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Lioton 1000 gel

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Pripremljeno od internacionalnog odeljenja Maj 2011 samo za internu upotrebu


Lioton
1000 gel

Struktura prezentacije

1. Proizvod
1.1 Glavne karakteristike
1.2 Doziranje i metod primene, sastav
2. Lioton formula
2.1 Visoka koncentracija
2.2 Gel formula
3. Nain dejstva
4. Efikasnost
4.1 Indikacije za Lioton
4.2 Kliniki testovi sa Lioton: ne-komparativni
4.3 Kliniki testovi sa Lioton: komparativni
4.4 Procena efikasnosti
5. Bezbednost
5.1 Bezbednosni podaci
5.2 Procena tolerancije

2
Lioton
1000 gel 1. The product

1.1 Main characteristics

A heparin-based gel formulation for topical


application
Contains a high concentration of heparin
equal to 1,000 I.U./1 g
(also expressed as 100,000 I.U./100 g)
Has various indications like superficial
venous diseases and their complications,
traumas and contusions
Is well documented with respect to scientific
data
Is readily accepted by physicians and
patients

3
Lioton
1000 gel 1. The product

1.2 Posology and method of administration,


composition

Posology and method of administration


One to three applications a day, by gently applying
3 - 10 cm of gel to the affected area
Due to the limited experience and to the available
data, it should not be used in children.
No specific data exist on the use of the medicinal
product during pregnancy and lactation.

Qualitative and quantitative composition


1 g of gel contains heparin 1,000 I.U.
Excipients: Carbomer 940, methyl p-hydroxy-
benzoate, propyl p-hydroxybenzoate, ethyl alcohol,
orange flower oil (neroli oil), lavender oil,
triethanolamine, purified water

Lioton 1000 gel SmPC, 02/2003

4
Lioton
1000 gel 2. Lioton formulation

Scientific data regarding pharmaceutical form


and composition

2.1 High concentration


2.2 Gel formulation

5
Lioton
1000 gel 2. Lioton formulation

Lioton formulation
Overview of related publications

Author year topic

Zesch 1976 Penetration, permeation and


resorption of heparin through
human skin

Stttgen 1990 Permeation of heparin through


human skin
Zesch A, Schaefer H. [Penetration,
permeation and resorption of heparin.
In vivo studies on human skin].
Schaefer 1976 Penetration of heparin through Arzneimittelforschung 1976;26:1365-8.
Stttgen G, Bauer E. The permeation
human skin of heparin through human skin. Acta
Therap 1990;16:265-76.
Schaefer A, Zesch A. [Penetration of
heparin into human skin]. Pharmazie
1976;31:251-4.

6
2. Lioton formulation
Lioton
1000 gel 2.1 High heparin concentration

Dose-dependent penetration of
Lioton

Permeation of
100 Lioton 1,000 I.U./g or 500
I.U./g (diluted) gel into the
1000 I.U./g gel skin of forearm in healthy
Skin concentration of heparin [g/ml]

500 I.U./g gel volunteers

10 Exposure time:
300 minutes

0.1

0.01 Stttgen G, Bauer E. The permeation


0 500 1000 1500 2000 of heparin through human skin. Acta
skin depth [m] Therap 1990;16.265-76.

Heparin penetration was shown to be markedly deeper


with 1,000 I.U./g vs. 500 I.U./g Lioton.

7
2. Lioton formulation
Lioton
1000 gel 2.1 High heparin concentration

Dose-dependent penetration of Lioton in different


skin layers

Permeation of
Concentration Skin layers Thickness Percentage of g/cm3 of
Lioton 1,000 I.U./g or 500
m amount applied* skin layer I.U./g (diluted) gel into the
skin of forearm in healthy
Horny layer 20 86.71 28.62 volunteers
Epidermis 120 1.06 0.35
Heparin Exposure time:
Upper dermis 640 0.79 0.26 300 minutes
Sodium 1,000
I.U./g Lower dermis 960 0.70 0.23
Subcutaneous
fatty tissue 300 0.15 0.05

Horny layer 20 34.95 5.68


Epidermis 120 0.25 0.04
Heparin
Upper dermis 640 0.04 0.006
Sodium 500 * After removal of residual gel from
I.U./g Lower dermis 960 0.02 0.003 the surface

Subcutaneous
Stttgen G, Bauer E. The permeation
fatty tissue 300 0.05 0.01 of heparin through human skin. Acta
Therap 1990;16.265-76.

Lioton 1,000 I.U./g gel achieves higher concentration of heparin in


relevant skin layers compared to the gel with 500 I.U./g heparin.

8
2. Lioton formulation
Lioton
1000 gel 2.1 High heparin concentration

Dose-dependent penetration of Lioton in different


skin layers

Lioton
500 I.U./g 1,000 I.U./g
Horny layer
Epidermis

Dermis

76.7 x higher
concentration

Heparin concentration (g/ml) Lioton 1,000 I.U./g


vs. heparin 500 I.U./g
500 I.U./g Lioton
1,000 I.U./g
Horny layer 5.68 28.62 5x
Epidermis 0.04 0.35 8.75 x
Upper dermis 0.006 0.26 43.3 x
Stttgen G, Bauer E. The permeation
Lower dermis 0.003 0.23 76.7 x of heparin through human skin. Acta
Therap 1990;16.265-76.

Lioton 1,000 I.U./g gel achieves higher concentration of heparin in


relevant skin layers compared to the gel with 500 I.U./g heparin.

9
2. Lioton formulation
Lioton
1000 gel 2.2 Gel formulation

Formulation-dependent penetration of
topical heparin

Permeation of
Exposure Skin layers Formulation Percentage of g heparin/cm I.U./ml heparin gel and ointment into
time amount applied tissue human skin in vivo

Note:
75 min Horny layer Gel A 45.3 4.35 327.0 Heparin concentration in all
three preparations was the
Epidermis 10.9 1.05 9.8
same.
Dermis 2.9 0.28 0.39

75 min Horny layer Ointment B 19.0 1.85 138.0


Epidermis 0.85 0.081 0.77
Dermis 1.1 0.11 0.15

75 min Horny layer Ointment C 26.3 2.38 179.0


Epidermis 0.82 0.074 0.69
Dermis 1.75 0.161 0.22
Zesch A, Schaefer H. [Penetration,
permeation and resorption of heparin.
In vivo studies on human skin].
Arzneimittelforschung 1976;26:1365-8.

Gel releases heparin much more rapidly than ointments.

10
Lioton
1000 gel 2. Lioton formulation

Summary of advantages of Lioton formulation

Statements without special reference


A gel form generally offers better
convenience for daily use.
The unique carbomer-based gel formulation
of Lioton provides optimal cosmetic features
with a cooling effect and pleasant smell
thanks to essential neroli and lavender oil,
without staining.

Stttgen G, Bauer E. The permeation


of heparin through human skin. Acta
Therap 1990;16:265-76.

11
Lioton
1000 gel 2. Lioton formulation

Summary of advantages of Lioton formulation

Reference-based statements
With high concentrations of heparin, high diffusion
pressure is achieved, resulting in a high tissue
concentration (Stttgen and Bauer, 1990).
Absorption was shown to be markedly higher with
1,000 I.U./g vs. 500 I.U./g (Stttgen and Bauer, 1990).
A gel formulation is superior to ointments and
provides greater heparin penetration into relevant
layers of the skin (Zesch, 1976).
Lioton with its high heparin concentration thus enables
higher heparin concentrations in the dermal skin Stttgen G, Bauer E. The permeation
layers to be achieved (Stttgen, 1990). of heparin through human skin. Acta
Therap 1990;16:265-76.
Zesch A, Schaefer H. [Penetration,
permeation and resorption of heparin.
In vivo studies on human skin].
Arzneimittelforschung 1976;26:1365-8.

12
Lioton
1000 gel 3. Mode of action

Mode of action of heparin

Based on non-clinical (experimental)


data on heparin

13
Lioton
1000 gel 3. Mode of action

Results of experimental studies revealed several


mechanisms of action of heparin:

Anti-coagulatory action
(Jaques, 1979; Craig, 2000; Lioton 1000 gel SmPC,
02/2003)*
Anti-inflammatory action
(Wang, 2002; Lever, 2007; Bazzoni, 1992; Salas, 2000;
Salek-Ardakani, 2000; Tyrell, 1995; Vlk, 1991; Lioton
1000 gel SmPC, 02/2003)*
Promotion of microcirculation
(Baldus, 2006; Heistad, 2006; Van Teeffelen, 2007;
Moaveni, 2008)*
Anti-exudative action
(Nazarov, 1979; Lioton 1000 gel SmPC, 02/2003)*

Note:
These mechanisms of action were demonstrated in non-clinical studies conducted
with heparin and not with Lioton. Therefore, when promoting them, please
emphasise that these are features of heparin the active substance of Lioton
and do not present them when talking about the efficacy of Lioton.
* For the full reference list please see
the comment below

14
Lioton
1000 gel 3. Mode of action

Anticoagulatory action of heparin

Cascade of blood coagulation and attack site of unfractionated heparin

Heparin inhibits clot formation


Intrinsic pathway Extrinsic pathway by activating antithrombin III
(ATIII) which, in turn,
XII XIIa progressively inactivates
thrombin and coagulation
Tissue factor + VII + Ca2+ XI XIa factor Xa, key enzymes in the
fibrinogen formation (Jaques,
IX IXa 1979).

X Xa

V, Ca2+ ,
phospholipid
Prothrombin Thrombin XII

Unfractionated XIIa
Antithrombin III
heparin
Graph:
Fibrinogen Fibrin Hamaad A et al. Ximelagatran: The
future in anticoagulation practice. Br
J Cardiol 2004;11:229-34.
Thrombus
Jaques LB. Heparins anionic
polyelectrolyte drugs. Pharmacol Rev
1979;31:99-167.

Heparin a classical anticoagulant

15
Lioton
1000 gel 3. Mode of action

Anti-inflammatory actions of heparin

Heparin modulates inflammatory processes on several levels

As shown in experimental studies:


Heparin has an effect on inflammatory mediators (cytokines,
nitric oxide (NO) ...).
Heparin has an effect on inflammatory cells (lymphocytes,
neutrophils, monocytes, mast cells).
Heparin has an effect on transmigration of inflammatory cells.
In addition, heparin interferes with non-cell-mediated inflammatory
responses by decreasing complement levels and inhibiting the Tyrell D et al. Therapeutic uses of
complement cascade. heparin beyond its traditional role as
an anticoagulant. Trends Pharmacol
Sci 1995;16:198-204.
Elsayed E, Becker RC. The impact of
heparin compounds on cellular
inflammatory responses: a construct
for future investigation and
pharmaceutical development. J
Thromb Thrombolysis 2003;15:11-8.

16
Lioton
1000 gel 3. Mode of action

Anti-inflammatory actions of heparin (I)

Effect on inflammatory mediators

Target: Heparin action Effect on inflammation


inflammatory mediators
Tumor necrosis factor- Reduces level, inhibits
(TNF) monocyte synthesis1
Interleukin-6 (IL-6) Reduces level1
Interleukin-10 (IL-10) Increases level1
Matrix Limits synthesis1
metalloproteinases
NO Promotes NO formation in NO inhibits platelet
endothelial cells1 aggregation, neutrophil
activation and endothelial
cell adhesion, vasodilator

Interleukin-1(IL-1), IL-6 Limits release1


Interleukin-8 (IL-8) Decreases IL-8 binding and
chemotactic responses1
Complement Anti-complement activity1 Inhibits complement 1. Tyrell D et al. Therapeutic uses of
heparin beyond its traditional role as
Decreases complement levels1 activity an anticoagulant. Trends Pharmacol
Sci 1995;16:198-204.

Heparin reduces levels of pro-inflammatory cytokines and promotes


formation of nitric oxide (NO) (as shown in experimental studies).

17
Lioton
1000 gel 3. Mode of action

Anti-inflammatory actions of heparin (II)

Effect on inflammatory cells (a)

Target: Heparin action Effect on inflammation


inflammatory cells
Leukocytes Binds to surface L-and P-selectin1 Inhibits adherence to
endothelial cell surface
Blocks superoxide generation and and subsequent migration
neutralizes superoxide radicals into tissue
produced by activated leukocytes Prevents harmful oxidative
indirectly by association with stress
superoxide dismutase1
Interacts with chemokines inducing
activation2
Modulates heparanase activity and Inhibits chemoattractant
expression2 activation of leukocytes
Attenuates 1. Tyrell D et al. Therapeutic uses of
Attenuates CD11b-dependent heparin beyond its traditional role as
leukocyte adhesion1 transendothelial migration an anticoagulant. Trends Pharmacol
of immune cells Sci 1995;16:198-204.
Lymphocytes Decreases cytotoxic T-lymphocyte Attenuates T-lymphocyte 2. Elsayed E, Becker RC. The impact
activity1 function of heparin compounds on cellular
inflammatory responses: a construct
Impairs T-cell adhesion and migration1 for future investigation and
Suppresses natural killer cell activity1 pharmaceutical development. J
Thromb Thrombolysis 2003;15:11-8.

Heparin interferes with activation and migration of various


inflammatory cells (as shown in experimental studies).

18
Lioton
1000 gel 3. Mode of action

Anti-inflammatory actions of heparin (III)

Effect on inflammatory cells (b)

Target: Heparin action Effect on inflammation


inflammatory cells
Neutrophils Limits granulocyte activation1
Inhibits production of granulocyte enzymes
lactoferrin and myeloperoxidase1
Attenuates infiltration1
Attenuates neutrophil-mediated
Phagocytosis1
Inhibits leukocyte integrin MAC-11
Inhibits neutrophil superoxide formation1 Prevents adhesion to
vascular endothelial cells
Reduces neutrophil chemotaxis in Prevents harmful oxidative
transendothelial migration2 stress
Eosinophils Inhibits eosinophil chemoattractants1 Inhibits recruitment into
tissues (infiltration) 1. Tyrell D et al. Therapeutic uses of
heparin beyond its traditional role as
Monocytes, mast-cells, Decreases monocyte adhesion and an anticoagulant. Trends Pharmacol
TF infiltration1 Sci 1995;16:198-204.
Attenuates mast-cell activation2 2. Elsayed E, Becker RC. The impact
Reduces monocyte TF production1 of heparin compounds on cellular
inflammatory responses: a construct
for future investigation and
TFPI (=tissue factor Enhances release1 Inhibition of coagulation
pharmaceutical development. J
pathway inhibitor) cascade Thromb Thrombolysis 2003;15:11-8.

Heparin interferes with activation and migration of various


inflammatory cells (as shown in experimental studies).

19
Lioton
1000 gel 3. Mode of action

Anti-inflammatory actions of heparin (IV)

Additional (specific) claims based on in vitro studies:

Heparin influences interaction between leukocytes and


endothelium (Lever, 2007) Lever R et al. Size-fractionated
heparins have differential effects on
Heparin reduces the production of oxygen free radicals by human neutrophil function in vitro. Br
polymorphonuclear cells (Bazzoni, 1992) J Pharmacol 2007;151:837-43.
Bazzoni G et al. Effect of heparin,
Heparin attenuates the inflammatory response to TNF dermatan sulfate, and related oligo-
proinflammatory cytokine (Salas, 2000) derivatives on human
polymorphonuclear leukocyte
functions. J Lab Clin Med
Heparin inhibits ligand binding to the leukocyte integrin Mac-1 1993;121:268-75.
(CD11b/CD18) (Peter, 1999). Salas A et al. Heparin attenuates
TNF-alpha induced inflammatory
response through a CD11b
dependent mechanism. Gut
2000;47:88-96.
Peter K et al. Heparin inhibits ligand
binding to the leukocyte integrin Mac-
1 (CD11b/CD18). Circulation
1999;100:1533-9.

20
Lioton
1000 gel 3. Mode of action

Anti-inflammatory actions of Lioton

Effects on haematological inflammation and coagulation parameters

30 patients
p < 0.001 with varicophlebitis,
50 10
p < 0.001 superficial thrombo-phlebitis
9 or periphlebitis

40 8 9.06 Lioton 1,000 I.U./g gel three


42 -35% times a day

Leukocytes [000/mmc]
7
1 hour ESR* [mm]

Mean duration: 20.6 days


30 6

-72% 5
5.87
20 4

3
* ESR: erythrocyte
10 2 sedimentation rate
12
1
Milio G et al. [Use of heparin sodium
in the form of a gel in venous
0 0 disorders of the lower limb marked by
Baseline Final Baseline Final inflammation]. Acta Cardiol Medit
1985;3:283-8.

Significant decrease in blood parameters of inflammation (number


of leukocytes and erythrocyte sedimentation rate) in patients with
various superficial venous disorders

21
Lioton
1000 gel 3. Mode of action

Action of heparin on improving blood flow

Heparin significantly enhances acetylcholine (ACh)-induced increase in


forearm blood flow as measured by venous occlusion plethysmography.
109 patients undergoing
18 coronary angiography
* p < 0.01 vs. NaCl *
Heparin Single heparin dose of 70
Forearm blood flow [ml 100ml-1 min-1]

16
I.U./kg of body weight
14

12

10 *
NaCl Note:
The study assessed
8
L-NMMA + parenteral application of
Heparin heparin. These results are
6 therefore to be used only
L-NMMA when mentioning the general
4 features of heparin.

2
Baldus S et al. Heparins increase
endothelial nitric oxide bioavailability
0 by liberating vessel-immobilized
0 7.5 15 30 myeloperoxidase. Circulation
ACh [g/min] 2006;113:1871-8.

Heparin increases endothelial NO bioavailability


and improves blood flow.

22
Lioton
1000 gel 3. Mode of action

Action of heparin on endothelial


activity and microcirculation

Heparin* accelerated vein endothelial turnover (re-


endothelisation) and preserved medial smooth muscle cell
integrity after stasis deep vein thrombosis (Moaveni, 2008).
* Parenteral application of low-molecular-weight heparin (LMWH)

Szczesny G et al. Heparin protects


Heparin application prevented the decrease in capillary local skin microcirculation in 210
minutes-long intravital microscopy
density in mice as measured by intravital fluorescent observations under general
anaesthesia. Eur J Med Res
microscopy (Szczesny, 2001). 2001;6:175-80.
Moaveni DK et al. Vein wall re-
endothelialization after deep vein
thrombosis is improved with low-
molecular-weight heparin. J Vasc
Surg 2008; 47:616-24.

Heparin helps re-endothelisation of "damaged" vessels and


helps protect microvasculature.

23
Lioton
1000 gel 3. Mode of action

Antioxidant action of heparin

Heparin increases superoxide dismutase concentration,


thus supporting the elimination of superoxide radicals and
oxidative stress in affected tissue (Heistad, 2006).

Heistad DD. Oxidative stress and


vascular disease. Arterioscler
Thromb Vasc Biol. 2006;26:689-95.

Heparin counteracts damage of the affected tissue by


decreasing oxidative stress levels.

24
Lioton
1000 gel 3. Mode of action

Anti-exudative action of heparin

Heparin induces microcirculatory changes in the


inflammatory area and significantly decreases vascular
permeability.
Decreased vascular permeability plays an important role
in the mechanism of antiexudative heparin action
(Nazarov, 1979).

Nazarov GF et al. [Mechanism of the


antiexudative action of heparin]. Biull
Eksp Biol Med 1979;87:304-5.

Heparin counteracts damage of the affected tissue by


decreasing oxidative stress levels.

25
Lioton
1000 gel 3. Mode of action

Role of heparin in neoangiogenesis

Please consider this


slide only for your
information!

Burns treated with heparin had blood flow restored in a Neoangiogenesis is not
listed under mechanisms of
shorter time, ischemic tissue was consistently action in the
revascularized and healing process was accelerated "Pharmacodynamic
properties" section of the
(Saliba, 2001). Lioton 1000 gel SmPC.
Lioton is also not indicated
for burns.

Saliba MJ Jr. Heparin in the


treatment of burns: a review. Burns
2001;27:349-58.

Clinical experience from the treatment of burns has pointed to


heparin having re-epithelising and neoangiogenic properties.

26
Lioton
1000 gel 4. Efficacy

Efficacy of Lioton

4.1 Lioton indications


4.2 Clinical trials with Lioton: non-comparative
4.3 Clinical trials with Lioton: comparative
4.4 Efficacy assessment

27
4. Efficacy
Lioton
1000 gel 4.1 Lioton indications

Lioton gel is indicated in

Treatment of superficial venous diseases such as


varicose syndromes and their complications,
phlebothrombosis, thrombophlebitis, superficial
periphlebitis, varicose ulcers
Postoperative varicophlebitis; sequelae of saphenectomy
Traumas and contusions; infiltrates and local oedemas;
subcutaneous haematoma
Traumas and sprains of the musculotendinous and
capsuloligamentous apparatuses

Lioton 1000 gel SmPC, 2003

28
4. Efficacy
Lioton
1000 gel 4.1 Lioton indications

Lioton indications

Note:

Relevant clinical data are presented below that may be


suitable to support product claims or to show differences
with regard to competitors.
Most data are related to the field of superficial vein
disease like phlebothrombosis, thrombophlebitis,
superficial periphlebitis, varico-phlebitis or venous ulcers.
Please be aware that, with regard to other indications,
there may be conflicting results, only limited data
available, or those indications may have not gained
medical acceptance.

29
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Treatment of superficial venous diseases


Overview of non-comparative trials (I)

Author Year Patients Indication Endpoint


Numerous subjective and
Milio 1982 30 Venous disease objective symptoms
systemic tolerability
Numerous subjective and
Cappelli 1984 20 Varices or phlebitis
objective symptoms
Pain, erythema, edema
Pola 1985 20 Varico phlebitis
systemic tolerability
Virgilio and Numerous subjective and
1985 71 Venous disease
Cavallaro objective symptoms
Chronic venous
Numerous subjective and
Marrapodi 1986 20 insufficiency, venous
objective symptoms
ulcers
Superficial thrombo-
Induration, pain, impaired
Navratilova 2000 32 phlebitis, infiltration
function, edema * For the full reference list please see
after sclerotherapy the comment below

30
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Treatment of superficial venous diseases


Overview of non-comparative trials (II)

Author Year Patients Indication Endpoint

Varicose and post-


Numerous subjective and
Kirienko 1998 40 thrombophletic
objective symptoms
conditions
Vascular disorders
Novosad 1999 107 Clinical symptoms
after surgery
Acute and chronic
venous Pain, edema, postop.
Sukharev 1999 110
insufficiency haematoma
after surgery
Numerous subjective and
Bihari 2001 412 Superficial phlebitis
objective symptoms

Numerous subjective and


Darczy 2002 147 Varicose syndrome
objective symptoms
* For the full reference list please see
the comment below

31
Lioton
1000 gel 4. Efficacy

Symptoms of superficial venous disease

Background and notes

Stage 1 Stage 2 Stage 3 Stage 4


Early venous First visible signs, Overt disease Advanced disease
insufficiency, like discoloration, with varicosis, with symptoms
characterised by spider veins, or swelling, eczema, like in stage 3,
subjective mild varicosis, skin changes and and additionally
complaints like may appear. an increased risk with ulcers and
heavy legs, Relief in of thrombosis. impairment of
swelling, itching or horizontal Only modest relief daily activities.
pain, particularly position in horizontal
after a long time position.
of standing

* Please be aware that this


In clinical studies, the influence of different treatments can either be measured with a slide is for internal use only!
subjective assessment of symptoms by the patient or investigator or with an objective It is intended to give you an
evaluation. orientation about symptoms of
In the following studies, the method of evaluation for the different symptoms differ, so superficial venous disease. If
please be aware that sometimes the result is based on subjective evaluation (like you should need an official
reduction of pain for example) and sometimes on an objective evaluation (e.g. oedema staging or classification,
measured by calf circumference). please refer to the CEAP slide
in the clinical trials section!

32
Lioton
1000 gel 4. Efficacy

Classification of venous diseases of the legs

Background

Classification
Clinical severity
Etiology or cause
Anatomy
Pathophysiology
Clinical severity
Grade Description
C0 No evidence of venous disease.
C1 Superficial spider veins (reticular veins) only
C2 Simple varicose veins only
C3 Ankle oedema of venous origin (not foot oedema)
C4 Skin pigmentation in the gaiter area (lipodermatosclerosis)
C5 A healed venous ulcer
C6 An open venous ulcer

33
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in varicophlebitis

Reduction of subjective perception of symptoms over time

20 patients with lower limb


3 varicophlebitis

Pain Lioton 1,000 I.U./g gel three


times a day for 15 days and
Erythema twice a day for a further 15
days
Oedema
Duration: 30 days
2
Symptom score

Pola P et al. [Trend of blood and


plasma viscosity and serum lipids
0 following topical treatment with
Baseline 15 days 30 days heparin sodium]. G Ital Angiol
1984;4:135-8.

Lioton provides progressive reduction of subjective


perception of pain, oedema and erythema.

34
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in superficial venous disease

Reduction in "subjective" symptoms

Spontaneous Provoked Heaviness Parestesia Nocturnal 20 patients with venous


pain pain cramps varices or phlebitis/
0
periphlebitis
Lioton 1,000 I.U./g gel two to
three times a day
20
Duration: 3-20 days
Reduction [%]

40 50%

60

75%
79%
80
88%
100%
Cappelli R. [Treatment of lower limb
100 vascular disorders with a gel
containing heparin sodium]. Farmaci
1984;9:163-7.

Lioton markedly relieves bothersome symptoms/ subjective


perception of pain, heaviness and paraesthesia in patients with
superficial venous disease.

35
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in superficial venous disease

Reduction in "objective" signs

Oedema Erythema Venous Venous Ulcers 20 patients with venous


induration turgidity varices or phlebitis/
0
periphlebitis
Lioton 1,000 I.U./g gel two to
three times a day
20
33% Duration: 3 - 20 days
Reduction [%]

40

64%
60

80% 79%
80
96%

Cappelli R. [Treatment of lower limb


100 vascular disorders with a gel
containing heparin sodium]. Farmaci
1984;9:163-7.

Lioton markedly improves various symptoms in superficial


venous disease.

36
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in superficial venous disease

Improvement in clinical parameters

30 patients with
100 ** ** varicophlebitis, superficial
** thrombophlebitis or
100% 100% *
96% periphlebitis
** 93% **
** ** Lioton 1,000 I.U./g gel three
80 85%
83% 82% times a day
* 80% *
Improved patients [%]

Mean duration: 20.6 days


72% 71%
60

40

* p < 0.05
20 ** p < 0.01

Milio G et al. [Use of heparin sodium


in the form of a gel in nervous
0 disorders of the lower limb marked by
Oedema Sponta- Provoked Erythema Func- Hema- Heavi- Para- Induration Vein
neous pain tional toma ness thesia turgidity inflammation]. Acta Cardiol Medit
pain limitation 1985;3:283-8.

Lioton significantly improves various symptoms in superficial


venous disease.

37
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in superficial thrombophlebitis

Reduction in clinical signs

31 patients with superficial


100 thrombophlebitisor infiltration
following sclerotherapy or
manifestation of hypodermitis
94% Lioton 1,000 I.U./g gel twice
80
89% daily
86%
80% Duration: 28 days
Success rate [%]

60

40

20

Navrtilov Z et al. [Local application


0 of heparin feasibility of its use in
Induration Pain Impaired function Oedema phlebology]. Cesk Dermat
(n = 30) (n = 27) (n = 16) (n = 21) 2000;75:230-2.

Lioton reduced clinical signs in superficial venous disease

38
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in superficial thrombophlebitis

Mean change in spontanous pain*

412 patients with superficial


p < 0.001 p < 0.001 phlebitis
3
Lioton 1,000 I.U./g gel twice
daily
2.5
2.76 -24% Duration: 14 days

2
Pain score

2.11 -35%
1.5

1.38 * on a four-point scale


1
(0 = none)
(1 = mild)
(2 = moderate)
(3 = strong)
0.5

Bihari I. Survey of the therapeutic


0 effect of heparin gel (Lioton) in
0 1 2 superficial phlebitis. Vasc Dis
Time [week] 2001;8:19-24.

Lioton significantly reduced spontaneous pain in patients with


superficial phlebitis.

39
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in superficial thrombophlebitis

Mean change in pain experienced on palpation and pressure*

412 patients with superficial


p < 0.001 p < 0.001 phlebitis
3
Lioton 1,000 I.U./g gel twice
daily
2.5
2.76 -21% Duration: 14 days

2
-28%
Pain score

2.18
1.5

1.57
* on a four-point scale
1
(0 = none)
(1 = mild)
(2 = moderate)
(3 = strong)
0.5

Bihari I. Survey of the therapeutic


0 effect of heparin gel (Lioton) in
0 1 2 superficial phlebitis. Vasc Dis
Time [week] 2001;8:19-24.

Lioton significantly reduced provoked pain in patients with


superficial phlebitis.

40
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in chronic venous insufficiency

Reduction of oedema

147 patients with chronic


28 venous insufficiency
Lioton 1,000 I.U./g gel three
p < 0.001 times a day
27.5 Duration: 14 days
Calf circumference* [cm]

27

26.5
* Average calf circumference
as measured 4 cm above the
ankle
26

Darczy J. [Effects of Lioton gel in


25.5 varicose syndrome of the lower
0 1 2 extremity]. rbetegsgek 2002;3:85-
Time [week] 90.

Lioton gel significantly reduced oedema as measured by calf


circumference.

41
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in venous ulcers (I)

Trophic effect

20 patients with varicose


No effect veins complicated by trophic
disorders
10% Lioton 1,000 I.U./g gel three
times a day
Duration: 30 days

Decreased
ulcer area 60 % 30 %
Healed ulcer

Kirienko AI et al. [Lioton 1000 gel


a new material for the topical
treatment of varicose disease of the
lower limbs and its complications]. J
Angiol Vasc Surg 1998;4:47-51.

Lioton showed a positive effect on healing of venous ulcers.

42
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in venous ulcers (II)

Reduction of ulcer extension

20 patients with chronic


p < 0.05 venous insufficiency, 9 with
12
lower limb ulcers
Lioton 1,000 I.U./g gel once a
10 day
Duration: 30 days
-55%
8
cm2

Marrapodi E et al. [The usefulness of


0 percutaneous heparin management
Baseline End of treatment in the phlebological therapy]. G Ital
Angiol 1986;6:115-22.

Significant reduction of the mean extension of ulcers after


Lioton gel gel treatment

43
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in chronic venous insufficiency


(partially complicated by venous ulcers)

Reduction of symptoms

20 patients with chronic


3 venous insufficiency, 9 with
lower limb ulcers
* p < 0.05 Heavy limb
** p < 0.01 Lioton 1,000 I.U./g gel once a
2.5 Hematoma day
Functional Duration: 30 days
limitation
2 Parathesia
Symptom score

**
Nocturnal
cramps
1.5
**
***
1
*
* **
0.5
**
** ** **
Marrapodi E et al. [The usefulness of
0 percutaneous heparin management
Baseline 15 days 30 days in the phlebological therapy]. G Ital
Angiol 1986;6:115-22.

Significant reduction of symptoms including haematoma after


Lioton treatment

44
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in chronic venous insufficiency


(partially complicated by venous ulcers)

Reduction of nocturnal cramps

20 patients with chronic


3 venous insufficiency, 9 with
lower limb ulcers
* p < 0.05
** p < 0.01 Lioton 1,000 I.U./g gel once a
2.5 day
Duration: 30 days
2
Symptom score

1.5

*
0.5
**
Marrapodi E et al. [The usefulness of
0 percutaneous heparin management
Baseline 15 days 30 days in the phlebological therapy]. G Ital
Angiol 1986;6:115-22.

Significant reduction of nocturnal cramps after


Lioton treatment

45
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Efficacy in local bruising injuries

Improvement in clinical parameters

Heaviness Hardening Haematoma Functional limitation 25 patients (athletes) with


0 local bruising injuries mainly
to the lower limbs
Lioton 1,000 I.U./g gel two to
three times a day
20
Duration: 7 days
Improvement (cases) [%]

40

60

80
96% 94%
100% 100% Colombo I et al. [Clinical experience
with a gel containing heparin in high
100 concentration (Lioton 1.000 gel
Menarini) in minor sports injuries].
Med Sport 1986;39:279-83.

Lioton significantly improves clinical parameters in local


bruising injuries.

46
4. Efficacy
Lioton
1000 gel 4.2 Clinical trials with Lioton: non-comparative

Summary of non-comparative trials in superficial


venous diseases

Lioton is effective in a broad spectrum of symptoms by in at least 80 % of cases


(Capelli, 1984; Milio et al., 1985; Navrtilov, 2000).
Lioton's high efficacy in relieving objective and subjective symptoms is clinically proven
(Cappelli et al.,1984).
In more than 80 % of cases, Lioton improves functional limitations in case of superficial
venous diseases (Milio et al., 1985).
After seven days already, Lioton significantly reduces spontaneous and provoked pain
in patients with thrombophlebitis (Bihari, 2001).
Lioton significantly reduces oedema as measured by calf circumference
(Darczy, 2002).
Lioton significantly improves haematoma in various superficial venous disorders
(Milio et al., 1985; Marapodi et al., 1986).
Lioton improves haematoma in bruising injuries (Colombo et al., 1986).
A positive effect in healing of venous ulcers has been shown in 90 % of patients
treated with Lioton (Kirienko et al., 1998; Marapodi et al., 1986).

47
4. Efficacy
Lioton
1000 gel 4.3 Clinical trials with Lioton: comparative

Treatment of superficial venous diseases


Overview of comparative trials (I)

Author Year Patients Treatment Indication Endpoint

Lioton Gel Different vascular Improvement of pain,


De Angelis 1985 44
vs. Hirudoid Gel diseases edema, heaviness

Lioton Gel Different vascular Numerous clinical


Inga 1985 40
vs. Essaven diseases parameters

Chronic venous
Lioton Gel insufficiency, superficial Numerous clinical
D'Amico 1987 30
vs. Essaven thrombophlebitis, post- parameters
phlebitic syndrome

Infusion related Clinical healing


Lioton Gel
Vilardell 1999 20 superficial investigators
vs. Placebo
thrombophlebitis global impression

Subjective symptoms
CEAP class C3 to C5
Lioton Gel of CVI, lower leg
Zielinski 2009 62 chronic venous
vs. Placebo circumference
insufficiency (CVI)
above the ankles
* For the full reference list please see
the comment below

48
4. Efficacy
Lioton
1000 gel 4.3 Clinical trials with Lioton: comparative

Background

Overview of the products used in comparative trials with Lioton

Product Formulation Ingredients

Lioton Gel Heparin 1,000 I.U./g

Essaven Gel Heparin 100 I.U./g,


aescinate 0.01 g/g,
essential phospholipids ~0.01 g/g

Hirudoid Gel Mucopolysaccharide


polysulfate 3 mg/g (heparinoid)

49
4. Efficacy
Lioton
1000 gel 4.3 Clinical trials with Lioton: comparative

Treatment of superficial venous diseases


Lioton vs. placebo

Catheter phlebitis healing

126 patients with venous


p = 0.033 catheter phlebitis
80
Heparin 1000 I.U./g gel Lioton 1,000 I.U./g gel once a
70 day
Placebo
Duration: 30 days
60
Double-blind, randomised
Healed patients [%]

p = 0.033
50

40

30

20

Vilardell M et al. Topical heparin for


10 the treatment of acute superficial
phlebitis secondary to indwelling
intravenous catheter. A double-blind,
0 randomized, placebo-controlled trial.
Intention to treat Per protocol Eur Journal Clin Pharmacol
1999;54:917-21.

The rate of phlebitis healing was over 70 % with Lioton (per


protocol) and significantly higher than with placebo.

50
4. Efficacy
Lioton
1000 gel 4.3 Clinical trials with Lioton: comparative

Treatment of superficial venous diseases


Lioton vs. placebo (I) as add-on therapy

Oedema reduction
Left ankle Right ankle 62 patients with CEAP class
Placebo Lioton Placebo Lioton C3 to C5 chronic venous
0
insufficiency (CVI)
Mean reduction of ankle circumference [cm]

Lioton 1,000 I.U./g gel vs.


placebo twice a day as add-
1
on therapy to compression
and phlebotrophic drug
Duration: 3 months
2
Prospective, randomised

3
-3.68 -3.84

4
-4.51
-4.74 Zieliski M et al. [The effectiveness
assessment of sodium heparin gel
use, in the combined conservative
5 treatment of advanced chronic vein
insufficiency]. Leczenie Ran
p < 0.05 p < 0.05 2009;6:1-6.

Significantly improved oedema reduction with Lioton as


additional therapy to compression and oral treatment in CVI

51
4. Efficacy
Lioton
1000 gel 4.3 Clinical trials with Lioton: comparative

Treatment of superficial venous diseases


Lioton vs. placebo (II) as add-on therapy

There is the following quote in the Zieliski publication:

"... In addition, it should be mentioned that patients in the treatment


group reported a significant relief (alleviation of symptoms) occurring
immediately after product application. This may be related to the
composition of the drug, which contains ethyl alcohol that cools the
skin while evaporating from its surface, giving a pleasant sensation
of immediate alleviation of discomfort ..."

Zieliski M et al. [The effectiveness


assessment of sodium heparin gel
use, in the combined conservative
treatment of advanced chronic vein
insufficiency]. Leczenie Ran
2009;6:1-6.

Feeling of immediate relief for the patient with Lioton in chronic


venous insufficiency

52
4. Efficacy
Lioton
1000 gel 4.3 Clinical trials with Lioton: comparative

Treatment of superficial venous diseases


Lioton vs. Essaven (I)

Improvement of symptoms

Oedema Provoked pain Erythema Skin abnormalities Hematoma 30 patients (15 in each
100 treatment group) with chronic
venous insufficiency,
superficial thrombophlebitis or
post-phlebitic syndrome
80
Lioton 1,000 I.U./g gel vs.
Essaven
twice a day
Patients [%]

60
Duration: 20 days
Open-label
40

20

D'Amico N et al. [Clinical contribution


0 to pharmacology in venous pathology
Essaven Lioton Essaven Lioton Essaven Lioton Essaven Lioton Essaven Lioton and its complications. Effects of
heparin in gel form]. Minerva
Unchanged Improved Very improved Cardioangiol 1987;35:195-203.

Lioton was significantly (p < 0.05) superior to Essaven in various


symptoms of superficial venous diseases.

53
4. Efficacy
Lioton
1000 gel 4.3 Clinical trials with Lioton: comparative

Treatment of superficial venous diseases


Lioton vs. Hirudoid
Overall clinical improvement in terms of spontaneous pain, provoked pain,
oedema and sensation of heavy legs as evaluated by patients and investigators
44 patients with different
100 superficial venous diseases
Lioton 1,000 I.U./g gel two to
three times a day
93%
80 Duration: 4 to 6 weeks
Improvement [%]

60
68%

40

20

De Angelis CP et al. [Clinical


evaluation of the effectiveness and
0 tolerance of heparin as a topical
Hirudoid gel Lioton 1000 I.U./g gel therapy in vascular diseases].
Antolog Med Ital 1985;5:524-7.

Efficacy assessment by investigators and patients was in favour of Lioton compared to Hirudoid.
36 % more patients and doctors reported improvement of symptoms after using Lioton than after
treatment with Hirudoid.

54
4. Efficacy
Lioton
1000 gel 4.3 Clinical trials with Lioton: comparative

Summary of comparative trials in superficial


venous diseases

Lioton is significantly superior to placebo in healing venous catheter phlebitis with a


healing rate of 70 % (Vilardell et al., 1999).
Addition of Lioton to compression and oral treatment resulted in a significant reduction
of oedema in patients with CVI. (Zieliski et al., 2009).
When Lioton was used as add-on treatment, patients reported a sensation of
immediate relief (Zieliski et al., 2009).
Lioton gel is beneficial as add-on therapy in CVI patients receiving oral treatment and
using compression stockings (Zieliski et al., 2009).
Lioton was significantly superior to Essaven in symptom
(oedema/erythrema/haematoma/provoked pain/skin abnormalities) improvement
(DAmico et al., 1987).
Lioton showed high efficacy in improving haematoma (D'Amico et al., 1987).
Lioton gel showed an improvement to clinical signs in nearly 100 % of patients with
various superficial venous diseases and was superior to Hirudoid
(De Angelis et al., 2008).

55
4. Efficacy
Lioton
1000 gel 4.4 Efficacy assessment

Efficacy assessment by physicians


and patients

56
4. Efficacy
Lioton
1000 gel 4.4 Efficacy assessment

Data from the following studies are presented:

Author year patients indication

Chronic venous insufficiency,


Marrapodi 1986 20
venous ulcers

Venous or traumatic pathologies


with a clear pain component, Marrapodi E et al. [The usefulness of
Colonna 1987 890 with edema, decreased percutaneous heparin management
in the phlebological therapy]. G Ital
functional capacity and Angiol 1986;6:115-22.
dystrophic skin Colonna CV et al.
[Pharmacovigilance report on a
topical heparin preparation]. Farmaci
1987;4:95-103.

57
4. Efficacy
Lioton
1000 gel 4.4 Efficacy assessment

Efficacy assessment in a post-marketing


surveillance survey
Global efficacy judgement

890 patients hospitalised with


50 venous or traumatic
pathologies with a clear pain
Physicians
component, with oedema,
Patients decreased functional capacity
40 44.1% 43.1% 42.6% and dystrophic skin
Lioton 1,000 I.U./g gel one to
38.1%
three times daily for at least
Percentage [%]

30 14 days. 48 % of patients
were treated with two daily gel
applications, 45.7% with three
daily gel applications.
20
Mean duration: 25.2 days
Open-label
14.4%
10
8.9%
4.4% 4.4%
Colonna CV et al.
0 [Pharmacovigilance report on a
Very good Good Fair Poor topical heparin preparation]. Farmaci
1987;4:95-103.

Efficacy of Lioton was assessed as very good or good in about


80 % of cases by both physicians and patients.

58
4. Efficacy
Lioton
1000 gel 4.4 Efficacy assessment

Efficacy assessment in a non-comparative study


in patients with chronic venous disease
Treatment efficacy judged by patients and physicians

Physicians Patients 20 patients with chronic


70 venous insufficiency, 9 with
lower limb ulcers
Lioton 1,000 I.U./g gel once a
60
day
60% 60% Duration: 30 days
50
Percentage [%]

40

30

30% 30%
20

10
10% 10%
Marrapodi E et al. [The usefulness of
0 percutaneous heparin management
Excellent Good Poor Excellent Good Poor in the phlebological therapy]. G Ital
Angiol 1986;6:115-22.

Efficacy of Lioton treatment was judged good/excellent in 90 %


of cases by physicians and patients.

59
4. Efficacy
Lioton
1000 gel 4.4 Efficacy assessment

Treatment efficacy judgment


Summary

Nearly all patients (90 %) were highly satisfied with the efficacy of Lioton
(Colonna et al., 1987; Marrapodi et al., 1986).
The efficacy of Lioton was judged as positive or very positive by over
80 % of physicians (Colonna et al., 1987; Marrapodi et al., 1986).
Overall, patients and doctors judge efficacy as excellent
(Marrapodi et al., 1986).

60
5. Safety
Lioton
1000 gel 5.1 Safety data

Safety data
Laboratory parameters

61
5. Safety
Lioton
1000 gel 5.1 Safety data

Data from the following studies are presented:

Author Year Patients Indication

Pola 1984 20 Varico phlebitis

Pola P et al. [Trend of blood and


plasma viscosity and serum lipids
following topical treatment with
heparin sodium]. G Ital Angiol
Milio 1985 30 Venous disease 1984;4:135-8.
Milio G et al. [Use of heparin sodium
in the form of a gel in nervous
disorders of the lower limb marked by
inflammation]. Acta Cardiol Medit
1985;3:283-8.

62
5. Safety
Lioton
1000 gel 5.1 Safety data

Interpretation of safety-relevant data


on heparin gel
Note:

When talking about the advantages of Lioton as a topical


heparin, it is important to emphasise that, despite the fact
that heparin is an anticoagulant, topical application has no
systemic effect on coagulation!

Thus, please bear in mind:


No change of coagulation parameters = no undesirable
systemic effect on blood circulation beneficial for safety
profile of Lioton.
A decrease in inflammatory parameters = desirable
anti-inflammatory action of heparin beneficial for Lioton.

63
5. Safety
Lioton
1000 gel 5.1 Safety data

Safety data in clinical trials (I)

Effects on haematological inflammation and


coagulation parameters
30 patients
Parameter Baseline Final % change p value
(mean + SD) (mean + SD) with varicophlebitis,
superficial thrombo-phlebitis
or periphlebitis
1 hour ESR 42 + 8 12 + 3 -71.6 < 0.001
(mm) Lioton 1,000 I.U./g gel three
times a day
Leukocytes 9.06 + 1.71 5.87 + 0.7 -35.2 < 0.001 Mean duration: 20.6 days
(000/mmc)

Coagulation time 6.90 + 0.64 6.86 + 0.72 -0.6 NS


(min)
ESR: erythrocyte
PTT 38 + 2 39 + 1 + 0.15 NS sedimentation rate
(sec)
PTT: partial thromboplastin
Platelets 229 + 47 225 + 44 -1.6 NS time
(000/mmc)
Milio G et al. [Use of heparin sodium
Prothrombin time 13.1 + 0.2 13.1 + 0.2 0.0 NS in the form of a gel in nervous
disorders of the lower limb marked by
(sec) inflammation]. Acta Cardiol Medit
1985;3:283-8.

Significant decrease in relevant inflammation markers


Unchanged coagulation parameters show that there is no systemic effect
on coagulation.

64
5. Safety
Lioton
1000 gel 5.1 Safety data

Safety data in clinical trials (II)

Effects on haematological coagulation and lipid parameters

20 patients with lower limb


Parameter Baseline 15 days 30 days p value varico-phlebitis
Prothrombin activity 12.5 (98%) 13 (95%) 12.5 (97%) NS Lioton 1,000 I.U./g gel three
times a day for 15 days and
PTT 39 40 38 NS twice a day for a further 15
days
Blood viscosity
Duration: 30 days
SR 171 sec-1 4.1 + 0.3 4.2 + 0.2 4.2 + 3 NS
SR 33 sec-1 5.8 + 0.5 5.9 + 0.6 6.1 + 0.6 NS
Plasma viscosity
SR 171 sec-1 1.3 + 0.1 1.3 + 0.2 1.4 + 0.1 NS
Total cholesterol (mg/dl) 231 + 45 228 + 39 235 + 51 NS PTT: partial thromboplastin
time
HDL-cholesterol (mg/dl) 51 + 10 50 + 9 53 + 12 NS
SR: shear rate
LDL-cholesterol (mg/dl) 146 + 22 148 + 27 150 + 20 NS
VLDL-cholesterol (mg/dl) 34 + 5 30 + 4 32 + 8 NS Pola P et al. [Trend of blood and
plasma viscosity and serum lipids
Triglycerides (mg/dl) 152 + 35 162 + 32 148 + 29 NS following topical treatment with
heparin sodium]. G Ital Angiol
1984;4:135-8.

Lioton treatment did not cause any significant change in laboratory


parameters, showing that topical application does not influence systemic
coagulation or lipometabolism.

65
5. Safety
Lioton
1000 gel 5.1 Safety data

Safety of Lioton gel


Summary

Topical application of Lioton does not influence systemic coagulation


(Milio et al., 1985; Pola et al.,1984).
Inflammation parameters decrease during topical treatment with Lioton
(Milio et al., 1985).
Both local and systemic tolerability is excellent (Lioton 1000 gel Patient
Information Leaflet, 2003).

66
5. Safety
Lioton
1000 gel 5.2 Tolerability assessment

Tolerability assessment
by physicians and patients

67
5. Safety
Lioton
1000 gel 5.2 Tolerability assessment

Tolerability assessment

Overall tolerability judgement by patients and physicians

890 patients hospitalised with


80 venous or traumatic
pathologies with a clear pain
Physicians component, with oedema,
70 decreased functional capacity
Patients and dystrophic skin
67%
60
Lioton 1,000 I.U./g gel one to
three times daily for at least
Percentage [%]

50 14 days. 48 % of patients
were treated with two daily gel
40 44.1% applications, 45.7% with three
42.6% daily gel applications.
30 Mean duration: 25.2 days
28.6% Open-label
20

10
2.6% 8.9% 2.4%
1.8%
Colonna CV et al.
0 [Pharmacovigilance report on a
Very good Good Fair Poor topical heparin preparation]. Farmaci
1987;4:95-103.

The tolerability of Lioton is assessed as good or very good by over 90% of physicians.
Nearly 90% of patients assessed the tolerability of Lioton as good or very good.

68
5. Safety
Lioton
1000 gel 5.2 Tolerability assessment

Tolerability assessment
Summary

Both patients and doctors report very good tolerability of Lioton


(Colonna et al., 1987).
Overall, physicians judge tolerability as very good
(Colonna et al., 1987).

69
Lioton
1000 gel

Impact of Lioton on subjective wellbeing

"Alleviation of subjective symptoms (pain sensation, burning-tingling


sensation, fatigue-heaviness sensation) could be seen in the
treatment group. A comparison of numeric values attributed on the
analogue scale to the subjective feeling of CVI symptoms showed a
statistically significant (p = 0.0003) reduction in feeling of symptoms
in the study period.
It seems that the use of treatment combining compression therapy
with oral phlebotropic drugs and topical application of heparin
elevates the quality of life of the patients through alleviation of
subjective symptoms." (Zieliski, 2009)
Zieliski M et al. [The effectiveness
assessment of sodium heparin gel
use, in the combined conservative
treatment of advanced chronic vein
insufficiency]. Leczenie Ran
2009;6:1-6.

Lioton as add-on to existing therapies relieved bothersome


symptoms in CVI patients, helping to improve subjective wellbeing.

70
Lioton
1000 gel

Summary of scientific data

For any further information, please contact:


Medical Marketing at HQ: Dr. Sanja Pavlovic-Masnikosa
Marketing at HQ: Edith Peters

71