Trauma, injuries, chronic venous insufficiency
Release of inflammatory markers¹

Inflammation
Is activated and is responsible for the increase of capillary permeability, which results in local soft tissue edema.²

Hypoxic damage
Hypoxia is one of the most common causes of vascular hyperpermeability.³

Soft tissue damage with oedema and swelling

A rational treatment should address both pathways. Reparil^® Gel, with the combination of two active components (Aescin & diethylamine salicylate) meets this need.

Aescin, administered 30 minutes after bradykinin injection, was able to antagonize the effect of bradykinin on capillary permeability, with a decrease of fluid outflow into tissues (prevention/stop of oedema formation)¹

Mechanism of Action of Aescin^1-3

• Reduction of existing swelling³
• Alleviation of pain³

The role of Diethylamine salicylate (DEAS)

• DEAS is a derivative of salicylic acid, a non-steroidal anti-inflammatory drug (NSAID) ¹
• Its anti-inflammatory action and analgesic effect are linked to direct inhibition of prostaglandins synthesis. Prostaglandins are pain mediators: they stimulate free nerve endings in the tissues thus provoking the sensation of pain ²
• DEAS reaches relevant concentrations in the muscles after topical administration: it is therefore able to relieve muscle and joint pains effectively ¹

Synergistic mechanism of action

Diethylamine Salicylate (DEAS) effect: Analgesic/Anti-inflammatory¹

 

DEAS is a NSAID with a very quick skin penetration.²

COX, cyclooxygenase; LOX, Lipoxygenase; NSAIDs, Non-steroidal Anti-inflammatory Drugs; PGs, Prostaglandins; PGI₂, Prostacycline; PGE₂,Prostaglandin E₂; TXA₂, Thromboxane A₂; LTC₄, Leukotriene C₄; LTD₄, Leukotriene D₄; LTB ₄, Leukotriene B ₄.

Is significantly effective in reducing oedema from traumatic lesion¹

Percutaneous gel therapy for blunt sport injuries¹

• A double-blind, randomized, placebo-controlled trial in limb injuries from sporting activities¹
• Evaluation: Symptoms, mobility, patient evaluation, and tolerability for 8 hours¹
• 81 patients were randomly into two groups Reparil^® Gel (1% aescin + 5% DEAS) and placebo¹

94% of patients evaluate the effect of Reparil^® Gel as very good and good with no adverse effects.¹

Reduced the pain scores significantly earlier than placebo²
A randomised, double blind, placebo controlled, multicentre study²

• Aim of the study: To investigate the clinical efficacy and safety of a gel containing aescin and DEAS in the topical treatment of blunt impact injuries²
• Patients were treated three times with Reparil^® Gel/Placebo within a period of eight hours²
• 156 competitors in soccer ball, handball or karate were enrolled within 2 hours of blunt injury²

Reparil^® Gel preparation produced more rapid pain relief than placebo gel. Reparil^® Gel ensures a quick reduction of oedema and pain.²

The time to reach the resolution of pain at the injured site was shorter in the treatment groups than in the placebo group (p<0.0001)²

Tenderness values (kp/cm²) the tenderness value of normal (contralateral, uninjured) site is 4.4 Kp/cm² in placebo group and 4.7 Kp/cm² in Reparil^® Gel group²

Reparil^® Gel preparation produced more rapid pain relief than placebo gel. Reparil^® Gel ensures a quick reduction of oedema and pain.²

Efficacy in reducing haematoma-induced tenderness³

• A study was conducted to compare the efficacy of an escin combination gel (2% aescin and 5% diethylamine salicylate) with that of a gel containing 1.16% diclofenac diethylamine salt.³
• The parameter measured was the pressure on the affected area of the skin until pain was experienced; measurements were carried out at 0.75, 1.5, 3, 4.5, 6, 9 and 12 hours after treatment.³
• A randomized, controlled, double-blind clinical trial was performed in 140 volunteers (70 in each treatment group) with sub-injection hematoma (i.e. injection of their own blood on the palmar side of one forearm).³

Time until tenderness pressure returned to the baseline level or Aescin combination gel (n=58) vs. Diclofenac gel (n=61).³

Faster efficacy of Reparil^® Gel versus the diclofenac gel³

Reparil^® Gel group, clearly shows the relevant role played by aescin in early protection of the capillary network, which effectively synergies with the anti-inflammatory and analgesic effect of DEAS.³

Is safe and well tolerated¹

Mean pressure exerted until pain was experienced¹

Adapted from Bonnekoh A,et al. 1992.

Reparil® Gel (Synergic combination: 2% Aescin plus 5% Diethylamine salicylate) treatment significantly increases pain tolerance as compared to Diclofenac gel (1.16% diclofenac diethylamine salt).¹

• The safety and tolerability of DEAS has been shown in toxicological and clinical experiments. It is a salt of salicylic acid and diethylamine. It has an anti-inflammatory effect, which has been demonstrated in numerous pharmacological models, by preventing the temperature of the skin from rising, and by inhibiting oedema formation and pain. DEAS penetrates into the subcutis and underlying muscles²
• Aescin is absorbed through the skin. The very low concentrations of aescin in blood and internal organs practically exclude any possibility of toxic side-effects after percutaneous application³

Summary of Product Characteristics (SPC)

1. NAME OF THE MEDICINAL PRODUCT

Reparil^®-Gel N
Active substances: 1 % escin and 5 % diethylamine salicylate

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substances: 100 g gel contains:
Escin 1 g
Diethylamine salicylate 5 g

Other ingredients:
For the complete listing of other ingredients see section 6.1.

3. PHARMACEUTICAL FORM

Gel
Reparil^®-Gel N is a transparent, colourless to slightly yellowish gel.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Injuries with contusions, sprains, bruises, haematoma formation, tendinitis (inflammation of tendon sheaths).

Vertebral pain syndromes (intervertebral disk, nuchal pain, lumbago, sciatica).
Superficial phlebitis, varicose veins. For vein care following injections or infusions.

4.2 Posology and method of administration
Reparil^®-Gel N should be applied once to several times daily.

Method of administration:
Reparil^®-Gel N should be applied to the affected area and spread over the skin. It need not be rubbed in, but it may be done if desired.
4.3 Contraindications
Reparil^®-Gel N should not be applied to broken skin (wounds), mucous membranes or skin areas which have been exposed to radiotherapy.
4.4 Special warnings and precautions for use
None known.
4.5 Interaction with other medicinal products and other forms of interaction
None known.

4.6 Pregnancy and lactation
Prolonged treatment covering large areas should be avoided during pregnancy, and the gel should not be applied to the breast area during lactation.

4.7 Effects on ability to drive and use machines
Not applicable.

4.8 Undesirable effects

Side effects’ rating was based on the following frequency data:
Very common ≥ 1/10
Common ≥ 1/100 - < 1/10
Uncommon ≥ 1/1.000 - < 1/100
Rare ≥ 1/10,000 - < 1/1,000
Very rare < 1/10,000
Not known cannot be estimated from the available data

Allergic cutaneous manifestations may arise in very rare cases.

4.9 Overdose

No manifestations of overdosage or intoxication have been reported to date.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Analgesic; antiexudative/antiphlogistic agent for percutaneous application
ATC code: M02AC55
The target site of escin is the vascular wall. In the case of inflammatory raised permeability, escin inhibits exudation by reducing extravasation of fluid into the tissue spaces, and it accelerates reabsorption of the existing oedema. The mechanism of action is based on a change in the permeability of the capillary openings involved. Furthermore, escin promotes capillary resistance, inhibits inflammatory processes and improves microcirculation.

Diethylamine salicylate (DEAS) has a pronounced analgesic effect. It penetrates freely through the skin and exerts its analgesic action in the depths of the affected area. The additional antiphlogistic action of DEAS enhances the anti-inflammatory effect of escin and thus combats the causal factors of the course of disease.

In three randomised, placebo-controlled double-blind studies on human pharmacology using the model of an experimentally induced haematoma (injection-induced haematoma), it was possible to demonstrate the effect of Reparil^®-Gel N by means of the development of tenderness on pressure and haematoma absorption.
During the first 24 hours of treatment and also over a period of 19 days, a significant lessening of the tenderness on pressure was observed compared with the placebo and the individual components escin and DEAS. On the other hand, each of the two individual components had a significantly superior effect to placebo. In comparison to the reference preparation diclofenac and the placebo, a clear superiority of both active study medications vs the placebo was recorded in the same model. The comparison between Reparil^®-Gel N and diclofenac revealed a trend in favour of the test preparation.

5.2 Pharmacokinetic properties
In order to investigate its percutaneous absorption, 3 H escin was applied to the dorsal or ventral skin of mice, rats, guinea pigs and pigs. An occlusive bandage was used to cover the site of application.
The concentration of total activity, non-volatile activity and acitivity of escin (after thin-layer chromatography) was determined in various tissues and organs at different times after the application. Biliary and urinary excretion were measured throughout the trial.

The absorption rate (estimated via the excretion in 1 – 2 days) was low in all species; it accounted for < 2 % of the applied dose. Relatively high escin concentrations, however, were found beneath the site of application and even in the deeper lying muscle tissues.

Twenty-four hours after percutaneous application, the concentration of non-volatile activity measured in pigs in the subcutis and muscle tissues beneath the area if application was approximately 50 times higher than that in the blood. Peak activity levels in cutis and subcutis were reached 6 hours after application.

In the course of the investigation, the activity in cutis and subcutis declined due to increasing diffusion. In the muscle tissues, however, it increased. Thin-layer chromatography revealed that approximately 50 % of this activity was identical escin. The results demonstrate that escin is absorbed by and also penetrates through the skin.

Very high escin concentrations, which are desirable are thus locally achieved in the muscle tissues at the site of application without considerable systemic involvement.
On the grounds of this pharmacokinetic behaviour, it is safe to assume that escin is very suitable for percutaneous treatment.
To determine the percutaneous absorption of the analgesic compound in Reparil^®-Gel N, ¹⁴C diethylamine salicylate was applied to the dorsal skin of Wistar rats. The determination of the absorption rate was carried out by ascertaining biliary and urinary elimination of the ¹⁴C activities.
Additional measurements included the concentrations in the plasma, in various organs and tissues. The metabolism of ¹⁴C diethylamine salicylate was also investigated. The absorption rate estimated by determination of excretion in 48 hours was on average 14 %. High concentrations of activity were recorded in the treated skin area, whereas the ¹⁴C activities measured in the organs and tissues at different times after the application were low.

A clinico-pharmacological investigation was carried out to determine the absorption of escin after topical application. The trial was carried out as an open study. The sample consisted of 20 patients with proctoligal conditions requiring surgery. A 2 % escin cream was applied to the affected skin area for 7 days before the operation. The determination of the escin concentration in tissue samples removed from the area operated on revealed, in the cutis and subcutis, escin concentrations which significantly differed from 0 (p < 0.001). Furthermore, a significant difference was noted in the concentrations of the individual tissue samples between cutis and subcutis and the fatty tissue.

5.3 Preclinical safety data

Investigations into local and sytemic tolerability were carried out in rats, rabbits and pigs.

In rats and rabbits 200 or 500 mg Reparil^® -Gel N was applied to the shaved dorsal skin over a period of 4 weeks. No macroscopically nor histologically specific local skin damage occurred. Changes in the sense of a low-grade acanthosis of the epidermis, as well as chronic inflammatory cellular infiltration into the sub-epidermal corium were also observed in the control after application of the gel base. Experience has shown that all findings are reversible.

To investigate local mucosal tolerability 100 mg Reparil^®-Gel N was instilled once into the conjunctival sac of the eye. Low to high-grade inflammatory changes occurred in the conjunctiva which however receded completely within 7 days. Rinsing of the eyes within 2 min following application clearly reduced the irritations.

In a long-term trial, 300, 1500 or 4000 mg/kg bodyweight was applied to the dorsal skin. Macroscopic examination revealed in the highest dosage group occasional erythemas. Histological examination revealed, apart from non-specific cutaneous reactions, e.g. suppurative pustular dermatitis, epidermal hyperplasia and hyperkeratosis, no specific reactions. Systemic substance-induced effects were not observed either.

6. PHARMACEUTICAL PARTICULARS

6.1 List of other excipients

Sodium edetate, polyacrylic acid, macrogol-6-caprylic/caprinic acid glycerides, trometamol, isopropanol, odourants.

6.2 Incompatibilities
None known.

6.3 Shelf life

in aluminium tubes: 3 years
in laminate tubes 3 years

Shelf life after first opening of the container: 6 months

6.4 Special precautions for storage
Keep out of reach and sight of children.
Store below 30°C in a dry place.

6.5 Nature and contents of container
Packs of 40 g gel and 100 g gel filled in aluminium tubes or laminate tubes.

6.6 Special precautions for disposal and handling
None.

7. MARKETING AUTHORISATION HOLDER
MADAUS GmbH
D-51101 Cologne
Tel.: + 49 221/8998-0; Fax: + 49 221/8998-711
Email: info@rottapharm-madaus.de

8. MARKETING AUTHORISATION NUMBER(S)
Authorisation no.: 6-130-83 (40);10-130-87 (100)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18.03.1995

10. DATE OF REVISION OF THE TEXT
March 2012

REP-2022-0024

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