006). More than 20 variant alleles of
the CYP2A6 gene have been characterized, including SNPs and whole gene deletion, with variable effects on enzyme activity (http://www.cypalleles.ki.se). Pharmacokinetics of coumarin is altered in individuals carrying the variant CYP2A6 alleles (Nakajima et al., 2006). In vitro studies with human liver microsomes have indicated that the coumarin
There are no available data on scopoletin or umbelliferone pharmacokinetic properties.
Assessor’s overall conclusions on pharmacokinetics
There are no data on absorption and distribution of other compounds, contained in melilot extract after oral use and through animal skin. There is only data on distribution of radiolabelled coumarin, after intraperitoneal administration to rats.
Comparatory data on absorption and metabolism of labelled coumarin, administered on human skin showed quick absorption and metabolism mainly through a pathway of
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
3.3.1. Single dose toxicity
Toxicity of a liquid ethanolic extract of Melilotus officinalis (DER and extraction solvent concentration not specified), diluted with saline (1:5), was tested on BALB/c mice after IM and IP administration and in Wistar rats after ip administration. LD50 was found to be in range 44‒52 ml/kg. There was no significant difference between IM and IP toxicity. LD50 in rats was 42‒44 ml/kg. The administration in doses close to LD50 was accompanied with depression, narcosis and sleep in animals. The pictures of intoxication of mice and rats were similar to the intoxication by ethanol. Therefore, the authors concluded the toxicity and observed effects were due to the extraction solvent (Abdollahi et al., 2008).
There are no available data on toxicity on melilot extract containing no alcohol.
Endell & Seidel (1978) tested single dose toxicity of coumarin in male DBA/2J mice and male CH3/HeJ mice. They have estimated oral toxicities in CH3/HeJ 420
LD50 values (mg/kg body weight) reported for coumarin are: mice (196 mg/kg (oral); 20 mg/kg (IP); 242 mg/kg (subcutaneous); for rats 293 mg/kg (oral) and guinea pigs 202 mg/kg (oral) (Lewis, 1992). Several extensive assessments concerning coumarin toxicity have been published during the past years (Lake, 1999; IARC, 2000; NTP, 2004).
3.3.2. Repeat dose toxicity
A liquid ethanol extract of Melilotus officinalis in dilution (prepared in proportion 1:5, DER and ethanol concentration not specified) was tested on rats in two doses: 0.07 and 0.21 ml/kg during a period of 3 months. The administration had no effect on body weight, general state of animals and their behavior. The authors did not detect any significant changes in hematological and biochemical parameters: total serum proteins, bilirubin, glucose content, triglycerides, cholesterol, blood urea, creatinine in tested and control groups receiving dissolute extract in both doses. Mean body weights of rats in both groups were not significantly different from control animals (Abdollahi et al., 2008).
A liquid ethanol extract of Melilotus officinalis in dilution (1:10, DER and ethanol concentration unknown) was tested in one month study on 8 male and 8 female dogs, divided into two 4 animals groups. The diluted extract was administered in dose 0.07 ml/kg once a day, while the control group received 0.9% sodium chloride. During the test following parameters were monitored: general state of the animals including body weight changes, appetite, motor activity and behavior, hair condition, ECG parameters, rectal temperature of animals and data of hematological and biochemical tests were monitored for signs of toxicity and
Repeat dose toxicity data for extract not containing ethanol are lacking.
were also significantly greater than those in the controls. There was a
In summary, there are no data on toxicity melilot extracts not containing ethanol. Data obtained indicate that coumarin causes: nephropathy in the kidney and of bile duct, hyperplasia in the liver, increased incidences of ulcers of the forestomach, and necrosis, fibrosis, and cytologic alteration of the liver. Administration of coumarin to mice is also associated with centrilobular hypertrophy, syncytial alteration, and eosinophilic focus in the liver. Coumarin is contained in melilot herb in only 0.3‒0.8 per cent and the properties of other substances contained in the herbal substance may influence the toxicity.
Ethanolic melilot extract (DER unknown) was tested in three genotoxicity tests. In an Ames test conducted on 3 Salmonella typhimurium strains: TA98, TA100, TA1537, with or without metabolic activation, no increase of revertants over a normal range (1.0‒1.6) was observed. In the chromosomal aberration test conducted on mice given 10 x diluted extract was administered (0.7 ml/kg) for 4 consecutive days, no induction of aberrations in bone marrow cells was observed. Also a dominant lethal mutation test was conducted on mice. The extract (1:10 diluted) was injected in the male mice which were then paired with virgin females. Administration of the extract did not increase the number of lethal mutations in implants and embryos (Khorram Khorshid, 2008).
Genotoxicity of coumarin has been studied in a number of relevant tests (NTP, 1993; IARC, 2000). Coumarin did not induce micronuclei in mice in vivo and was not mutagenic in Drosophila melanogaster. It was weakly positive in induction of micronuclei in human cells in vitro, but failed to induce unscheduled DNA synthesis in human liver cells in vitro. Coumarin induced sister chromatid exchanges without metabolic activation and chromosomal aberrations with metabolic activation, but not micronuclei or gene mutations in mammalian cells in vitro. It was mutagenic in only two of 11 Salmonella typhimurium strains tested, with metabolic activation. Coumarin was antimutagenic in various assays, but also had
Data on human carcinogenicity of melilot preparations are not available.
The IARC Working group concluded,concluded that no epidemiological data relevant to the carcinogenicity of coumarin were available, whereas there is limited evidence in experimental animals for the carcinogenicity of coumarin (IARC monograph, 2000). The overall evaluation was that coumarin is not classifiable as to its carcinogenicity to humans (Group 3). The U.S. Environemental Protection Agency came to the same conclusion.
Carcinogenicity of coumarin was found to be
3.3.5. Reproductive and developmental toxicity
There are no data on melilot preparations.
The teratogenic effects of a combination of coumarin and rutin have been investigated in white New Zealand rabbits. Iv administration of either coumarin alone or a coumarin/rutin combination at 10 and 100 times the therapeutic dose has shown no increase in malformation rates compared to controls, nor increased number of resorptions or fetal mortality (Grote & Weinmann, 1973).
The developmental toxicities of coumarin,
The experiments with influence of coumarin on frog zebrafish embryos development (Weigt, 2012) indicate its possible embryotoxic potential. This effect was observed with doses higher than the blood concentrations that are obtained at therapeutic doses of melilot extracts.
3.3.6. Local tolerance
No studies on melilot extracts were available.
3.3.7. Other special studies
Species differences in toxicity
The target organs for coumarin toxicity are primarily the liver in rats and the liver and lung in mice. There are marked species differences in these responses, with the mouse being particularly susceptible to
No studies on melilot extracts were available.
Only limited toxicity data are available for melilot preparations. These data do not indicate any serious toxicity in normal therapeutic conditions. However, tests on reproductive toxicity have not been performed for melilot extracts.
The genotoxicity and carcinogenicity of defined herbal preparations have not been performed. Coumarin toxicity has been extensively studied; its primary target organ in rats and mice is the liver. However, toxicity was also observed in kidneys and lungs. Approximate no effect levels in rats and mice are in a range of 10‒50 mg/kg regarding tissue toxicity. Thus, toxic effects occur at high doses of coumarin, which are not attained in normal use of melilot preparations. It seems probable that the mechanism of
3.4. Overall conclusions on
Results from relevant experimental studies on the
Laboratory animal tissues showed after exposure to melilot extracts morphological effects such as decreased edema volume after burns.
Data on pharmacokinetics are only available from experiments with intraperitoneal radiolabelled coumarin administration and skin melilot extract or radiolabelled coumarin administration.
Data on interactions are not available.
There is no information on reproductive and developmental toxicity for melilot preparations used in humans. However, coumarin possesses some embryotoxic potential which is observed in fish and frog embryos at higher concentrations than blood levels obtained after therapeutic use of herbal medicinal products containing melilot preparations. For this reason (and in the absence of sufficient data from women), the use of these preparations during pregnancy and lactation cannot be recommended.
Genotoxicity and carcinogenicity studies have not been performed with melilot preparations.
Overall conclusions on safe use
Humans are one of the species with predominating
Assuming a hepatotoxic risk of coumarin doses above 90 mg/day and taking into account potential toxic doses above a cut point of 25 mg coumarin/day., the TDI level of 0.1 mg coumarin/body
weight/day given by EFSA, 2004, 2008 may also be used for herbal medicinal products (see also section 5.1).
4. Clinical Data
4.1. Clinical pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
There are no special data on pharmacodynamics, regarding melilot herbal preparations.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
There are no pharmacokinetic data on melilot preparations after oral use.
In volunteers receiving an oral 60 ml dose of syrup (containing 17.6 mg of coumarin, 1.1 mg of o- cumaric acid and 8.9 mg kanurenoic acid) no peak absorption in serum was observed until 600 min after syrup administration. The limit of coumarin detections in plasma was 3 ng/ml (Gasparetto et al., 2015). To obtain pharmacokinetic data the authors had to use a syrup with a higher amount of coumarin added. After 100 mg of coumarin had been added a peak of 8 ng/ml with appeared max 180 min after administration.
Pharmacokinetic data on coumarin skin permeation from cutaneous patches containing melilot extract are available (Minghetti et al. 2000). The authors studied, in two experiments, the permeation of coumarin from melilot extract patches through the skin. Samples of 2.54 cm2 patches were first analysed on coumarin content and then dissolution tests were performed. The authors prepared 4 patches: containing melilot extract in two concentrations 0.95 g (1A) and 1.28 g (2A) in 100 g or coumarin 0.16 g (1B) and 0.22 g (2B) in 100 g. The content of coumarin was the same in patches with extract and with coumarin. The original melilot dry extract used for preparation of patches contained 17% to 20% of coumarin (w/w). The skin permeation was studied in two ways. Ex vivo permeation through human skin (stratum corneum and epidermis, from 3 different donors) was quicker from the patch containing lower concentration of melilot extract; after 5 hours about 25% of content of patch 1A and about 13% from 2A was absorbed; after 10 hours about 45% from patch 1A and 25% from 2A and after 24 hours over 80% of content of patch 1A and more than 50% from 2A. For patch 1A, containing 20.9 ± 0.9 µg/cm2 of coumarin, the release rate was
4.2. Clinical efficacy
4.2.1. Dose response studies
There are no
4.2.2. Clinical studies (case studies and clinical trials)
Venous circulatory disturbances with feelings of heavy legs itching and swelling
Melilot mono preparations
In an open study 20 patients suffering from chronic venous insufficiency were treated with 200 mg dry extract of melilot daily (no specification given), another 15 by ozontherapy and 20 with combined therapy for 15 days. Melilot therapy significantly reduced ankle oedema, nocturnal cramps and feelings of heaviness and was superior to ozontherapy. An influence on the symptoms “pain”, “paraesthesia” and “hyperthermia” was not seen. Details regarding the extent of the observed effects are not given. Ozontherapy is not an accepted “gold standard”. The clinical relevance of the observed effects is doubtful (Stefanini et al 1996).
Aloisi & Scondotto (1999) studied 4536 patients suffering from chronic venous insufficiency of various causes, treated with a daily dose of 4 to 8 mg of a melilot extract standardized to 20% coumarin for 3 to 8 months in the years 1995 to 1998. Symptoms, e.g. feeling of heavy legs, pain, nocturnal cramps, oedema and pruritus, as well as assessment of oedema were assessed on a 3 level symptom score.
Details regarding the extent of the observed effects are not given. According to the authors, good results were seen in 70% of the patients. The symptom score is not validated. An objective measurement of efficacy is missing. Side effects, predominantly gastrointestinal complaints, were seen in 55 patients (1.2%). Allergic reactions occurred in 12 patients (0.25%).
In an open clinical trial 20 patients with lymphoedema of the lower limbs, stage
Due to the lack of an acceptable control group and of objective measurement of efficacy, the available data are not sufficient to propose an indication for well established medicinal use. However, the data supports a traditional use melilot preparation for venous disturbances like symptoms of heavy legs, oedemas, and nocturnal cramps.
The efficacy of a product in form of sugar coated tablets, containing 25 mg of melilot extract (no specification given, coumarin content 0.25 mg), was assessed in a group of 80 patients with post- traumatic swellings. The authors observed that the addition of the melilot extract tablets to the conventional treatment, for 7 days after traumas, remarkably diminished symptoms of inflammation, pain and swellings in comparison to the group treated conventionally (Yang et al., 2010, abstr.).
No clinical data are available from Europe.
The available clinical data for melilot preparation in treatment of sprains and bruises are only preliminary observation.
Therefore the data are not sufficient to propose a
A 3 center, controlled, randomized trial was conducted on 25 patients suffering from diabetic foot ulcers. Sixteen patients received intravenous infusions of a product, containing an extract of Melilotus officinalis (specification not available), additionally to the conventional treatment used in the ulceration. Nine patients (control group) received conventional therapy. The inclusion criteria were: diabetes mellitus (type 1 or 2) on medication; age 18‒75 years; foot ulcers, open, without improvement for more than 2 weeks. Excluded were patients with severe heart failure, symptoms of chronic and severe ischemia, other situations that impair ulcer improvement. The patients were randomized in every study center. Patients received intravenously 4 cm3 of the product for 28 days, diluted in 50‒100 cm3 of saline. In both groups conventional treatments were used: betaine baths, antibiotic therapy, pressure decompression. The primary recorded parameters were: ulcer diameters in planimetric evaluation and steadiness of regression. After 28 days of treatment a 64% regression of the ulcer surfaces in treated group, compared to 25% in conventional therapy group, which received saline infusions instead of the melilot extract (Larijani et al., 2008).
The study was conducted on a small patients group and verum and placebo groups were not balanced. The authors admitted that further studies on larger population are required. Neither there are details on the strength of the product nor its standardisation.
In an open clinical trial 50 patients with cyclic or
4.3. Clinical studies in special populations (e.g. elderly and children)
No data available.
4.4. Overall conclusions on clinical pharmacology and efficacy
Clinical pharmacology trials with Melilotus officinalis herba preparations were not performed.
The results of open clinical trials on use of melilot extract preparations in patients with symptoms of venous insufficiency, like feeling of heavy legs, lymphoedema of lower limbs, due to the lack of control groups and of objective efficacy measures are not sufficient to demonstrate efficacy at a level required for well established medicinal use. However, the results support the traditional use for the relieve symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances.
The use of melilot extracts in diabetic food ulcers was a subject of clinical trials in Asia. The indication and the method of administration used in the this study are not suitable for traditional use because they require medical supervision.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
There are no available clinical safety data on humans for melilot preparations.
Coumarin contained in herbal medicinal products is metabolized in humans predominantly via 7- hydroxylation by CYP2A6 and they seem to be generally less susceptible to hepatotoxicity than other species. Due to genetic polymorphisms, a high interindividual variability exists. Case reports of hepatotoxicity in humans are predominantly reported in daily doses above 90 mg coumarin, but a few case reports after a daily intake of 25 to 90 mg coumarin are also documented. Some authors pointed that data from patients treated with medicinal products revealed a few percent subgroup of human population being more sensible for the coumarin hepatotoxic effect (Abraham et al., 2010). It is not known if these are cases of “poor metabolizers” with limited
In 2004, EFSA established a tolerable daily intake (TDI) for coumarin for 0.1 mg/kg body weight, based on available hepatotoxicity data. The proposed TDI was maintained in 2008 after reassessment of data and taking into account metabolism of coumarin human CYP2A6 population (EFSA 2008).
5.2. Patient exposure
Aside from market presence and data from studies, there are no data concerning patient exposure.
5.3. Adverse events, serious adverse events and deaths
In general melilot preparations were well tolerated in clinical trials. In some studies adverse events as gastrointestinal complaints, allergic reactions and photosensitivity are mentioned. So far, adverse events in Member States that have preparations on the market have not been recorded.
Data from WHO database VigiLyze Monitoring Center
The VigiLyze database contains data of 32 reports on adverse reactions observed in years
Eleven reactions were observed after oral use of Melilotus officinalis (melilot) extracts and only 1 reaction was recorded after topical use. 3 of the Korean cases were adverse reactions for oral or topical use forms, relevant to Europe. The reactions relevant to oral or topical preparations used in Europe were as follows: vomiting, nausea, contact eczema rhinitis, conjunctivitis, pruritus, rash, urticaria and ecchymosis.
For a cutaneous patch (Emplastrum Meliloti) of the European market, that contains oil extract of Meliloti herba and a colophony as additive, no adverse reactions have been reported. However, the colophony (rosin) is known to cause allergic skin reactions after occupational exposure.
Serious events and deaths
None are known for Meliloti herba and preparations thereof for used by oral or topical administration.
5.4. Laboratory findings
There are no data on melilot preparations’ influence on laboratory findings in humans. Sometimes transaminases elevation is attributed to interaction with coumarin contained in different products.
5.5. Safety in special populations and situations
So far, there were no reports on human embryotoxicity or teratogenicity caused by herbal medicinal products containing melilot preparations. For animal embryotoxicity and teratogenicity data on coumarin, see in 4.2.
5.5.1. Use in children and adolescents
None known. Preparations used orally are not suitable for children.
Hypersensitivity to melilot or to coumarin.
5.5.3. Special warnings and precautions for use
The use in children and adolescents under 18 years of age has not been established due to lack of adequate data.
Use to relieve symptoms of discomfort and heaviness of legs:
If the symptoms of thrombophlebitis or subcutaneous induration, sudden swelling of one or both legs, cardiac or renal insufficiency appear during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.
Use for minor skin inflammation:
If symptoms of skin inflammation worsen or signs of skin infections occur during the use of the medicinal product for the treatment of minor skin inflammations, a doctor or a qualified health care practitioner should be consulted.
5.5.4. Drug interactions and other forms of interaction
There are no data on interactions of monocomponent medicinal products containing melilot preparation with other products.
There are only data on products containing melilot preparations in combination with other herbal preparations or substances of herbal origin.
Tamura et al., (2012) reported a case of transaminases elevation in a 23
levels rised markedly (235 and 681 IU/l accordingly). After the discontinuation of
In two clinical studies intravenously administrated combination of melilot extract and rutoside did not affect parameters of blood clotting (prothrombin time respectively “coagulation analysis”, details not given) (Völkner, 1961; Mayer & Sukthaworn, 1963).
There is one case report of a young woman in whom hemorrhagic diathesis (abnormal clotting function and mild menometrorrhagia) occurred as a result of drinking large amounts of a “seasonal tonic” herbal tea, for approximately 2 months. The major ingredients of the patients tea were tonka beans (1/2 lb), melilot (2 oz), and sweet woodruff (3 oz). Natural coumarins are found in all three of them with the highest content in tonka beans (1 to 3% coumarin). Additionally the patient was taking medications, which might potentiate the effect of oral anticoagulant drugs, e.g. propoxyphene, vitamin A in “fairly large daily doses” and bromelain (Hogan, 1983).
There is also a report of a possible interaction between oral anticoagulant treatment and topical treatment with a cream containing extracts of Ruscus and melilot. A 66
5.5.5. Fertility, pregnancy and lactation
There are no human fertility data for melilot preparations.
Embryotoxic potential of
No influence on bleeding time, thrombelastogram and prothrombin time was seen in 2 clinical trials with combination of 60 mg coumarin daily with troxerutin, given to pregnant and breastfeeding women (Krajnovic et al., 1974, 1977a, 1977b).
Because safety during pregnancy and lactation has not been established systematically and in the absence of sufficient data, the use during pregnancy and lactation is not recommended.
Hager’s Handbuch cites information that intake of 4 g of melilot extract triggered nausea, vomiting, headache and weakness. However the information could not be confirmed.
5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability
5.5.8. Safety in other special situations
5.6. Overall conclusions on clinical safety
There are no clinical safety data with herbal medicinal products, containing melilot preparations as single active ingredient.
6. Overall conclusions
Clinical trials on use of melilot extract in patients with symptoms of venous insufficiency are not sufficient to show efficacy at a level required for well established medicinal use, because of lack of an acceptable control group and of objective efficacy measures. However, these studies support the traditional use of melilot preparations for the relieve of symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances.
Emplastrum Meliloti, containing melilot herb oil extract, has a long tradition of use for skin inflammations and mild sores. The use in skin inflammations could be considered plausible because melilot extract exhibited antinflammatory properties in
Due to the lack of sufficient safety data the use of melilot herb cannot be recommended during pregnancy and
As no data from the use in children are available, the use of melilot herb preparations is not recommended in children.
Coumarin was considered to contribute to the activity of the melilot herb preparations as an active marker, although its pharmacological role among other substances possessing pharmacological activities has not been clarified. Therefore, neither constituents with known therapeutic activity nor active markers contributing to the therapeutic activity could be recognized by the HMPC.
A European Union list entry is not supported due to lack of adequate data on genotoxicity.