Discussion in Working Party on European Union monographs and European Union list (MLWP)

May, July, November 2013 January, May, July, November 2014 January, May 2015

Adoption by Committee on Herbal Medicinal Products (HMPC) for release for consultation

7 July 2015

Start of public consultation

22 July 2015

End of consultation (deadline for comments). Comments should be provided using this template to hmpc.secretariat@ema.europa.eu

31 October 2015

Rediscussion in MLWP

Adoption by HMPC

Well-established use

Traditional use

With regard to the marketing authorisation

With regard to the registration application of

application of Article 10(a) of Directive

Article 16d(1) of Directive 2001/83/EC as

2001/83/EC as amended

amended

Silybum marianum (L.) Gaertn., fructus (Milk

Silybum marianum (L.) Gaertn., fructus (Milk

thistle fruit)

thistle fruit)

i) Herbal substance

i) Herbal substance

Not applicable.

Not applicable.

ii) Herbal preparations

ii) Herbal preparations

Dry extract (DER 36-44:1), (extraction solvent:

a) Comminuted herbal substance

ethyl acetate) standardised to contain 40-65% silymarin, calculated as silibinin

b)    Powdered herbal substance

c)    Dry extract (DER 20-70:1), extraction solvent acetone 95% (V/V)

d)    Dry extract (DER 30-40:1), extraction solvent ethanol 96% (V/V)

e)    Dry extract (DER 20-35:1), extraction solvent ethyl acetate

f)    Dry extract (DER 26-45:1), extraction solvent ethyl acetate

g)    Liquid extract (DER 10-17:1), extraction solvent ethanol 60% (V/V)

Well-established use

Traditional use

Herbal preparations in solid dosage forms for oral use.

The pharmaceutical form should be described by

Comminuted herbal substance as herbal tea for oral use.

Herbal preparations in liquid or solid dosage forms

Well-established use

Traditional use

the European Pharmacopoeia full standard term.

for oral use.

The pharmaceutical form should be described by the European Pharmacopoeia full standard term.

Well-established use

Traditional use

Herbal medicinal product for supportive treatment of alcoholic liver disease.

Traditional herbal medicinal product for the symptomatic relief of digestive disorders with a sensation of fullness, bloating and flatulence.

The product is a traditional herbal medicinal product for use in the specified indication exclusively based upon long-standing use.

Well-established use

Traditional use

Posology

Posology

Adults and elderly

Adults and elderly

Single dose: 173 - 186.7 mg extract standardized to a content of 108.2 mg silymarin, calculated as silibinin⁴

Herbal preparation a)

Comminuted herbal substance for tea preparation. Single dose: 3-5 g in 100 ml of boiling water,

Daily dose: 3 times daily

Daily dose: 2 or 3 times daily, before meals

The use in children and adolescents under 18 years of age is not recommended (see section 4.4 'Special warnings and precautions for use')

Herbal preparation b)

Single dose: 300 mg - 600 mg

Daily dose: 2-3 times daily, up to 1800 mg daily,

before meals

Duration of use

Herbal preparation c)

The average duration of use is 2 months.

Single dose: Dry extract corresponding to 120 mg

If the symptoms persist during the use of the medicinal product, a doctor or a pharmacist should be consulted.

silymarin, calculated as silibinin

Daily dose: 3 times daily, up to 360 mg, before

meals

Method of administration

Herbal preparation d)

Single dose: 200 mg dry extract

Oral use.

Daily dose: 200 mg dry extract

Well-established use

Traditional use

Herbal preparation e)

Single dose: 162.5-250 mg dry extract Daily dose: 3-4 times daily

Herbal preparation f)

Single dose: 123-208.3 mg dry extract Daily dose: 3-4 times daily

Herbal preparation g)

Single dose: 15 ml equivalent to 392 mg soft extract

Daily dose: 30 ml (2 times 15ml) equivalent to 784 mg soft extract

The use in children and adolescents under 18 years of age is not recommended (see section 4.4 'Special warnings and precautions for use')

Duration of use

If the symptoms persist longer than 2 weeks during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.

Method of administration

Oral use.

Well-established use

Traditional use

Hypersensitivity to the active substance and to other plants of the Asteraceae (Compositae) family.

Hypersensitivity to the active substance and to other plants of the Asteraceae (Compositae) family.

Well-established use

Traditional use

The use is not recommended in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.

The use in children and adolescents under 18 years of age has not been established due to lack of adequate data.

If the symptoms worsen during the use of the medicinal product, a doctor or a pharmacist should be consulted.

If the symptoms worsen during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.

For extracts containing ethanol, the appropriate labelling for ethanol, taken from the 'Guideline on excipients in the label and package leaflet of

Well-established use

Traditional use

medicinal products for human use', must be included.

Well-established use

Traditional use

None reported.

None reported.

Well-established use

Traditional use

Safety during pregnancy and lactation has not

Safety during pregnancy and lactation has not

been established. In the absence of sufficient

been established. In the absence of sufficient

data, the use during pregnancy and lactation is

data, the use during pregnancy and lactation is

not recommended.

not recommended.

No fertility data available.

No fertility data available.

Well-established use

Traditional use

No studies on the effect on the ability to drive and use machines have been performed.

No studies on the effect on the ability to drive and use machines have been performed.

Well-established use

Traditional use

Mild gastrointestinal symptoms such as dry

Mild gastrointestinal symptoms such as dry

mouth, nausea, upset stomach, gastric irritation

mouth, nausea, upset stomach, gastric irritation

and diarrhoea may occur; headache; allergic

and diarrhoea may occur; headache; allergic

reactions (urticaria, skin rash, pruritus,

reactions (dermatitis, urticaria, skin rash,

anaphylaxis, asthma) may occur. The frequency is

pruritus, anaphylaxis, asthma), have been

not known.

reported. The frequency is not known.

If other adverse reactions not mentioned above

If other adverse reactions not mentioned above

occur, a doctor or a pharmacist should be

occur, a doctor or a qualified health care

consulted.

practitioner should be consulted.

Well-established use

Traditional use

No case of overdose has been reported.

No case of overdose has been reported.

Well-established use

Traditional use

Pharmacotherapeutic group: Liver therapy, lipotropics

Proposed ATC code: A05B

5.2. Pharmacokinetic properties

Not required as per Article 16c(1)(a)(iii) of Directive 2001/83/EC as amended.

Well-established use

Traditional use

After oral administration, absorption is low and maximum plasma concentrations are reached after 4-6 hours.

Silibinin and other individual components from silymarin are rapidly conjugated with sulphate and glucuronic acid in liver, then reaching plasma and bile.

Metabolites are found mainly in the bile. Through this way, 20-40% of the initial dose is eliminated.

Silymarin half-life is between 6 and 8 hours, with a maximum plasmatic concentration between 1.31.9 pg/ml.

5.3. Preclinical safety data

Not required as per Article 16c(1)(a)(iii) of Directive 2001/83/EC as amended.

Well-established use

Traditional use

Silymarin has proved nontoxic in rats and mice after oral doses of 2,500 mg or 5,000 mg/kg. In a 12 month study, rats received silymarin up to

Not required as per Article 16c(1)(a)(iii) of Directive 2001/83/EC as amended, unless necessary for the safe use of the product.

2,500 mg/kg, showed no evidence of toxicity.

No evidence of ante or postnatal toxicity in animals was reported, nor did silymarin affect fertility in rats.

Adequate tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed.

Adequate tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed.

Well-established use

Traditional use

Not applicable.

Not applicable.