Reparil® Tablet
Pharmacological activity
Anti-inflammatory Activity
Glucocorticoids (GCs) inhibit pro-inflammatory signalling pathways in the endothelium and reduce the loss of adhesion molecule that maintain the endothelial function.1
Anti-inflammatory mechanism of action of aescin is correlated with the glucocorticoid receptor pathways.2
Adapted from Zielińska KA, et al. Front Immunol. 2016.
AP-1: Activator protein 1; eNOS: Endothelial nitric oxide synthase-3; GCs: Glucocorticoids; GR: Glucocorticoid receptor; ICAM-1: Intercellular cell adhesion molecule-1; NF-kB: Nuclear factor kappa B; MKP-1: Mitogen-activated protein kinase (MAPK) phosphatase 1; ROS: Reactive oxygen species; TTP: Tristetraprolin; VCAM-1: Vascular cell adhesion molecule-1.
References:
- Zielińska KA, et al. Endothelial Response to Glucocorticoids in Inflammatory Diseases. Front Immunol. 2016;7:592.
- Wang H, et al. Anti-inflammatory effects of escin are correlated with the glucocorticoid receptor/NF-κB signaling pathway, but not the COX/PGF2α signaling pathway. Exp Ther Med. 2013;6(2):419–422.
Anti-edemetous Activity
Anti-inflammatory and anti-oedema effects of aescin may at least partially be mediated by the GR/NF-kB signalling pathway and PGF2α pathway respectively.1
Aescin achieves GC-like anti-inflammatory effects, reducing carrageenan-induced paw oedema.1
Time-effect curves of Aescin and Dexamethasone in carrageenan-induced paw oedema1
GR: Glucocorticoids receptor; NF-kB: Nuclear factor kB.
References:
- Wang H, et al. Anti-inflammatory effects of escin are correlated with the glucocorticoid receptor/NF-κB signaling pathway, but not the COX/PGF2α signaling pathway. Exp Ther Med. 2013;6(2):419–422.
Role of aescin in anti-edemotous activity
Anti-oedematous Activity
Aescin plays a role within the classical inflammatory cascade by inhibiting the effect of bradykinin and other catabolic enzymes.1,2
References:
- Gallelli L. Escin: a review of its anti-edematous, anti-inflammatory, and venotonic properties. Drug Des DevelTher. 2019;13:3425–3437.
- Dudek-Makuch M, et al.Horse chestnut – efficacy and safety in chronic venous insufficiency: an overview. Revista Brasileira de Farmacognosia. 2015;25(5):533–541.
Efficacy
A placebo-controlled, parallel-group, 4-arm study assessed the efficacy of amorphous aescin in 50 patients with post-plaster oedema and 50 patients with post-traumatic oedema.1
Adapted from Gallelli L, et al. Drug Des DevelTher.2019.
A significant improvement in both types of oedema, particularly in the first 3 weeks of treatment with aescin, was observed in both the groups: 92% Patients of post-plastering oedema and 95% Patients of post-traumatic oedema.1
References:
- Gallelli L. Escin: a review of its anti-edematous, anti-inflammatory, and venotonic properties. Drug Des DevelTher. 2019;13:3425–3437.
Safety profile
A meta-analysis of studies using a range of oral escin preparations demonstrated that these products were well tolerated, with no severe adverse events reported1
Safety in Preclinical Studiesx`x`
A preclinical study in rabbits and rats investigated the effects of aescin on healing of tibia fracture and abdominal wound after surgery.2
Adapted from Zhang L, et al. Exp Ther Med. 2012.
Aescin did not affect the process of fracture.*2
Aescin showed no inhibition of the wound healing process.*2
Adapted from Zhang, et al.* Effect of aescin on bone mineral density (BMD) values of the fracture site at 2, 4 and 6 weeks after osteotomy. A DEXA (Dual-energy X-ray absorptiometry) scanner was used to measure the BMD value of a 15-mm long and 30-mm wide “ROI” centrally between the second and third screws, which included the proximal and distal old bone and the callus. No significant difference was found among groups.2
7-day treatment with intravenous injection of dexamethasone induced a significant increase in spleen apoptosis and in thymus apoptosis, whereas with aescin no significant increase in apoptotic cells was observed.3
Safety in Clinical Studies with Horse Chestnut Seed Extracts4
In a criteria-based systematic review reported potential adverse effects of horse chestnut seed extracts are:4
The frequency of these ranges from 0.9% to 3% across experiments, and several studies have found no more adverse effects with horse chestnut seed extracts that with placebo.4
ROI: region of interest
References:
- Gallelli L. Escin: a review of its anti-edematous, anti-inflammatory, and venotonic properties. Drug Des DevelTher. 2019;13:3425–3437.
- Zhang L, et al. Potent anti-inflammatory agent escin does not affect the healing of tibia fracture and abdominal wound in an animal model. Exp Ther Med. 2012;3(4):735–739.
- Zhang L, et al. The potent anti-inflammatory agent escin does not increase corticosterone secretion and immune cell apoptosis in mice. Fitoterapia. 2011;82(6):861–867.
- Robert W. Frick, Three Treatments for Chronic Venous Insufficiency:Escin, Hydroxyethylrutoside, and Daflon. Angiology. 2000;51:197..
Reparil prescribing information
- NAME OF THE MEDICINAL PRODUCT
Reparil ®-Dragees (coated tablets)
20 mg, gastro-resistant coated tablet
For use in adults and children over 7 years of age
Active substance: aescin - QUALITATIVE AND QUANTITATIVE COMPOSITION
Active substance:
Each gastro-resistant coated tablet contains:
Aescin 20 mg
For the full list of excipients, see section 6.1. - PHARMACEUTICAL FORM
Gastro-resistant coated tablet - CLINICAL PARTICULARS
4.1Therapeutic indications
Localized swelling following injury
4.2 Posology and method of administration
Posology
Adults and adolescents aged 14 years and above initially take 2 tablets 3 times daily, as maintenance dose and in milder cases 1 tablet unchewed with some liquid after meals
3 times daily.
Paediatric population
Children aged 7 to 14 years take 1 tablet unchewed with some liquid after meals 2 to 3 times daily.
Reparil coated tablets are not indicated in children under the age of 7 years.
Method of administration
The tablets are taken unchewed with some liquid after meals.
4.3 Contraindications
Reparil coated tablets must not be taken by patients with
- hypersensitivity to the active substance or to any of the excipients listed in section 6.1,
- renal insufficiency or renal diseases,
- pregnancy and breast-feeding.
4.4 Special warnings and precautions for use
Patients with rare hereditary (deficiency) problems of galactose intolerance, lactase deficiency, glucose-galactose malabsorption, fructose intolerance or sucrase isomaltase
deficiency should not use Reparil coated tablets.
Information on some of the excipients
This medicine contains less than 1 mmol sodium (23 mg) per coated tablet, that is to say essentially 'sodium-free'.
Paediatric population
Reparil coated tablets are not indicated in children under the age of 7 years.
4.5 Interaction with other medicinal products and other forms of interaction
Administration of aescin can enhance the effect of anticoagulant medicinal products.
Concurrent use of aminoglycosides (e.g. gentamicin) should be avoided because an increase in the nephrotoxicity of aminoglycosides cannot be completely excluded.
The plasma protein binding of aescin can be inhibited by antibiotics. Cephalotin and ampicillin, for instance, raise the concentration of free aescin in the serum.
Therefore, concurrent administration of these medicinal products with Reparil coated tablets is not recommended.
4.6 Pregnancy and lactation
Reparil coated tablets should not be used during pregnancy because the product has only inadequately been tested in animal studies and no experience with pregnant women
has been documented. Breast-feeding during treatment is not recommended, because it is not known to which extent the active substance passes into breast milk.
4.7 Effects on ability to drive and use machines
Not applicable.
4.8 Undesirable effects
The following convention has been used for the classification of side effects in terms of frequency:
Very common: ≥ 1/10
Common: ≥ 1/100 to < 1/10
Uncommon: ≥ 1/1,000 to < 1/100
Rare: ≥ 1/10,000 to < 1/1,000
Very rare: < 1/10,000
Not known: Frequency cannot be estimated from the available data.
The following side effects are known for Reparil coated tablets:
Immune system disorders :
Very rare: hypersensitivity reactions (e.g. urticaria)
Gastro-intestinal disorders:
Uncommon: gastro-intestinal tract disorders
If hypersensitivity reactions occur, use of Reparil coated tablets should be discontinued.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions via the following:
To report side effect(s):
Saudi Arabia:
The National Pharmacovigilance Centre (NPC):
Fax: +966-11-205-7662
SFDA Call Center: 19999
E-mail:npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa/
Other Countries:
Please contact the relevant competent authority.
4.9 Overdose
No cases of overdose have been reported. - PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Capillary stabilizing agents ATC Code: C05CA07
The site of action of aescin is the vascular wall. In case of abnormally raised permeability, aescin inhibits exsudation by reducing extravasation of fluid into the tissue and
accelerating re-absorption of the existing oedema. The mechanism of action is based on a change in the permeability of the capillary openings involved. Furthermore, aescin
promotes capillary resistance, inhibits inflammatory processes and improves microcirculation.
5.2 Pharmacokinetic properties
After oral administration of tritium-labelled aescin , a mean 12 – 16% of the applied activity was absorbed from the intestinal tract in mice and rats. Excretion occurs via the bile
as well as the urine. The metabolisation rate is higher after oral administration than after intravenous injection. Organ distribution is negligibly low in the excretory organs liver and kidneys in comparison to the higher values in the blood.
5.3 Preclinical safety data
Aescin was only inadequately tested in animal experiments. In these experiments it proved to be moderately to highly toxic. Nephrotoxic changes were particularly significant.
Complete testing for mutagenicity produced no evidence of mutagenic effects. No carcinogenicity studies have been carried out.
Aescin was inadequately tested for reproductive toxicity. After oral administration of aescin in mice and rabbits during organogenesis embryotoxic effects occurred (reduced
foetal weights, delayed skeleton ossification, in higher doses embryo lethality). No effects on the viability of offspring with prenatal exposure were found. - PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate, Povidone (K29-32), Magnesium stearate (Ph. Eur.), Sucrose (sugar), Talc, Gum arabic , Titanium dioxide E 171, Colloidal anhydrous silica, Poly(ethyl
acrylate, methacyrylic acid), Macrogol 8000, Sodium hydroxide, Carmellose sodium, Triethyl citrate, Simeticone emulsion, Bleached wax, Carnauba wax.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4 Special precautions for storage
Store below 30°C, in a dry place.
6.5 Nature and contents of container
PVC and printed aluminium blister packs in strips of 10 coated tablets Packs of 40 coated tablets
6.6 Special precautions for disposal
No special requirements. - MARKETING AUTHORISATION HOLDER
MEDA Pharma GmbH & Co. KG Benzstrasse 1,
61352 Bad Homburg, Germany - MARKETING AUTHORISATION NUMBER
5-130-83 - DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
1983 / 05-Sep-2020 - DATE OF REVISION OF THE TEXT
September 2020 - GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
REP-2022-0026