dh16687 - monograph pages · mediator and cellular involvement. 1.1. allergic phases the role of...

Atopic diseases, ie, primarily, allergic rhinoconjunctivitis,bronchial asthma, atopic dermatitis, and urticaria, were rare a few decades ago, but constitute today an increasingly severepublic health problem. The World Health Organization and theWorld Allergy Organization are concerned about the highprevalence of allergic disease, which has reached 40% in many countries.

Allergic diseases can affect many organs and systems with both histamine and allergic inflammation playing important roles in symptom development and severity. Treatment with antihistaminic and anti-inflammatory drugs is required andmost beneficial.

Levocetirizine (Xyzal®) is the active enantiomer of the well-established, second-generation antihistamine, cetirizine.Xyzal® is approved for the symptomatic treatment of allergicrhinitis (including persistent allergic rhinitis) and chronicidiopathic urticaria. It has been approved in some Europeancountries in children from 2 years of age (approval pending in other countries).

This scientific monograph offers a useful background to themechanisms of allergy, allergic rhinitis and urticaria, anddocuments the research and clinical development programmethat has resulted in the launch and success of Xyzal®.

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Foreword

Allergy 06

1. Allergic mechanisms 071.1. Allergic phases 071.2. Allergic inflammation 081.3. The nose versus the skin 10Summary 11

2. Allergic diseases 122.1. Allergic rhinitis 122.2. Urticaria 14Summary 16

3. Management of allergic diseases 183.1. Drug treatment of allergic rhinitis 19

3.1.1. Challenge models evaluating drug treatmentsfor allergic rhinitis 20

3.1.2. Clinical studies evaluating drug treatments for allergic rhinitis 21

3.2. Drug treatment of chronic urticaria 213.2.1. Challenge models evaluating drug treatments

for chronic urticaria 213.2.2. Clinical studies evaluating drug treatments

for chronic urticaria 223.3. Allergic disease management in children 23Summary 24

Levocetirizine 26

4. Pharmacology of levocetirizine 264.1. Receptor binding affinity of levocetirizine 264.2. Pharmacokinetics of levocetirizine 27

4.2.1. Absorption 274.2.2. Bioavailability 274.2.3. Distribution 284.2.4. Metabolism 284.2.5. Elimination 28

Summary 29

5. Anthihistaminic properties of levocetirizine 305.1. Histamine nasal provocation studies 305.2. Facial thermography with histamine nasal provocation 305.3. Allergen nasal provocation studies 335.4. Allergen challenge chambers (ACC) 355.5. Histamine-induced wheal and flare studies 38Summary 44

6. Anti-inflammatory properties of levocetirizine 466.1. In vivo studies 46Summary 48

7. Clinical efficacy of levocetirizine 507.1. Clinical studies in seasonal allergic rhinitis (SAR) 507.2. Clinical studies in perennial allergic rhinitis (PAR) 517.3. Clinical studies in persistent allergic rhinitis (PER) 527.4. Clinical studies in chronic idiopathic urticaria 547.5. Clinical studies in paediatrics 55Summary 58

8. Contribution of levocetirizine to improvement in patients’ Quality of Life 60

8.1. Improvement in quality of life in adults 608.2. Improvement in quality of life in urticaria 618.3. Improvement in quality of life in children 62Summary 64

9. Contribution of levocetirizine to improvement in health-economic savings 66

9.1. Health-economic savings in allergic rhinitis 669.2. Health-economic savings in chronic urticaria 67Summary 68

10. Safety 7010.1. Undesirable effects 7010.2. CNS safety 7010.3. Cardiac safety 7110.4. Interaction with other medicinal products and

other forms of interaction 71Summary 72

Summary of product characteristics 74

Bibliography 78

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Contents

Allergy refers to an acquired potential of the organism todevelop immunologically mediated adverse reactions tonormally harmless substances. An allergen is defined as either the source of an allergy-producing substance,the allergy-producing substance itself, or one or more of thespecific proteins that make up the substance and provoke theimmune response. Allergens, eg, pollens, house dust mites,animal dander, moulds, foods, medicines and chemicals,can enter the body through a number of routes: by inhalation,ingestion, contact with the skin, or injection.

Allergy is characterised by a hypersensitivity reaction thatoccurs upon re-exposure to the sensitising allergen, causingthe release of inflammatory mediators, which, on their part,provoke symptoms. The clinical outcome depends on thesystem or part of the body involved. The resulting symptomsexperienced by the patients, eg, itching, skin rash, coughing,wheezing, difficulties breathing, sneezing, blocked nose, wateryeyes, fatigue, are always annoying, frequently debilitating, and,in some cases, could be life threatening (eg, hypotension andoedema related to anaphylaxis and shock).

Allergic diseases are among the most frequent humanpathologies reaching a prevalence of 40% in many countries,with children and adolescents generally affected more than the elderly. Over the last several decades there has been a constant increase in the prevalence of allergic rhinitis,asthma and atopic dermatitis. Many patients suffer from more than one allergic disease. In the UK, 11% of children (2 to 15 years), 10% of young adults (16 to 44 years) and 5% of older adults (45+ years) have been diagnosed withmore than one atopic disorder1. Generally, approximately 40% of the patients suffering from allergic rhinitis also sufferfrom allergic asthma and around 80% of asthmatics are also diagnosed with having allergic rhinitis2.

On a daily basis, allergies cause time lost from work, school,and leisure activities and decrease productivity at work,at school, and at home. Allergic diseases can be controlled with appropriate treatment; symptoms can be prevented orminimised. Learning what triggers allergies and understandinghow to treat the diseases may make the difference between a chronic debilitating illness and a productive, healthy lifestyle.

Although diagnosis is relatively easy, especially with skinallergies, many cases (approximately 50%) of respiratoryallergies remain undiagnosed. Evidence supports a directrelation between allergic rhinitis and allergic asthma.The ‘unified airway disease’ theory holds that these areessentially two forms of the same systemic inflammatoryprocess directed toward different organ systems. Thus, allergicrhinitis should be promptly diagnosed and managed not only in order to decrease the bothersome symptoms of rhinitis butalso to avoid the development of allergic co-morbidities.

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Allergy

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All allergic conditions, regardless of the involved organ,share common inflammatory mechanisms. The latter arecharacterised by stepwise developing phases with variousmediator and cellular involvement.

1.1. Allergic phases

The role of the immune system is to protect us from harmfulexternal aggressors, eg, viruses, bacteria, and parasites.Similarly, many allergens, such as pollen and house dust mite,are proteolytic enzyme aggressors that attack mucosalmembranes, the response to which is an allergic reaction,mounted by the immune system, which stimulates a localinflammatory response. The latter makes the local environmenthostile to the invader (the early phase response) andrecruits eosinophils and other cells to attack the allergen(allergic inflammation).

Upon invasion of the mucous membranes by an allergen,eg, pollen or house dust mite ([1] and [2], respectively,Figure 1.1), which cross-links with IgE bound to its high affinity receptor (FcεR1), mast cells [3] are activated to releasethe inflammatory mediators of the allergic response,

with histamine being dominant. The interaction of histaminewith the H1-receptors on the sub-epithelial tissues causesarteriolar vasodilation [4], leakage of proteins into theextravascular space from post-capillary venules (oedema) [5],sensory nerve stimulation (itch) [6] and mucus secretion [7].As all these events occur within minutes of allergic exposurethey are termed collectively ‘the early phase allergicresponse’. The nasal clinical symptoms characteristic of this response are mucosal oedema, rhinorrhoea, sneezing,nasal itch, and oedema-associated obstruction, whereas theskin symptoms are intense itch, wheals and flares.

The early phase response is followed by the increasedproduction of eosinophils by the bone marrow and increasedexpression of cell adhesion molecules, eg, intercellular adhesion molecule-1 (ICAM-1) and the vascular cell adhesionmolecule-1 (VCAM-1), which facilitate the adhesion ofcirculating leukocytes to the endothelial cells.

1. Allergic mechanisms

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Figure 1.1. The early phase response to allergen challenge.

1. Pollen; 2. House dust mite; 3. Mast cells; 4. Arteriolar vasodilation; 5. Leakage of proteins into the extravascular space from post-capillary venules (oedema); 6. Sensory nerve stimulation (itch); 7. Mucus secretion.

In addition, cytokines and chemokines, formed by immune cells (eg, monocytes and lymphocytes), promote migration of cells (eosinophils, neutrophils, basophils, T lymphocytes,macrophages) to the sites of inflammation where they migratefrom the blood vessels or through the tissues ([3] and [4],respectively, (Figure 1.2) and infiltrate the mucosa. Hours afterallergen exposure (pollen [1] and house dust mite [2]),these cells become activated, and release inflammatorymediators, including those that initiated the early-phase,eg, histamine, in an attempt to drive away the allergen ([5]).This cellular-driven late inflammatory reaction is termed the‘late phase allergic response’. This reaction may beclinically indistinguishable from the immediate reaction,especially with skin allergy; however, nasal congestion tends to predominate.

1.2. Allergic inflammationAllergic inflammation is initiated and maintained by theaccumulation and activation of eosinophils in the tissues(Figure 1.3). Via their granule-associated substances,eg, major basic protein (MBP), eosinophil cationic protein (ECP)

and eosinophil derived neurotoxin (EDN), and through the denovo formed leukotriene C4 (LTC4), eosinophils aggravate thesymptoms of allergy and make the tissues hyper-responsive.In the nose, allergic inflammation aggravates, in particular,nasal obstruction, and renders the nose hyper-responsive tonon-allergic stimuli, eg, cold air, smoke and dust. In the lungallergic inflammation causes major structural changes,which characterise asthma and that cannot be readily reversed.

The transcription factor, nuclear factor-kappa B (NF-κB),is widely recognised as a critical mediator of immune andinflammatory responses. It is normally in a resting state on thesurface of the cellular membrane; however, it can be activatedby histamine or tumour necrosis factor alpha (TNFα) afterwhich it migrates to the cellular nucleus where it stimulates thetranscription of messenger RNA for pro-inflammatory cytokinesand adhesion proteins (Figure 1.4A). Prevention of NF-κBactivation is a primary mechanism of the anti-inflammatoryactivity of corticosteroids. Also, the anti-inflammatory activity of H1-antihistamines is suggested to involve an inhibition of theNF-κB activation (Figure 1.4B).

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Figure 1.2. Eosinophil migration during the late phase response to allergen challenge.

1. Pollen; 2. House dust mite; 3. Blood vessels; 4. Tissues; 5. Eosinophils driving away the allergen.

E-SelectinICAM-1VCAM-1IL-8GM-CSFTNFα

EosinophilsNeutrophils

INFLAMMATIONINFLAMMATIONINFLAMMATION

Activation

HistamineTNFα

NF-κB INFLAMMATIONINFLAMMATIONINFLAMMATION

Antihistamine

NF-κB

E-SelectinICAM-1VCAM-1IL-8GM-CSFTNFα

EosinophilsNeutrophils

Figure 1.4. Activation of NF-κB leading to inflammation (A) and the inhibitory effects of antihistamines on NF-κB (B).

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This effect is a result of the H1-receptor inhibiting activity ofantihistamines. Although these effects are weaker than those of corticosteroids, they may explain why regular and long-termtherapy with H1-antihistamines ameliorates the symptoms ofallergic rhinitis better than when used ‘as required’. It alsoexplains why the effects are most obvious with the more potent antihistamines.

To appreciate how drugs may reduce allergic inflammation,it is first necessary to understand the cellular and biochemicalmechanisms underlying its development. The basic cellularmechanisms are illustrated in Figure 1.3. The blood vesselendothelial cells have been stimulated by TNFα and histamine,which express, via NF-κB, the adhesion proteins, E-Selectin,ICAM-1 and VCAM-1 [1]. Eosinophils [2], primed by cytokines

released into the circulation, initially adhere loosely to theendothelium and then undergo a shape change as theirattachment becomes more firm [3]. Then they force their wayout of the vasculature [4] and migrate towards the focus of the allergic response [5].

Before the cellular events illustrated above can proceed, it isfirst necessary to increase the production of the cytokines,such as interleukin-8 (IL-8), granulocyte macrophage-colonystimulating factor (GM-CSF), and (TNFα), that drive allergicinflammation, as well as adhesion proteins, such as E-Selectin,ICAM-1 and VCAM-1, which allow inflammatory cells to adhereto the vascular endothelium prior to their migration into thetissues. This process is initiated by the activation of a numberof transcription factors, NF-κB being one of the most important.

TNFα Histamine

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Figure 1.3. The cellular mechanisms of allergic inflammation: eosinophil extravasation and migration.

1. Adhesion proteins, E-Selectin, ICAM-1 and VCAM-1; 2. Eosinophils; 3. Eosinophils undergoing a shape change; 4. Eosinophils forcingtheir way out of the vasculature; 5. Eosinophils migrating towards the focus of the allergic response.

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Figure 1.5. Histamine diffuses freely through the relatively ‘loose’ nasal mucosa and therefore, does not reach highconcentrations locally.

1.3. The nose versus the skin

Figure 1.6. Diffusion of histamine in the skin is no more than a millimetre from its site of release resulting in very highlocal histamine concentrations.

For effective relief of urticaria symptoms, the most effective H1-antihistamines are usually necessary, while the less potentare usually sufficient in allergic rhinitis. The reason for thesedifferences between the tissues lies in the different ability ofhistamine to diffuse through them.

While the effects of the relatively small concentrations of histamine in the nasal mucosa (Figure 1.5) can be

counteracted by any antihistamine in relatively small doses,the tough and impermeable skin confines histamine to the sites of its release (Figure 1.6); therefore, more potentantihistamines (sometimes at higher doses) are necessary forthe relief of urticaria symptoms caused by the relatively highhistamine concentrations in the skin. Severe allergic rhinitisalso requires potent antihistamines.

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Summaryn Allergy, caused by proteins or other substances called

allergens, is an inappropriate and harmful response to a normally harmless substance

n Common allergens can be pollens, dust mites, animals,moulds, food, medicines and chemicals

n Common allergic diseases include asthma, allergicrhinoconjunctivitis, urticaria and atopic dermatitis

n Histamine, the major mediator released during both theearly and the late phase allergic reactions, is responsiblefor most of the allergic symptoms regardless of the organ affected

n Allergic inflammation is initiated by the activation of a number of transcription factors (eg, NF-κB) and cells (eg, accumulation and activation of eosinophils in the tissues)

n Treatment of urticaria and severe allergic rhinitis issuccessful with potent antihistamines, whereas milderforms of allergic rhinitis can be treated more easily.

Further readingLeurs R, Church MK. Tagliatela M. H1-anti-histamines: inverse agonism,anti-inflammatory actions and cardiac effects. Clin Exp Allergy 2002;32:489–98.

Church MK, Lichtenstein LM, Simon H-U. Wardlaw AJ, Haslett C, Lee TH,Hawrylowicz CM. (2000). Effector Cells of Allergy. In Allergy 2nd Edition (Eds: Holgate ST, Church MK, Lichtenstein LM), pp. 303–24. London: Mosby).

O’Byrne P, Persson CGA, Church MK. (2000). Cellular and MediatorMechanisms of the Allergic Inflammation. In Allergy 2nd Edition (Eds: HolgateST, Church MK, Lichtenstein LM), pp. 325–36. London: Mosby).

Miller S, Busse WW, Holgate ST. (2000). Drugs for the Treatment of AllergicDisease. In Allergy 2nd Edition (Eds: Holgate ST, Church MK, Lichtenstein LM),pp. 337–52. London: Mosby).

Downs SH, Marks GB, Sporik R, Belosouva EG, Car NG, Peat JK.Continued increase in the prevalence of asthma and atopy.Arch Dis Child 2001;84: 20–3.

Dykewicz MS, Fineman S. Diagnosis and management of rhinitis: parameterdocuments of the Joint Task Force on Practice Parameters in Allergy,Asthma, & Immunology. Executive Summary of the Joint Task Force on Practice Parameters on Diagnosis and Management of Rhinitis.Ann Allergy Asthma Immunol 1998;81(Suppl):463–8.

Gupta R, Sheikhw A, Strachan DP, Anderson HR. Burden of allergic disease in the UK: secondary analyses of national databases.Clin Exp Allergy 2004;34:520–6.

Petersen LJ, Church MK, Skov PS. Histamine is released in the wheal but not the flare following challenge of human skin in vivo: a microdialysis study.Clin Exp Allergy 1997;27(3):284–95.

2.1. Allergic rhinitis

Allergic rhinitis is a major health problem affectingapproximately 20% of the general population in Western Europe (European Community Respiratory Health Survey) withindividuals between 15 and 25 years old being the mostaffected age group. It is characterised by local nasal mucousmembrane symptoms. It is often associated with severeimpairment in a patient’s quality of life, and it can be an important cause of school and work absenteeism,resulting in major socioeconomic implications. Furthermore,this inflammatory disease may compromise normal sleep,productivity, and performance at work or school, and mayimpair a broad range of cognitive functions. Importantly, allergicrhinitis can be the local manifestation of a systemic allergiccondition, and, therefore, co-morbidities are common.The prevalence rate of allergic rhinitis in children with otitismedia with effusion is 50%3, whilst that in children and adults with asthma is >80%. Since histamine and allergicinflammation play important roles in symptom development and severity of allergic rhinitis, treatment with drugs thathave antihistaminic and anti-inflammatory properties is normally required.

The same mechanisms that cause airway inflammation in thelungs (asthma) cause allergic rhinitis, which, especially in itsintermittent/seasonal form, is probably the most classical IgE-mediated disease. Most of the major effects in the nose,eg, rhinorrhoea, itching and sneezing, and in the eye,eg, redness and itching, are a direct consequence of the actionof mast cell-derived histamine (Figure 2.1). All these symptomscan be relieved by H1-antihistamines. Nasal obstruction,a major feature of allergic rhinitis, is caused by a more complexmechanism, where histamine is partially involved. The majorcomponent of obstruction is the dilatation [1] of the normallysmall venous capacitance vessels [5], which significantlyincreases tissue mass with poor response to traditionalantihistamine treatment. The other components, arteriolarvasodilatation [2], excess secretions [3], which physicallyimpede airflow, and tissue oedema [4], are histamine-mediatedand can be influenced by antihistaminic drugs.

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2. Allergic diseases

Figure 2.1. Allergic reactions in the nasal mucosa leading to rhinitis symptoms.

1. Dilatation of venous capacitance vessel; 2. Arteriolar vasodilatation; 3. Excess secretions; 4. Tissue oedema; 5. Normal capacitance vessel.

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Symptoms of allergic rhinitis occur in twophases, early and late.

The early phase symptoms (occur within minutes of exposure):

n Rhinorrhoea (runny nose)

n Sneezing (frequent or repetitive)

n Itching in the nose, eyes, throat, or palate

n Oedema-associated obstruction.

The late phase symptoms (occur 4 to 8 hours after exposure):

n Inflammatory (cellular) nasal obstruction

n Fatigue / tiredness

n In some cases irritability, a slight decrease in attention,worsened memory, and slower thinking

n Other symptoms: decreased sense of smell, plugged ears,sinus headache, and post-nasal drip. In severe allergies,dark circles under the eye. The lower eyelid may be puffyand lined with creases.

Allergic rhinitis has historically been divided in two types,seasonal allergic rhinitis (SAR) and perennial allergic rhinitis(PAR), based on the time and duration of exposure to theoffending allergen. However, with a better understanding of the mechanisms of allergic rhinitis and, in particular the role of allergic inflammation, this classification has becomeunsatisfactory.

Studies have shown that in the nose of patients with allergicrhinitis, like those with asthma, minimal persistent inflammationmay be present even in the absence of symptoms or allergenexposure. In these patients treatment must be continued forweeks or even months after their symptoms have subsided,regardless of the type of allergic rhinitis.

As a consequence, in 2001 the ARIA (Allergic Rhinitis and itsImpact on Asthma) group, in collaboration with the WHO (World Health Organization), decided on a new classification,which is based on the duration of symptoms, and the patient’squality of life, rather than on the duration of allergen exposure(Figure 2.2).

This new classification divides allergic rhinitis into intermittentand persistent forms, each of which are sub-divided into mildand moderate-severe. Details of this new classification and itsconsequences for treatment are contained in a Pocket Guideentitled ‘Management of allergic rhinitis and its impact onasthma’ details of which may be found on the ARIA website(www.whiar.com). In this monograph, both classifications havebeen used depending on the terms used by the authors of theoriginal studies presented.

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ARIAClassification of allergic rhinitis (in untreated patients)

Bousquet J Van Cauwenberge P, Khaltaev N. ARIA Workshop Group, World Health Organization. Allergic rhinitis and it’s impact onasthma. J Allergy Clin Immunol 2001;108:S147-334. Adapted from the ARIA official slide kit, slide No. 20 - Used with permission.

Intermittent

<4 days per weekor<4 weeks

Mild

n Normal sleep

n No impairment of daily activities, sport, leisure

n Normal work and school

n No troublesome symptoms

Persistent

≥4 days per weekand≥4 weeks

Moderate to severe (one or more times)

n Abnormal sleep

n Impairment of daily activities, sport, leisure

n Abnormal work and school

n Troublesome symptoms

Figure 2.2. The new classification of allergic rhinitis (according to ARIA).

2.2. Urticaria

Urticaria or ‘nettle rash’ is a common condition affecting up to20% of individuals at some time in their life, and should not be seen as a single condition, but as a syndrome, as there are many underlying aetiological factors and mechanisms.It is a transient (usually disappearing within 24 hours) butrecurrent skin eruption composed of erythematous papules oranaemic (blanched) papules (hives, wheals) with surroundingerythema due to circumscribed oedema of the upper dermis.It is characterised by pruritus (itch) with or without pain andburning, which can be especially bothersome in the evenings and at night.

The trunk and extremities are the most common sites,but lesions may appear anywhere. Urticaria symptoms areoften accompanied by angioedema (acute localised swelling of subcutaneous or submucosal tissue) and may be daily orepisodic. The hives are distressing, and the angioedema can beworrying for patients who fear the possibility of choking and death.The disability of patients with chronic urticaria, as evidenced bylack of energy, social isolation, emotional reactions and sleepdisruption, can be as severe as that experienced by patientsawaiting triple coronary bypass surgery4.

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Urticaria symptoms are caused by the release of largeamounts of cutaneous mast cell-derived histamine [1] (Figure 2.3), which causes localised oedema [2] giving rise tothe wheal. Histamine also activates sensory nerves [3], whichleads to two effects: firstly, it stimulates the itch response orpruritus [4], which is usually the most bothersome symptom of urticaria; and, secondly, it causes initiation of axon reflexes [5] that results in the release of neuropeptides [6]causing widespread neurogenic erythema or flare.

Some forms of urticaria are allergic in origin with mostly foodsor drugs acting as allergens. Allergic urticaria is usually acuteand, in most patients, a correlation with the causal agent iseasy to make. In chronic urticaria, however, it is more difficult to determine the cause. In many cases, possibly up to 60%, auto-antibodies against IgE or the IgE-receptor on the mast cells are usually the cause. However, in other cases,correlation with a causative agent is never made and patients are diagnosed as having chronic idiopathic urticaria(Figure 2.4).

Another common group are the physical urticarias, in which the precipitating factors can be cold, heat, different types of skin pressure or sun exposure. Physical urticarias canaccompany chronic idiopathic urticaria or they can exist asindividual conditions.

Figure 2.3. The epidermis and upper layers of the dermis with urticarial lesions.

1. Mast cell-derived histamine; 2. Localised oedema; 3. Activation of the sensory nerves; 4. Stimulation of pruritus; 5. Initiation ofaxon reflexes; 6. Release of neuropeptides.

Figure 2.4. Chronic idiopathic urticaria.

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Summaryn Allergic diseases are a major health problem in the

developed world

n Impaired quality of life due to allergic rhinitis and chronicidiopathic urticaria is a cause of school and workabsenteeism with major socioeconomic implications

n The disability caused by chronic idiopathic urticaria,as evidenced by lack of energy, social isolation, emotionalreactions and sleep disruption, could be as severe as thatreported by patients with cardiovascular disease

n Symptoms of allergic rhinitis (eg, rhinorrhoea, nasal itchingand sneezing, ocular redness and itching) and of chronicidiopathic urticaria (eg, itching, wheals and flare) are a direct consequence of histamine action

n Nasal obstruction is caused by a more complex mechanism,where histamine is also, albeit partially, involved

n Allergic rhinitis is frequently the local manifestation of a systemic disease with a number of co-morbidities

n Persistent allergic rhinitis (as defined by ARIA) is the mostserious and debilitating form of rhinitis

n Treatment of moderate-severe allergic rhinitis and chronicidiopathic urticaria is successful with drugs that havepotent antihistaminic and anti-inflammatory properties.

Further readingBauchau V, Durham SR. Prevalence and rate of diagnosis of allergic rhinitis inEurope. Eur Respir J 2004;24:758–64.

Bousquet J, Van Cauwenberge P, Khaltaev N; Aria Workshop Group; World Health Organization. Allergic rhinitis and its impact on asthma.J Allergy Clin Immunol 2001;108(Suppl 5):S147–334.

Bousquet J, Jacot W, Vignola AM, Bachert C, Van Cauwenberge P. Allergic rhinitis: A disease remodelling the upper airways? J Allergy Clin Immunol 2004;113:43–9.

Downie SR, Andersson M, Rimmer J, Leuppi JD, Xuan W, Akerlund A, Peat JK,Salome CM. Association between nasal and bronchial symptoms in subjectswith persistent allergic rhinitis. Allergy 2004:59:320–6.

O'Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact ofchronic urticaria on the quality of life. Br J Dermatol 1997;136:197–201.

Roland P, McCluggage CM, Schneider GW. Evaluation and Management ofAllergic Rhinitis: A Guide for Family Physicians. Texas Academy of FamilyPhysicians (Monograph) 2001.

Schoenwetter WF, Dupclay L Jr, Appajosyula S, Botteman MF, Pashos CL.Economic impact and quality of life burden of allergic rhinitis.Curr Med Res Opin 2004;20(3):305–17.

Skoner DP. Allergic rhinitis: Definition, epidemiology, pathophysiology,detection, and diagnosis. J Allergy Clin Immunol 2001;108 (Suppl 1):S2–8.

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3. Management of allergic diseases

Figure 3.1. Most widely used general and specific QoL instruments in the treatment of allergic diseases.

SF-36 = Short-Form questionnaire with 36 questions; SAT-P: Satisfaction Profile; SIP = Sickness Impact Profile; RQLQ = Rhinoconjunctivitis QoL Questionnaire; PRQLQ = Paediatric Rhinoconjunctivitis QoL Questionnaire; DLQI = Dermatology Life Quality Index.

Health Status and Quality of Life Instruments

Could be combined for a more complete assessment of disease burden and treatment outcomes

General Specific

SF-36, SAT-P, SIP RQLQ, PRQLQ, DLQI

n Less sensitive to symptom changes

n Allow comparisons between diseases

n Could be used in any disease

n More sensitive to symptom changes

n Used for comparisons between treatments

n Restricted usually to one disease only

There are three reasons that can be identified for treatingpatients: to increase longevity, to reduce the probability of futuremorbidity and to improve a patient’s well-being. Especiallyrelevant are the prevention of future morbidity, co-morbidities,and the improvement of patient’s quality of life (QoL).

Symptomatic relief has been traditionally the main goal ofallergy treatment with the individual symptoms or their totalscores (eg, Total 4 Sympton Score and Total 5 Sympton Score)being the primary parameters of clinical studies. Safety hasalso been a major target for assessment.

General and specific instruments are available for assessingHealth-Related QoL (HRQoL) and the general impact of boththe allergic disease and its treatment on patients’ dailyactivities, as perceived by the patients themselves5.

General questionnaires, eg, SF-36, can be administered topersons in every clinical condition, thus allowing health statuscomparisons between patients affected by different diseasesand the normal population. Generic instruments are notdesigned to detect very small changes in general health status (Figure 3.1). On the other hand, specific instruments,eg, RQLQ (Rhinoconjunctivitis QoL Questionnaire), PRQLQ(Paediatric RQLQ), DLQI (Dermatology Life Quality Index),describe the patients’ difficulties due to a specific disease and detect relatively small changes in HRQoL (Figure 3.1)6.

Four general principles are used for managing allergic diseases:

n Educate the patient and appropriate caregiver(s) how tominimise exposure and to follow treatment regimens

n Avoid or minimise exposure to allergens and irritantsthrough environmental control

n Use the right medication with proven efficacy in challengemodels and clinical trials

n Evaluate for allergen immunotherapy.

The established first-line therapy for allergic diseases are theantihistamines, substances having the capacity to prevent orcontrol histamine-mediated symptoms such as sneezing,rhinorrhoea, nasal and conjunctival itching and lacrimation(allergic rhinitis) and itching, wheal and flare (urticaria).Additional anti-inflammatory effects with the newer generationantihistamines have also been described.

Though the members of this class of medications are allreferred to as ‘antihistamines’, they differ substantially in theirpharmacology and clinical efficacy. Even among the newgeneration antihistamines, differences exist in terms of H1-affinity, pharmacokinetic behaviour, pharmacodynamicperformance, onset and duration of action, clinical efficacy,scope of indicated allergic pathologies (as proven via clinicaltrials or labelling differences), side-effects profile, etc. Thus, theselection of any one of these agents should be made, especiallyfor the large majority of patients who have persistent disease,in consultation with an experienced healthcare practitioner.

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3.1. Drug treatment of allergic rhinitis Because allergic rhinitis is not a life-threatening condition, someclinicians may not pay enough attention to optimal management.Therefore, many patients suffer needlessly. Allergic rhinitis notonly causes uncomfortable symptoms with a marked reductionin quality of life, but also may cause complications, such asheadache, sleep disturbance, and sinusitis, which cause further discomfort and economic losses (due to reduced workproductivity and absenteeism from work). Co-morbidities, eg,asthma, otitis media, and upper respiratory infections, can beaggravated by an undiagnosed and untreated allergic rhinitis.

Importantly, recent data suggest that, in patients with asthma,treatment of concomitant allergic rhinitis may reduce the

frequency of asthma exacerbations with significant reductionsin the risk of emergency room treatment and hospitalisation forasthma. Published results imply that 47% of subjects treatedfor their allergic rhinitis do not report an asthma-related event7.

The responsiveness to drug therapy of allergic rhinitis depends largely on its severity and on the properties of themedications used.

In mild to moderate forms of allergic rhinitis, antihistamines are the drugs of choice. In the more severe or prolonged forms(eg, persistent rhinitis), a potent antihistamine or a nasalcorticosteroid, both of which may relieve venous congestion,probably by reducing the severity of allergic inflammation,should be used.

Table 3.1. Requirements for antihistamines in the treatment of allergic rhinitis (adapted from8).

Scope Requirements

The pharmacodynamic, pharmacokinetic, clinical efficacy properties and safety of the anti-allergic medications can be evaluated invarious models and clinical settings. The most reliable and widely used evaluation methods are discussed in chapter 3.1.1.

Pharmacologic properties n Potent and selective H1-receptor blockaden Additive anti-allergic activities (see below)n No clinically relevant pharmacokinetic interference with foods, medications or intestinal

transport proteinsn No known interaction with cytochrome P4503A (CYP3A).

Pharmacodynamics n Rapid onset of actionn Long duration of action (sustained efficacy at the end of the 24-hour dosing period)n No tolerance (tachyphylaxis).

Efficacy n Confirmed efficacy in clinical trials for the treatment of intermittent and persistent rhinitis (as per ARIA) and of seasonal and perennial rhinitis (older classification)

n Effective for all nasal symptoms including nasal obstructionn A demonstrated reduction of asthma exacerbations in long-term studies

(if efficacy in asthma is claimed)n Should be evaluated not only in adults but also in children.

Anti-allergic effects n Should be linked to a clinical benefit (eg, corticosteroid sparing effect in asthma,relief of nasal congestion in long-term persistent rhinitis studies, etc.)

n Demonstrated as inhibitory effects on pro-inflammatory mediators and/or inflammatorycells, adhesion molecules or cytokines in nasal or ocular secretions/tissues

n Demonstrated during allergen chamber challenge or natural allergen exposuren Demonstrated at the recommended therapeutic doses.

Side effects n No sedation, cognitive or psychomotor impairmentn No anti-cholinergic and no cardiac side effectsn Clinical trial safety data in young childrenn Prospective post-marketing safety analyses.

3.1.1. Challenge models evaluating drugtreatments for allergic rhinitis

Histamine nasal provocation studies evaluate the activityof drugs against histamine effects, the most important mediator of allergic rhinitis, in the nose of healthy individuals.The strengths of such studies are that they provide importantdata about the pharmacodynamic parameters of drug actionand allow reliable comparisons to be made betweenmedications under controlled conditions. The weakness ofhistamine provocation studies is that they are performed on healthy volunteers and do not take into account thecontribution of other inflammatory mediators also released in the tissues and involved in symptoms development.

Facial thermography (FT) is a new non-invasive technique,which objectively records very small changes in nasal skintemperature associated with vasodilation resulting from anintranasal histamine or allergen challenge9. Vasodilatation, oneof the main effects of histamine in the tissues, is associatedwith an increase in local temperature. As a consequence,changes in nasal temperature induced by histamine provocationmay be used as a marker of the intensity of the actions ofhistamine in the nose. Facial thermography uses an infraredthermographic camera, which scans and averages thetemperature of the skin area under investigation.The temperature changes can be represented either graphicallyor calorimetrically (Figure 3.2). Vascular response is animportant element of allergic reactions as nasal congestion is largely a vascular phenomenon.

Nasal allergen challenge studies are a step closer to clinicaldisease as they use real patients with asymptomatic, ‘out ofseason’, allergic rhinitis.

Intranasal allergen challenge is a technique in whichallergen is sprayed or administered by drops directly into the nose10. The advantage of these studies is that the patientsare treated individually, and detailed objective measurements of symptoms and nasal function can be made. The majorweakness is that a large quantity of allergen is administeredover an extremely short period in order to produce symptoms of a sufficient severity for objective measurements to be taken.

Allergen challenge chambers (ACC) mimic more closelya real-life situation of allergen exposure. Each chamber is a specially constructed room in which a variable number of asymptomatic patients may be exposed to a constantconcentration of allergen over several hours. The greatadvantage of ACC is that they allow the simultaneous challengeof a large group of individuals at a time with fixed andreproducible concentrations of allergen, under rigorouslycontrolled conditions. Also, compliance is ensured andrecording of the data is optimal, as the patients are under closeobservation for the entire period. Thus, they are essentially half way between intranasal challenge models and clinicalstudies where allergen exposure varies greatly with climaticand environmental conditions. The major limitation of thesechambers is that, although the periods of allergen exposure are much longer than in intranasal challenge models, they areshorter than the days, weeks or, possibly months of exposure in true disease. Two major ACCs have been widely used:the Vienna Challenge Chamber (VCC™) and the EnvironmentalExposure Unit (EEU™).

20

Figure 3.2. Thermographic recordings.In these pictures, low temperatures are seen as black and purple while higher temperatures are indicated by yellow, red and white.Before histamine provocation, the nose is colder than the rest of the face but 10 minutes after provocation it appears much warmer.

Before provocation 10 minutes after provocation

35

30

25

37.0˚C

25.0˚C

21

3.1.2. Clinical studies evaluating drugtreatments for allergic rhinitis

The classical clinical studies, evaluating the effect of drugsin patients with active disease under natural allergen exposureconditions, have been traditionally the ultimate ‘gold standard’for drug testing. These studies usually evaluate the classicalrhinitis symptoms of rhinorrhoea, sneezing, nasal and ocularpruritus, combined in a Total 4 Symptom Score (T4SS).In practice, however, nasal congestion, is one of the mostbothersome symptoms for patients with allergic rhinitis andwhen added to the previous 4 symptoms, the Total 5 Symptomscore (T5SS) is formed. Safety is by default always reportedeither as spontaneous adverse events or as part of thesymptom reporting. There are some potential confoundingfactors that make reproducible results difficult to obtain withthese classical studies. For example, patient compliance totreatment and the recording of data may be not as accurate as in a laboratory situation because the patients are notsupervised at all times. Also in real life situations, the constantchanges in allergen levels with the weather cause highvariations in the responsiveness of individuals to treatment.

In order to overcome these limitations a new approach ofconducting more complete clinical studies has recentlygained popularity. Multiple measures in the same patientpopulation over time are usually needed to establish a morecomplete patient response profile to treatment. Patients’ QoL,patients’ medication preferences, work productivity, and costeffectiveness of treatment, among many, are measures thathelp us achieve an overall evaluation of treatment outcomesthat reflect better real life situations and are becomingindispensable for clinical research. Generation of complete set of data in the same patient population, over the same long-term period of time, in the same environmental conditions,using the same methods and analysis, in a highly-controlledand double-blind fashion, can only be achieved with a completestudy that looks at the patient as a social human being with his/hers perceptions, expectations, quality of life andeconomic interests.

Overall health-care costs for allergic rhinitis, which areconstantly increasing, include direct costs, ie, costs related to patient care, eg, medications, hospitalisations,physician’s visits, etc, and indirect costs, ie, costs of diseaseconsequences, such as absenteeism and reduced productivityat school or work. In addition, there are ‘hidden costs’ ofallergic rhinitis, such as those related to its tendency to lead to inflammatory airway diseases and respiratory complications

and those related to the adverse effects of over-the-countersedating antihistamines and decongestants used in self-treatment. When possible, cost savings due to treatment of allergic rhinitis should be evaluated and reported.

3.2. Drug treatment of chronic urticaria

As would be expected from the importance of histamine in thepathogenesis of urticaria, H1-antihistamines are the drugs ofchoice. However, due to particular morphological characteristicsof the skin, only the most potent antihistamines are effectiveand, sometimes, higher doses may be necessary for clinicaleffectiveness (see chapter 1.3. “The nose versus the skin”).The role of systemic corticosteroids is limited. There iscontroversy as to whether the addition of an H2 antagonist or a leukotriene antagonist is helpful. The aims of treatment are:reduction of pruritus, wheal size, wheal number and whealingfrequency, improvement of sleep quality (less night-timeawakening), total symptom score, overall improvement andpermanent remission of disease.

3.2.1. Challenge models evaluating drugtreatments for chronic urticaria

The unpredictable nature of the disease, due to the variation in its activity, makes the efficacy of treatments in the classicalclinical situations difficult to assess. Wheal and flare induced by either histamine or allergens is a favoured method inurticaria-treatment studies since it offers well-controlled andguaranteed ‘symptomatology’.

Histamine-induced wheal and flare studies evaluate theactivity of antihistamines in the skin of healthy individuals.The response may be provoked by either an intradermalinjection of histamine or by a skin prick test (SPT), in whichhistamine is introduced into the dermis by pricking the skinthrough a drop of histamine (Figure 3.3A) using a fine needleor lancet (Figure 3.3B). Because diffusion of histamine in theskin is no more than a millimetre from its site of injection,this results in a relatively high local histamine concentration.Antihistamines with strong activity show effective andconsistent inhibition of the response (Figure 3.3D), while thosewith weaker activity have a weak and variable effect.

Allergen-induced wheal and flare studies are similar to thehistamine-induced studies; however, they are a step closer to clinical disease since the allergen induces the release of not only histamine but of other mediators, as is the case in skin allergy.

3.2.2. Clinical studies evaluating drugtreatments for chronic urticaria

Clinical studies evaluate the effect of antihistamines in relievingthe symptoms of active urticaria. Wheals, flares and itching areusually evaluated separately and not as a total symptom score.The usual length of the treatment period is 4 to 6 weeks.Safety of treatment can be reported either as spontaneousadverse events or as part of the symptom reporting. The usualconfounding factors of lack of patient compliance to treatmentand inaccurate data recording are also valid in the urticariastudies. In addition, wheals and flares are very dynamic (usuallyappear and disappear within 24 hours) and therefore treatmenteffects are sometimes difficult to distinguish from the naturaldisease history.

Similar to other therapeutic areas, urticaria studies alsoevaluate disease and treatment effect on general health status and HRQoL. DLQI is a dermatology specific QoLinstrument consisting of 10 easy to respond questions.Patient preferences, work productivity (through absenteeismand presenteeism), and treatment effect on decreasing costs tosociety, can be also used for the overall evaluation of treatmentoutcomes that reflect better real life situations. Compared withasthma and allergic rhinitis, fewer studies have evaluated thehealth economic impact of chronic urticaria treatment.

Recently, chronic urticaria has been reported to be moredisturbing in everyday life than psoriasis and similar to theeffects of atopic dermatitis.

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Figure 3.3. Histamine drop introduced to the skin (A); Skin prick through histamine drop (B); Wheal and flare responseto histamine (C); Inhibition of the response after a potent antihistamine (D).

A B

C D

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3.3. Allergic disease management in children

Some allergic diseases, eg, asthma, allergic rhinitis, atopicdermatitis, are more prevalent in childhood. A high percentageof children suffering from atopic dermatitis and/or from allergicrhinitis go on to develop asthma and other co-morbidities.This is why successful treatment of allergic diseases in thepaediatric population is of utmost importance and should beevaluated in well-controlled, double-blind, randomised studies.In addition, if left untreated, allergic diseases can be detrimentalto the child’s physical and psychosocial well-being. At thephysical level, sleep disturbance, daytime fatigue, headache,weakness, malaise and poor appetite are common. At theemotional level, there is evidence that allergic individuals aremore likely to exhibit shyness, depression and anxiety. Allergicchildren can have difficulties learning with a significant numberof school days being lost because of their allergy.

Challenge studies, eg, histamine nasal provocation studies,wheal and flare, ACC, are rarely performed in children due toethical considerations. Although the more traditional clinicalstudies with symptom control and QoL assessments are thepreferred way of evaluating anti-allergic medications in thepaediatric population, extra care is usually required sincechildren frequently lack the ability to report and explain their symptoms.

Importantly, their parents are involved in the symptom reportingand in the treatment compliance, which may be a confoundingfactor for clinical paediatric research. Allergic children aregenerally successfully managed with oral antihistamines,which are the first-line treatment for allergic rhinitis, urticariaand atopic dermatitis (for itch relief). Although largely used,controlled data on the use of antihistamines in children is not abundant.

Since allergies can have a profound effect on a child’s QoL,assessment of subjective health status and patient’s well-being,as measured by disease and age-specific questionnaires,eg, the Paediatric Rhinoconjunctivitis Quality of LifeQuestionnaire (PRQLQ)11 has been recognised over the lastdecade as one of the primary goals of disease treatment.Recently, care-givers QoL has also become an interesting target for clinical research.

Summaryn Antihistamines are the established first-line therapy for

allergic diseases

n Treatment efficacy and safety outcomes of anyantihistamine should be clinically confirmed in all forms of allergic rhinitis: seasonal (SAR), perennial (PAR),intermittent (IAR) and persistent (PER) allergic rhinitis

n Only long-term studies, eg, covering the whole allergicseason (in cases of SAR) or studies over several months (in cases of PER), can provide reliable clinical results oftreatment outcomes

n Antihistamines should show effectiveness for all nasalsymptoms including nasal obstruction

n Nasal and skin provocation studies provide the most accurate, reproducible and reliable way of detecting differences in antihistaminic potency of various antihistamines

n Facial thermography is an innovative technique useful inassessing antihistaminic activity in the nose

n Allergen challenge chambers, eg, VCC™ and EEU™,are highly controllable and reproducible environmentsuseful for assessing and comparing treatment outcomes in allergic rhinitis patients

n No clinically relevant pharmacokinetic interference byfoods, medications or intestinal transport proteins should be reported for a safe and reliable antihistamine

n Measurements of patient preferences, quality of life andhealth status outcomes should be used in every study

n Cost effectiveness of treatment via health-economicassessments is becoming an indispensable part of clinicalresearch and should be used in allergy treatment studies.

Further readingBousquet J, Van Cauwenberge P, Bachert C, Canonica GW, Demoly P,Durham SR, Fokkens W, Lockey R, Meltzer EO, Mullol J, Naclerio RM, Price D,Simons FE, Vignola AM, Warner JO; European Academy of Allergy and Clinical Immunology (EAACI); Allergic Rhinitis and its Impact on Asthma (ARIA).Requirements for medications commonly used in the treatment of allergicrhinitis. Allergy 2003;58:192–7.

Corren J, Manning BE, Thompson SF, Hennessy S, Strom BL. Rhinitis therapyand the prevention of hospital care for asthma: A case-control study.J Allergy Clin Immunol 2004;113:415–9.

Crystal-Peters J, Neslusan C, Crown WH, Torres A. Treating allergic rhinitis inpatients with co-morbid asthma: The risk of asthma related hospitalizations andemergency department visits. J Allergy Clin Immunol 2002;109:57–62.

Schoenwetter WF, Dupclay L Jr, Appajosyula S, Botteman MF, Pashos CL.Economic impact and quality of life burden of allergic rhinitis.Curr Med Res Opin 2004;20(3):305–17.

Juniper EF, Thompson AK, Roberts JN. Can the standard gamble and rating scale be used to measure quality of life in rhinoconjunctivitis?Comparison with the RQLQ and SF-36. Allergy 2002;57:201–6.

Majani G; Baiardini I; Giardini A; Pasquali M; Tosca MA; Canonica GW. Allergicrhinitis and quality of life: where are we? Clin Exp All Rev 2003;3:90–4.

IR Bell, ML Jasnoski, J Kagan and DS King. Is allergic rhinitis more frequent in young adults with extreme shyness? A preliminary survey.Psychosom Med 1990;52(5):517–25.

Greisner WA 3rd, Settipane RJ, Settipane GA. The course of asthma parallelsthat of allergic rhinitis: a 23-year follow-up study of college students.Allergy Asthma Proc 2000;21(6):371–5.

Vuurman EF, van Veggel LM, Uiterwijk MM, Leutner D, O'Hanlon JF.Seasonal allergic rhinitis and antihistamine effects on children's learning.Ann Allergy 1993;71(2):121–6.

Dykewicz MS, Fineman S. Executive summary of joint task force practice parameters on diagnosis and management of rhinitis.Ann Allergy Asthma Immunol 1998;81(5 Pt 2):463–8.

Juniper EF, Howland WC, Roberts NB, Thompson AK, King DR.Measuring quality of life in children with rhinoconjunctivitis.J Allergy Clin Immunol 1998;101(2 Pt 1):163–70.

Fireman P. Therapeutic approaches to allergic rhinitis: treating the child.J Allergy Clin Immunol 2000;105(6 Pt 2):S616–21.

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Levocetirizine is the active enantiomer of a well-established,second-generation antihistamine (cetirizine). The molecularstructure of levocetirizine confers high H1-receptor affinitywithout any impurities from inactive isomers and with noinactive molecular parts.

In the late 20th century it was well recognised that separationof active from inactive isomers producing purer moleculeswould result in safer and more effective medicinal products12.During the 1990s, a great deal of pressure was put on thepharmaceutical industry by leading medicinal chemists toisolate the active enantiomers of chiral molecules and marketthem as ‘purer drugs’. Responding to these recommendations,UCB developed and marketed the only pure stereospecificantihistamine isomer for the treatment of allergic diseases.

4.1. Receptor binding affinity of levocetirizine

To assess the affinity with which levocetirizine binds to H1-receptors, studies were performed in which increasingconcentrations of the drug were used to displace[3H]mepyramine (a radioactive antihistamine), from thereceptor. Results from such a study13 are shown in Figure 4.1A.From the resulting curves, the concentrations of levocetirizineand cetirizine that displace [3H]mepyramine by 50% (their IC50)have been calculated, resulting in equilibrium dissociationconstants (Ki) of 3 nM and 6 nM, respectively (Figure 4.1B).

Since higher affinity drugs have lower Ki values, these resultsshow that levocetirizine has a 2-fold higher affinity for the H1-receptor than cetirizine, whilst the affinity of the otherenantiomer (dextrocetirizine) is approximately 30-fold less than levocetirizine.

Levocetirizine is a newly developed, highly-selective and potent H1 antagonist. It belongs to the latest new-generationantihistamines introduced at the beginning of the 21st centurycharacterised by high clinical efficacy, and unsurpassed safety.It exhibits many of the desirable characteristics of an idealantihistamine, both pharmacologically and clinically.

Numerous studies have demonstrated the potent antihistaminicactivity, high and sustained clinical efficacy and excellent

safety of levocetirizine, which are closely related to its highbioavailability and degree of receptor occupancy, high receptoraffinity and selectivity for the H1-receptors, rapid onset ofaction, limited tissue distribution and minimal metabolism.Levocetirizine is indicated for the treatment of all types ofallergic rhinitis (including the persistent allergic rhinitis asdefined by ARIA) and chronic idiopathic urticaria.

26

Levocetirizine

4. Pharmacology of levocetirizine

Figure 4.1. Affinity curves for levocetirizine and itsparent molecule for cloned human H1-receptors (A).Due to its 2-fold higher affinity for the H1-receptor,far less levocetirizine is needed to displace[3H]mepyramine when compared with cetirizine (B).

[3 H]M

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27

In addition, levocetirizine stays bound to the H1-receptor for a much longer time with a dissociation half-time of 142 minutescompared with only 6 minutes for dextrocetirizine13 .

Receptor selectivity is also of significant clinical importance.Muscarinic receptors for acetylcholine and H1-receptors areclosely related structurally, which accounts for the markedanticholinergic effect of first-generation antihistamines,such as chlorpheniramine and diphenhydramine.Cross-reactivity of the three most widely used new-generationantihistamines with muscarinic receptors is shown in Figure 4.2.Levocetirizine has the highest selectivity ratio for the H1-receptorof >20 000, followed by fexofenadine with >10 000.In contrast, desloratadine has significant binding to allmuscarinic receptors with selectivity ratios for H1-receptor ofbetween 50 and 125. This suggests that desloratadine is likely to have muscarinic side effects whereas levocetirizine is completely devoid of these14.

4.2. Pharmacokinetics oflevocetirizine

(Most data in this section appears in the product’s SmPC)

The pharmacokinetic profile of levocetirizine is linear,dose and time independent, with low inter-subject variability. No clinically relevant gender differences have been observed15.

4.2.1. AbsorptionLevocetirizine is rapidly and extensively absorbed; the extentof which is dose-independent. Peak plasma concentrations areachieved within 1 hour of dosing and are typically ~300 ng/mlfollowing a single 5 mg oral dose. Food intake may delay andreduce the peak plasma concentration but not the absoluteamount of drug absorbed.

4.2.2. BioavailabilityAs all antihistamines are orally administered, a high oralbioavailability is considered to be a desirable feature.Unlike most of the first and second-generation antihistamines,which were generally poorly bioavailable, the systemic oralbioavailability of levocetirizine is >77% (Figure 4.3).The low bioavailability of some other antihistamines is due to a high hepatic first-pass effect, which confers a high inter-individual variability in the pharmacokinetics of thesedrugs. Unlike them, levocetirizine undergoes minimal hepaticmetabolism (see chapter 4.2.4.) and thus is not likely to showdifferences in efficacy between individuals.

The plasma half-life in adults for levocetirizine is 7.9±1.9 hours16 and steady state is achieved after 2 days of a once-daily administration. The plasma half-life oflevocetirizine is shorter in small children.

Figure 4.2. Levocetirizine is highly selective for H1-receptors without significant affinity for muscarinic receptors(no clinically relevant muscarinic side effects)

pKi

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Desloratadine Fexofenadine Levocetirizine

10

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H1 M2 M3 M4 M5M1

4.2.3. DistributionOf particular importance for the pharmacokinetics of a drug is the apparent volume of its distribution (Vd). The apparent Vd of a drug does not represent an actual physical volume,but describes how a drug is distributed inside the body.For example, a Vd of ~0.2 l/kg means that the drug isrestricted to the extracellular fluid only, eg, in plasma,while a Vd >0.6 l/kg shows that the drug has either extensivetissue binding or is taken up and concentrated intracellularly.For an antihistamine, which interacts with extracellular H1-receptors, a low Vd of between 0.1 and 0.6 l/kg (ie, restricted to body water) is ideal17.

With a Vd of 0.4 l/kg (Table 4.1) and extensive plasma proteinbinding (91%) levocetirizine is within the ideal range for anantihistamine. In contrast, the Vd values for desloratadine and fexofenadine are much higher, indicating that they areextensively tissue bound or intracellularly distributed andtherefore they are located far from the H1-receptors.Thus, although desloratadine has an approximately 10-fold greater affinity for the histamine H1-receptor thanlevocetirizine, its Vd of 49 l/kg is approximately 100 timesgreater. This means that it is ~100 times more diluted in the extracellular fluid – the place of interaction with the H1-receptors. In comparison, fexofenadine has a 3-fold weakeraffinity for the H1-receptor and an approximately 10-foldgreater Vd than levocetirizine14, 15.

Levocetirizine is a weak substrate for the organic aniontransporting protein, P-glycoprotein (PgP). The clinicalsignificance of this is that it is unlikely for levocetirizine tohave PgP-mediated drug interactions and that this maycontribute to the prevention of its absorption into the brain.

4.2.4. MetabolismThe extent of metabolism of levocetirizine in humans is less than 14% of a total oral dose. Consequently,genetic polymorphisms of liver metabolising enzymes or the concomitant intake of enzyme inhibitors are expected to have a negligible effect on systemic concentrations oflevocetirizine (Figure 4.3).

In addition, since levocetirizine has no effect on the activities of the cytochrome P450 isoenzymes even atconcentrations well above those achieved following therecommended dose16, it has an extremely low potential for drug–drug interactions.

4.2.5. EliminationLevocetirizine is excreted, predominantly unchanged,in the urine, by glomerular filtration and active tubularsecretion. After administration of 14C-levocetirizine to healthy volunteers, 85% and 13% are recovered from urineand faeces, respectively (Figure 4.3).

28

>77% Bioavailability

85% Renalexcretion

Negligible hepatic metabolism

Figure 4.3. Absorption, metabolism and excretion of levocetirizine.

Table 4.1. Dissociation Constants (Ki) and ApparentVolumes of Distribution (Vd) of commonly usedantihistamines15, 18.

Ki (nM) Vd (l/kg)

Levocetirizine 3 0.4

Desloratadine 0.4 49

Fexofenadine 10 5.6

Cetirizine 6 0.8

29

Summaryn The molecular structure of levocetirizine confers high

H1-receptor affinity without any impurities from inactiveisomers and with no inactive molecular parts

n Levocetirizine has a 2-fold higher affinity for the H1-receptor and a longer residence time bound to thereceptor than cetirizine

n Levocetirizine has the highest selectivity ratio for the H1-receptor among the newer generation antihistamines

n Pharmacokinetically levocetirizine shows a low inter-subject variability, which is a prerequisite forconsistent clinical efficacy

n Unlike most of the first- and second-generationantihistamines, which are generally poorly bioavailable,the systemic oral bioavailability of levocetirizine is >77%

n Due to its low volume of distribution (Vd = 0.4l/kg) thatis in the range of the ideal Vd for an antihistamine (0.1–0.6 l/kg) plus its extensive plasma protein binding(91%), levocetirizine is available only where it is supposedto act – at the H1-receptors

n Levocetirizine has no effect on cytochrome P450isoenzymes (even at concentrations well above those with the recommended dose) and therefore has anextremely low potential for drug–drug interactions.

5.1. Histamine nasal provocationstudies

A randomised, double-blind, placebo-controlled, 4-waycrossover study19 using nasal provocation with histaminecompared the antihistaminic properties of levocetirizine to its parent molecule cetirizine and the inactive enantiomer(dextrocetirizine). Twenty-four healthy non-allergic volunteers were randomised to receive 10 mg cetirizine,5 mg levocetirizine, 5 mg dextrocetirizine or placebo.Four hours after drug administration all the subjects underwenta histamine nasal provocation by application of aerosols withincreasing doubling doses of histamine (from 0.25 mg/ml to 32 mg/ml). The parameters evaluated were increased airwayresistance (measured by passive anterior rhinomanometry) andthe absolute number of sneezes after each challenge.

The results showed that treatment with levocetirizinesignificantly attenuated the histamine-induced increase innasal airway resistance (Figure 5.1). At the maximal histamineconcentration of 32 mg, the nasal airway resistance was 50% less in the levocetirizine group compared with placebo(p<0.025). As expected, dextrocetirizine showed no significant effects compared with placebo. Interestingly,while levocetirizine was significantly more efficacious in reducing the nasal resistance than both placebo anddextrocetirizine, no significance could be achieved betweendextrocetirizine and cetirizine.

Evaluation of the number of sneezes after the nasal histamine provocation showed that levocetirizine significantly reduced the number of histamine inducedsneezes (p<0.01 vs placebo). No significance could beachieved with dextrocetirizine (p>0.10) (Figure 5.2).

5.2. Facial thermography withhistamine nasal provocation

Two studies have been performed with levocetirizine usingfacial thermography with histamine nasal provocation.

The ability of levocetirizine to inhibit histamine-inducedincrease in nasal skin temperature was first compared with desloratadine in a randomised, double-blind,placebo-controlled, 3-way crossover study using facialthermography (Figure 5.3)20.

30

5. Antihistaminic properties of levocetirizine

p<0.025 versus placebop<0.05 versus dextrocetirizine

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Figure 5.2. Absolute number of sneezes after nasalhistamine provocation.

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Figure 5.3. Study design of the FT study comparinglevocetirizine and desloratadine.

Levocetirizine 5 mg ordesloratadine 5 mg

2 hours

-2 min 10 min

Provocation with140 µg histamine

Facial thermography

Figure 5.1. Comparison of nasal airway resistance atprovocation with 32 mg/ml histamine.

31

Eighteen healthy male volunteers were randomised to receive 5 mg levocetirizine, 5 mg desloratadine or placebo. Two hoursafter drug administration volunteers were challenged with 140 µg histamine sprayed into each nostril. Thermographicrecording was performed from 2 minutes before histamineprovocation to 10 minutes after provocation (Figure 5.4A).The endpoint was the change in nasal skin temperature from baseline, recorded for 10 minutes after nasal histaminechallenge. A reduction of >0.3°C was considered to be ofclinical significance.

Temperature values recorded during the 10-minute intervalfollowing histamine provocation showed that only levocetirizinewas active in reducing histamine-induced increase in nasal skin temperature 2 hours after administration (Figure 5.4B).The mean increase in nasal skin temperature from baseline in the levocetirizine group was 54% smaller than placebo(p=0.0001), while that in the desloratadine group was only 7% (not significant). The difference between the two drugs washighly significant (p=0.0006) (Figure 5.4A).

Levocetirizine at its recommended dose has a potent antihistaminic activity already 2 hours after intake,as demonstrated by its ability to significantly inhibit histamine-induced increase in nasal skin temperature.In contrast, desloratadine showed no significant inhibitoryactivity in these conditions.

In another study21, the ability of levocetirizine and fexofenadineto inhibit histamine-induced vasodilatation in the nose wascompared using facial thermography. Thirty healthy non-atopicmales were randomised to receive 5 mg levocetirizine,120 mg fexofenadine or placebo, in a double-blind, crossovermanner (Figure 5.5). Nasal provocation was performed byspraying 140 µg histamine into the nose 2 hours and 24 hours after drug intake.

Figure 5.4. Facial thermographic images taken beforeand 10 minutes after histamine challenge (A).The increase in nasal temperature over time induced by histamine 2 hours after drug intake (B).

Mea

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35

30

25

37.0˚C

25.0˚C

Thermographic recordings were made for 2 minutes beforeand 20 minutes after nasal provocation on both days. In orderto validate the response, other non-thermographic parameterswere included: total symptom score of four nasal symptoms(T4SS) (sneezing, rhinorrhoea, nasal pruritus, nasalcongestion) and histamine-induced wheal and flare responsein the skin.

The primary study end-point was the mean increase in nasalskin temperature from baseline after histamine challenge 2 hours and 24 hours after drug intake. The secondaryendpoints were changes in T4SS after nasal provocation andpercentage of inhibition of the histamine-induced wheal andflare area at 2 hours and 24 hours after drug intake.

In contrast to placebo, both levocetirizine and fexofenadinereduced the increase in nasal skin temperature after histamineprovocation (Figure 5.6). Both drugs were significantly moreactive than placebo (p<0.001) in reducing nasal temperature2 hours after drug intake. Importantly, the inhibitory activity oflevocetirizine, 24 hours after administration, was significantlygreater than that of fexofenadine (p=0.024) indicating thatlevocetirizine has a longer duration of action (Figure 5.6).This was confirmed also by the significantly greater efficacy of levocetirizine versus fexofenadine (p=0.043) on the T4SS.

32

Levoceterizine orDesloratadine

Levocetirizine 5 mg orfexofenadine 120 mg

2 hours

24 hours

-2 min 20 min



Facial thermography

-2 min 20 min

Facial thermography

DAY 1 DAY 2

Mea

nte

mpe

ratu

rein

crea

se(˚C

)

Placebo Fexofenadine 120 mg Levocetirizine 5 mg

2 hours after drug dosing 24 hours after drug dosing

1.0

0.8

0.4

0

0.2

0.6

Figure 5.5. Study design of the facial thermography study comparing levocetirizine and fexofenadine.

Figure 5.6. Increase in nasal temperature (mean ± SE)induced by histamine at 2 hours and 24 hours following administration of levocetirizine, fexofenadineand placebo.

p<0.001 versus placebop=0.024 versus fexofenadine

33

When the skin wheal and flare response to histamine wasinvestigated, although at 2 hours inhibition of the reaction wassimilar with both drugs (Figure 5.7A), at 24 hours, the inhibitoryaction of levocetirizine was sustained, while that offexofenadine was significantly reduced (Figure 5.7B).

This study demonstrated that levocetirizine, at itsrecommended dose of 5 mg, has a significant anti-histaminicactivity at 2 hours following administration; this effect beingsustained for at least 24 hours. The same anti-histaminic effectis evident in the skin as well as in the nose, confirming thatthere are no organ differences in its anti-histaminic activity.In contrast, fexofenadine at its recommended dose of 120 mg,exhibits potent anti-histaminic properties initially (at 2 hours)but is less effective than levocetirizine 24 hours later in bothnose and skin. In conclusion, levocetirizine has a longerduration of action over 24 hours than fexofenadine.

5.3. Allergen nasal provocationstudies

A double-blind, placebo-controlled, crossover study22 usingallergen nasal challenge compared the efficacy of levocetirizineand desloratadine in individuals with seasonal allergic rhinitis.Twenty-four volunteers with sensitivity to grass pollen and a history of allergic rhinitis were randomised to receive a singledose of 5 mg levocetirizine, 5 mg desloratadine or placebo 4 hours before nasal provocation with grass pollen.Nasal provocation was performed using 7 increasing serialdilutions of allergen: 1:100, 1:330, 1:1 000, 1:3 300,1:10 000, 1:33 000 and 1:100 000 SQs/ml (levels 1–7,Figure 5.8) administered at 20-minute intervals.

Inhi

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p<0.001 versus placebo

p<0.0001 versus placebop=0.02 versus desloratadinep<0.001 versus placebo

p<0.001 versus placebop<0.001 versus fexofenadine

Figure 5.7. Wheal and flare response at 2 hours (A); and at 24 hours (B) after drug dosing.

Figure 5.8. Number of patients presenting a significantnasal reaction at increasing allergen challenge doses(levels 1 to 7 correspond to increasing grass pollenallergen concentrations).

B

The main parameter evaluated was the difference in allergen threshold dose inducing a significant change in thecombined clinical score recorded 10 minutes after challenge.The combined clinical score was defined as at least two of thethree following criteria: (1) five or more sneezes; (2) at least 0.5 g nasal secretion; (3) decrease in peak nasal inspiratoryflow (PNIF) of 40% or greater or a decrease in minimal cross-sectional area of the nasal cavities of 30% or greater of baseline values. In an attempt to identify anti-inflammatoryproperties of the two drugs, the number of eosinophils andlevels of eosinophilic cationic protein (ECP), albumin, as well as mast cell tryptase, IL-4, IL-5, IL-8 and eotaxin wereassessed in nasal lavage fluids at 10 minutes and 24 hoursafter the challenge.

In both the levocetirizine and desloratadine groups, theallergen threshold dose inducing a change in the combinedclinical score was significantly increased compared with theplacebo group (p<0.0001 for levocetirizine and p<0.001 fordesloratadine). Moreover, levocetirizine significantly increasedthe allergen threshold dose necessary to reach the combinedclinical score compared with desloratadine (p=0.02). A highernumber of individuals were protected from allergen challengein the levocetirizine group compared with the desloratadinegroup (Figure 5.8).

Similar results were seen when sneezes and the amount ofnasal secretions were individually evaluated, with levocetirizinesignificantly more active than desloratadine (p=0.021 forsneezes and p=0.015 for nasal secretion). The otherparameters were not significantly influenced with treatment.

The albumin concentration, as a marker of fluid extravasation,was markedly enhanced in nasal lavage fluid after 33,000SQs of allergen compared with baseline values (Figure 5.9).Compared with placebo, albumin extravasation wassignificantly reduced following treatment with levocetirizine(p<0.05) but not after treatment with desloratadine.Neither levocetirizine nor desloratadine reduced tryptase levelsshowing that neither are mast cell stabilisers (Figure 5.9).Similarly, the other inflammatory parameters were notinfluenced by either of the two drugs.

In conclusion, in the presence of levocetirizine, a significantlyhigher dose of allergen was required to produce a significantchange in the combined clinical score when compared with desloratadine. A single dose of levocetirizine, but notdesloratadine, significantly reduced albumin levels in nasallavage fluid, suggesting that levocetirizine is more potent indecreasing nasal oedema. As expected, neither levocetirizinenor desloratadine demonstrated mast cell stabilisingproperties. Also, due to the short duration of the study,the high experimental allergen concentrations used and thesingle-drug dosing, no significant anti-inflammatory propertieshave been observed. Since anti-inflammatory properties havebeen previously reported for the two antihistamines, this study may indicate that anti-inflammatory effects appear whenantihistamines are administered on a regular, long-term basis,as opposed to single doses or ‘on demand’ basis.

34

Albu

min

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g/l)


Baseline

Albumin

After allergen challenge

600

400

0

200

Tryp

tase

conc

entr

atio

n(µ

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Baseline

Mast cell tryptase

After allergen challenge

15

10

0

5


Figure 5.9. Albumin and tryptase levels (mean ± SD) in the nasal lavage fluid at baseline and 10 minutes afterchallenge with 33,000 SQs of allergen.

35

5.4. Allergen challenge chambers (ACC)Levocetirizine has been evaluated in the two major ACCs in the world: the Environmental Exposure Unit (EEU™) and the Vienna Challenge Chamber (VCC™).

In a study using exposure to pollen in the EEU™23, theeffectiveness of levocetirizine was compared with that ofdesloratadine in patients suffering from seasonal allergic rhinitis.A total of 373 individuals aged ≥16 years with a documentedhistory of ragweed-induced allergic rhinitis in the previous twoconsecutive seasons were enrolled in the study. All individualswere exposed to ragweed pollen in the EEU™ from 8:00 hoursto 15:00 hours on the first day (Period 1) and from 8:30 hours to10:00 hours (Period 2) and 10:00 hours to 14:30 hours (Period 3) on the second day of the study (Figure 5.10).

Patients were randomised to receive a single dose of 5 mglevocetirizine (141 patients), 5 mg desloratadine (140 patients)or placebo (92 patients) at approximately 10:00 hours on eachof the two consecutive days. The severity of the clinicalmanifestation was assessed by major symptom complex (MSC)score recorded at half-hour intervals during pollen exposure inthe EEU™, before and after drug administration. The MSC scoreincluded six symptoms: runny nose, itchy nose, sniffles, noseblows, sneezes, and watery eyes. The primary efficacyparameter was the reduction from baseline in the MSC scoreover period 1. Secondary efficacy parameters were the onset ofaction, reduction in MSC score over periods 2 and 3, andreduction in nasal obstruction score over periods 1, 2 and 3.

The results of this study demonstrated that levocetirizine had a faster onset of action than desloratadine. The first significantreduction in MSC score from baseline compared with placebowas reached at 1 hour for levocetirizine and 3 hours fordesloratadine (Figure 5.11). In addition, levocetirizine was more active than desloratadine over the whole period 1,with a difference in mean MSC score change from baselineversus desloratadine of -1.87 (p=0.001). When compared withplacebo, the difference was -3.68 (p<0.001) in favour oflevocetirizine. Levocetirizine remained significantly superior to desloratadine and placebo over periods 2 and 3, whichmeans that levocetirizine has a longer duration of action (22 to 24 hours after drug intake) and more sustained efficacycompared with desloratadine.

92 SubjectsPlacebo

140 SubjectsDesloratadine 5 mg

141 SubjectsLevocetirizine 5 mg

Baseline

15.00 10.008.00 8.30 14.3010.00

Second doseFirst dose

Period 1 Period 2 Period 3

DAY 1 DAY 2

Impr

ovem

entf

rom

base

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MSC

scor

eLS

Mea

n

Levocetirizine 5 mg

Hours after first drug intake

Period 110

0 1

Drug intake Drug intake

2 3 4 5

8

6

-2

2

0

4

Placebo Desloratadine 5 mg

Period 2 Period 3

23 24 25 26 27 28

Figure 5.10. EEU™ allergen exposure study design.

p<0.05 versus placebo p<0.05 versus desloratadine

Figure 5.11. Improvement in MSC scores from baseline (periods 1–3) and onset of action of the two active drugs (arrows).

In addition, during the first 5 hours after drug intake,levocetirizine reduced nasal obstruction to a greater extent than both desloratadine and placebo (p=0.007 and p<0.001,respectively) (Figure 5.12) and this significant effect wasmaintained versus placebo during period 3. Desloratadine was not significantly better than placebo at any time period.

In conclusion, levocetirizine had a faster onset and longerduration of action than desloratadine. Moreover, it demonstrateda better overall allergen-induced symptom control in patientswith a history of seasonal allergic rhinitis. Levocetirizine wasactive on nasal obstruction whereas desloratadine was notsignificantly active at any time-point.

Using fexofenadine as a comparator, efficacy of levocetirizine was evaluated in a randomised, double-blind,placebo-controlled, three-way crossover study using exposureto pollen in the Vienna Challenge Chamber (VCC™)24.Eighty-five patients with a documented sensitivity to grasspollens were randomised to receive 5 mg levocetirizine,120 mg fexofenadine or placebo (Figure 5.13).

The subjects were exposed to various grass pollens in theVCC™, 2 hours before and 2 hours after drug administrationon the first day of the study, and for 6 hours on the followingday, 22 to 28 hours after drug administration. Efficacyassessments were performed over four time intervals (Figure 5.13). Upon entering the VCC™ (on both study days),subjects recorded their symptoms every 15 minutes on a computer using a 5-point scale ranging from 0 (absent) to 4 (severe/>5 sneezes).

The efficacy variables evaluated were the change from baselinein the Major Symptom Complex (MSC) score (rhinorrhoea,sneezing, itchy nose and itchy eyes) and nasal congestion overall time intervals. In addition, patient satisfaction with thetreatment and readiness to use the same medication in thefuture were also evaluated. Safety information was collected bycontinuously monitoring the adverse events.

Both levocetirizine and fexofenadine improved symptoms (MSC plus nasal congestion score) within the first 2 hourswhen statistically significant differences versus placeboappeared (p<0.001 for both drugs) (Figure 5.14).Their superiority over placebo was maintained during the restof the study (22 to 28 hours after drug intake). Interestingly,highly significant differences (p<0.001) in the MSC plus nasalcongestion score in favour of levocetirizine over fexofenadinewere demonstrated over all the day 2 periods (22 to 28 hoursafter drug intake). Individual symptoms followed the pattern of the MSC score.

36

Impr

ovem

entf

rom

base

line

scor

e

2 hours after drug dosing


0.8

0.6

0

0.2

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Allergenexposure 4 hours

Allergenexposure 6 hours

0-2 2

Medication

Time interval 1

Time interval 2

Time interval 3

Time interval 4

2422 2826

DAY 1 DAY 2

p<0.001 versus placebop=0.007 versus desloratadine

Figure 5.12. Improvement in nasal obstruction scorefrom baseline during period 1. Figure 5.13. VCC™ allergen exposure study design.

37

During all periods of day 2, levocetirizine was significantly betterthan fexofenadine in improving satisfaction with treatment.The differences in favour of levocetirizine increased throughoutday 2 (p=0.017 during time interval 3 and increasing top=0.002 for interval 4) (Figure 5.15).

In conclusion, levocetirizine controlled the allergen-inducedsymptoms in subjects allergic to grass pollen already during the first 2 hours after drug intake and its protective activity was sustained for more than 24 hours. Levocetirizinedemonstrated better efficacy than fexofenadine on nasalsymptoms 22 to 28 hours after intake. Changes in subjects’treatment satisfaction scores correlated with the efficacy results,showing a better improvement in the levocetirizine group from22 hours onwards.

Another randomised, double-blind, placebo-controlled,three-way crossover study using the VCC™25 compared theefficacy of a single dose of levocetirizine 5 mg and loratadine10 mg in subjects suffering from seasonal or perennial allergicrhinitis. Both drugs were shown to improve significantly betterthan placebo allergen-induced symptoms in both SAR and PAR subjects but levocetirizine was significantly better thanloratadine in controlling the symptoms in SAR subjects.

Placebo

Mea

nsc

ore

(MSC

scor

e+

nasa

lcon

gest

ion)

Fexofenadine LevocetirizineDrug intake

Hours afterdrug intake

T 1 ( )

Day 1 in the VCC™ = 4 hours Day 2 in the VCC™ = 6 hoursT 2 ( ) T 3 ( ) T 4 ( )

14

-2 -1 0 1 2

12

10

0

2

5

6

8

22 23 24 25 26 27 28

Figure 5.14. Major symptom complex score plus nasal congestion score change from baseline over all time intervals.

Satis

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ange

from

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(VAS

scal

e)


Time interval 3 Time interval 4

20

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5

-5

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p<0.001 versus placebop<0.05 versus fexofenadine

p<0.001 Levocetirizine and fexofenadine versus placebop<0.001 Levocetirizine versus fexofenadine

Figure 5.15. Improvement (change from baseline) insubject satisfaction score.

5.5 Histamine-induced wheal and flare studies

Numerous skin wheal and flare studies have been performedwith levocetirizine that supplement the nasal challenge data.The ability of levocetirizine to inhibit the cutaneous response to histamine in healthy volunteers was compared in a placebo-controlled study26 to four other widely usedantihistamines. Levocetirizine 5 mg, ebastine 10 mg,fexofenadine 180 mg, loratadine 10 mg, mizolastine 10 mg,or placebo in single doses, were given to 18 healthy malevolunteers in a double-blind, crossover, randomised fashion.Antihistamine activity was assessed by the ability to inhibithistamine-induced wheal and flare responses. Skin prick testswith histamine (100 mg/ml) were performed before drug intake and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours afteradministration of each drug.

The global effect of each drug on wheal and flare response was evaluated using the area-under-the-curve (AUC over 0 to 24 hours). Additional study parameters were the onset and duration of action, and the maximal inhibitory activity of the antihistamines.

All five active treatments were shown to be significantly moreactive than placebo but levocetirizine was superior to all other active drugs in blocking wheal (Figure 5.16A) and flare (Figure 5.16B) responses to histamine.

Levocetirizine was significantly more active than placebo 2 hours after intake and reached its maximal effect 2 hourslater (4 hours after intake), when more than 95% inhibition of both wheal and flare was observed in 100% of subjectstreated with levocetirizine (Figure 5.17). The inhibitory effectremained approximately constant for up to 12 hours afterintake and then decreased slowly. At 24 hours, the wheal areain the levocetirizine group was still inhibited by approximately66% compared with placebo. A similar pattern of onset ofaction and time to reach the maximal activity was seen forfexofenadine and mizolastine, however, activity of both drugsstarted to decrease after 4 hours and was significantly lessthan that of levocetirizine at 24 hours. Ebastine and loratadinehad a slower onset of action than levocetirizine, and loratadineappeared to be the least active drug; its maximal inhibitoryactivity being less than that of the other drugs. Interestingly,only subjects in the levocetirizine group had full inhibition ofthe wheal and flare 24 hours after drug intake.

38

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Figure 5.16. Proportion of subjects in whom a maximuminhibition (Imax >95%) of the wheals was reached (A) and the median surface area of the flare for the sixstudy groups over 24 hours (B).

Figure 5.17. Percentage of patients reaching maximalinhibition of the wheal area (Imax >95%) at each timepoint in the six study groups.

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39

Furthermore, there was a lower inter-subject variability in thesubjects treated with levocetirizine, compared with any otheractive drug or placebo (Figure 5.18). In the levocetirizine group,most volunteers (72%) continued to show maximal whealinhibition for up to 12 hours; whilst for fexofenadine onlyapproximately 50% of the volunteers had this level of inhibition from 2 to 8 hours. Similar data were recorded for the flare reaction.

To conclude, levocetirizine was the most effective inhibitor ofhistamine-induced wheal and flare responses compared with themajority of antihistamines currently on the market. It had a rapidonset and longer duration of action and a stronger inhibitoryactivity compared with the other evaluated antihistamines.Significant inhibition by levocetirizine of the cutaneous responseto histamine was maintained for up to 24 hours.

In another histamine-induced wheal and flare study27,the potency of levocetirizine and desloratadine was comparedin a double-blind, placebo-controlled, three-way cross-overstudy. Eighteen healthy volunteers were assigned to receive a single dose of levocetirizine 5 mg, desloratadine 5 mg,or placebo. A skin prick test with histamine 100 mg/ml wasperformed before drug administration and at 0.5, 1, 2, 3, 4, 6,8, 10, 12 and 24 hours afterwards. Antihistaminic activity wasevaluated by the ability to reduce the wheal and flare areas.

While both drugs exhibited a significant inhibitory activity onboth wheal (Figure 5.19A) and flare (Figure 5.19B) versusplacebo (p<0.0001), levocetirizine showed a significantlygreater and more consistent antihistaminic activity thandesloratadine (p<0.0001).

Levocetirizine reduced the wheal area by 100% in all but oneindividual (in whom the inhibition was 96.8%) at 4 hours;inhibition remained at nearly 70% over 24 hours after drugintake. In contrast, total wheal inhibition (defined as >95% ofthe baseline value) was never reached in the desloratadinegroup. The median values of maximal wheal inhibition were 55% with desloratadine (occurred most often after 4 hours),and 100% with levocetirizine (Figure 5.20). After 24 hours the level of inhibition with desloratadine was only 38%.The difference in the wheal response between treatments was highly significant, with activity in the following order ofmagnitude: levocetirizine>desloratadine>placebo (p<0.0001).Levocetirizine attained its maximal activity between 2 to 4 hours after administration while for desloratadine the peaktime ranged from 3 to 24 hours.

Placebo

Ebastine10 mg

Loratadine10 mg

Fexofenadine180 mg

Mizolastine10 mg

0 10000 20000 30000 40000 50000

Levocetirizine5 mg

AUC0-24h flare (mm2.h)

Figure 5.18. Consistency of activity for severalantihistamines. The consistency of response in a highernumber of subjects suggests a higher predictability ofresponse to levocetirizine in patients with skin allergicdiseases where histamine is the major mediator.

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p<0.0001 versus placebop<0.0001 versus desloratadine

Figure 5.19. Time response curves of the histamine-induced wheal (A) and flare (B) after treatment withlevocetirizine 5 mg, desloratadine 5 mg and placebo.Results are expressed as mean ± SEM; p-values are for AUC0-24.

In conclusion, the potency of a single dose of levocetirizine tosuppress skin reactivity to histamine was significantly superiorto desloratadine. Total inhibition of wheal and flare occurredonly with levocetirizine and this effect was present in allsubjects. In addition, levocetirizine had a more rapid onset ofaction, as well as a shorter time to reach its maximal activity,and maintained high levels of inhibition for a substantiallylonger period of time. Inhibition of the wheal response bylevocetirizine at 24 hours was greater than the maximalinhibition reached by desloratadine.

Another randomised double-blind, placebo-controlled,cross-over study28 in 12 healthy male volunteers with nohistory of allergy, compared levocetirizine with desloratadineagainst histamine-induced wheal, flare and itch. All subjectsreceived levocetirizine 5 mg, desloratadine 5 mg, or placebo 4 hours before skin histamine provocation by intradermalinjection of 20 µl of histamine 100 µM or vehicle (control).Flare area was assessed every 30 seconds for 9 minutes using scanning laser Doppler imaging. Itch was scored every 30 seconds for 10 minutes using a 10 cm visual analoguescale and wheal perimeter was measured by planimetry at 10 minutes. For comparison of individual responses andtreatment groups, mean values of flare area and itch scoresbetween 0 and 5 minutes (flare0–5 and itch0–5, respectively)and the wheal area at 10 minutes after histamine provocationwere calculated.

Inhibitions of flare, wheal and itch were significantly greaterwith both active drugs compared with placebo, however,levocetirizine had a significantly greater inhibitory action thandesloratadine (Figures 5.21, 5.22 & 5.23).

Levocetirizine showed a 67% reduction for mean flare0–5

compared with placebo, (p<0.001) while, with desloratadine,this value was only 12% (p=0.036). The inhibitory effects oflevocetirizine were superior to those of desloratadine and were of high significance (p<0.001) (Figure 5.21). The areas of the wheal responses, assessed at 10 minutes, revealed a 51% reduction (p<0.001) for levocetirizine and only a 17% reduction (p=0.033) for desloratadine (Figure 5.22).Again, levocetirizine had significantly superior inhibitory effectsto those of desloratadine (p=0.007).

40

Figure 5.20. Maximal wheal inhibition (median values) at any time over the 24 hours after drug intake.

%w

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p<0.001 versus placebo and desloratadine p=0.036 versus placebo

p<0.001 versus placebop=0.007 versus desloratadinep=0.033 versus placebo

Figure 5.21. Reduction of the flare response (mean ± SEM) by levocetirizine and desloratadinecompared with placebo.

Figure 5.22. Reduction of the wheal response (mean) bylevocetirizine and desloratadine compared with placebo.

41

The itch response was significantly reduced only bylevocetirizine with a 78% reduction in mean itch0–5 comparedwith the placebo (p=0.003), which was also significantly higherthan the effect of desloratadine (p=0.02) (Figure 5.23).

In conclusion, in this single dose-study, the inhibitory effects of levocetirizine 5 mg were more consistent and greater onhistamine-induced wheal, flare and itch than desloratadine 5 mg. Levocetirizine, but not desloratadine, significantlyreduced histamine-induced itch. A constant feature noticedwith desloratadine was the high inter-subject variability of the

drug effect, while levocetirizine had a consistent effect in allindividuals, regardless of the parameters evaluated.

A previous study performed by the same authors using thesame study protocol29 compared the inhibitory effects oflevocetirizine and loratadine. Levocetirizine 5 mg administered4 hours before provocation, produced a consistent inhibition of histamine-induced wheal, flare and itch (Figure 5.24).In contrast, loratadine 10 mg, which was also taken 4 hoursbefore provocation, was shown to have a significantly weakereffect, which varied markedly between individuals.

A possible reason for the inconsistent efficacy of loratadine wassuggested at the time to be due to the variability of its hepaticmetabolism to desloratadine. However, the above study byDenham and colleagues showed that desloratadine has thesame variability of response, proving that this inconsistency of effect is not due to variability in the rate of metabolism ofloratadine to desloratadine. Thus, the difference in efficacybetween both loratadine and desloratadine on one side, andlevocetirizine on the other side, is probably due to a betterpharmacokinetic profile of levocetirizine.

Another study in adults30 used the histamine skin prick test tocompare pharmacological activity of levocetirizine and its parentcetirizine. In this randomized, double-blind, crossover fashion,18 volunteers received single oral doses of levocetirizine 2.5 mg, dextrocetirizine 2.5 mg or cetirizine 5.0 mg. Wheal andflare responses induced by a skin prick test with 100 mg/ml ofhistamine were assessed over a period of 32 hours followingdrug administration and expressed as percentage inhibition ofthe histamine-induced wheal and flare areas before treatment.

Itch

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0 1 2 3 4 5

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p=0.003 versus placebop=0.02 versus desloratadinep=0.447 versus placebo

p<0.001 versus placebop<0.001 versus loratadinep<0.005 versus placebo

Figure 5.23. Itch scores (mean ± SEM) in the threetreatment groups. Levocetirizine reduced itchsignificantly more than desloratadine.

Figure 5.24. Effect of levocetirizine and loratadine on wheal, flare and itch responses induced by intradermal histamine.

The study demonstrated that both levocetirizine and cetirizinecaused a marked inhibition of histamine-induced wheal andflare, whereas dextrocetirizine was inactive. Inhibition of thewheal response by levocetirizine and cetirizine was apparentwithin 1 hour after intake, reaching a maximal effect of around80% within 6 hours and lasted for more than 24 hours (Figure 5.25A). Analyses of the AUC0–32 values revealed thatlevocetirizine had a significantly greater (p=0.018) inhibitoryeffect than cetirizine.

Furthermore, a study in very young children (1 to 2 years old)31 reported 100% median inhibition of the wheal withlevocetirizine treatment 3 and 90 days after drug intake and 99.6% and 98.9% inhibition of the flare response atrespectively day 3 and day 90 (Figure 5.26) (see details of the study design in chapter 7.5).

A recent double-blind, placebo-controlled cross-over study32

recruited 24 healthy volunteers with no history of atopy toreceive weekly single doses of levocetirizine 1.25, 2.5 or 5 mg, desloratadine 2.5, 5 or 10 mg or placebo. Four hoursafter drug intake, two skin prick tests using 100 mg/mlhistamine were performed and 10 minutes later the wheal andflare responses were measured.

42

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p=0.018 Levocetirizine versus cetirizine

p=0.018 Levocetirizine versus cetirizine

Figure 5.25. Mean (± SEM) percent inhibition of thehistamine-induced wheal over time (A) and over thewhole 32-hour treatment period (B) after treatment with levocetirizine, dextrocetirizine and cetirizine.

Figure 5.26. Inhibition of the wheal and flare response in children after 3 and 60 days of treatment withlevocetirizine.

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All doses of levocetirizine significantly (p<0.001) inhibited bothwheal and flare responses versus placebo 4 hours after drugintake. Also, the effects were significantly dose-related with the recommended dose of 5 mg being the most potent.With desloratadine, only the highest 10 mg dose led to a significant inhibition of the wheal only but not of flare.

There were no major differences between the different doses of desloratadine. Importantly, the lowest levocetirizine dose of1.25 mg was significantly more effective in inhibiting both thewheal and flare than the highest desloratadine dose of 10 mg(p=0.009 for wheal and p=0.001 for flare). Neither drugcaused significant side effects.

Figure 5.27. Wheal and flare inhibition of various doses levocetirizine and desloratadine.

Summaryn Levocetirizine has potent antihistaminic activity at the

recommended dose of 5 mg starting 1 hour and lastingfor at least 24 hours after administration, as demonstratedby various nasal challenge models

n Levocetirizine has a faster onset and a longer duration of action than desloratadine

n Levocetirizine has a similar onset but a longer duration of action than fexofenadine

n Levocetirizine maintains more than 65% of its maximaleffect 24 hours after administration (before nextrecommended intake)

n Levocetirizine relieves faster nasal congestion ascompared to desloratadine (as shown in the EEU™ with subjects suffering from SAR)

n In wheal and flare models levocetirizine, but notdesloratadine, significantly decreases the histamine-induced itch

n Levocetirizine demonstrates consistently high responder rates while desloratadine shows high inter-subject variability.

44

6.1. In-vivo studiesIf the anti-inflammatory effects of levocetirizine are to beinterpreted as being clinically relevant, it is essential that activityis demonstrated in humans in vivo at therapeutic doses.One such study was the skin chamber study33, which was of a double-blind, cross-over design enrolling 15 volunteers.Levocetirizine 5 mg or placebo were given daily for 6 days.On treatment day 4, a suction cup (A) was applied to the skin to raise a suction blister (B). The roof of the blister was then cutoff (C) and a plastic cup (D) glued to the skin over the blisterarea (Figure 6.1). The cup was then filled with Hank’s balancedsalt solution. On the morning of day 5, allergen or vehicle wasintroduced into the cup and samples withdrawn on the morningof day 6, 25 hours after allergen challenge.

Significant reductions in protein exudation and soluble VCAM-1in the cup were observed in patients who took levocetirizine.This is probably due to the inhibition of the oedema-causingeffects of histamine that lead to protein exudation (Figure 6.2A).If the inhibition of the sVCAM-1 accumulation in the cup wasdue to the same mechanism, the mean concentration of theadhesion protein would have been predicted to be at the level of the open red column in Figure 6.2B (approximately40% reduction versus placebo). However, the level was muchlower, suggesting an additional effect of levocetirizine, probablyan anti-inflammatory effect via inhibition of NF-κB activation34.

46

6. Anti-inflammatory propertiesof levocetirizine

Figure 6.1. The skin chamber technique.

A

C

B

D

47

Furthermore, when taking levocetirizine, a decrease ineosinophil recruitment was observed in volunteers with higheosinophil migration, n=4 (Figure 6.3). This finding wasconfirmed by a study35 in patients with seasonal allergicrhinitis, which demonstrated that levocetirizine significantlyreduced the number of eosinophils (p=0.029) andneutrophils (p=0.005) found in the nasal scrapings.In contrast, desloratadine did not significantly affect either ofthe two cell types (Figure 6.4A) (neutrophil data not shown).

Both levocetirizine and desloratadine significantly decreased the IL-4 levels in the nasal lavage (p=0.041 and p=0.044,respectively) (Figure 6.4B), while IL-8 levels were affectedonly by treatment with levocetirizine (p=0.02).

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Figure 6.2. Protein (A) and VCAM-1 (B) accummulation in the skin chamber following allergen challenge.Levocetirizine significantly reduces protein exudationand adhesion molecules (VCAM-1) thus limiting theinitiating steps of the inflammatory reaction.

Figure 6.3. Levocetirizine markedly reduced eosinophilmigration into the skin chamber.

In conclusion, levocetirizine has demonstrated both in an in vivo setting and in real SAR patients that it has clinicallyrelevant anti-inflammatory properties. It reduces the number of pro-inflammatory cells, eg, eosinophils and neutrophils,and modulates cytokine generation at therapeutic doses.These findings are in line with the ability of levocetirizine toimprove nasal obstruction, since it is known that this symptomis more representative of the allergic inflammation.

Summaryn Levocetirizine has anti-inflammatory activity at therapeutic

doses in in vivo studies

n Modulated cytokine generation and reduced number of eosinophils and neutrophils are seen with levocetirizine treatment

n Levocetirizine significantly reduces protein exudation and sVCAM-1

n The anti-inflammatory properties of levocetirizine areprobably due to inhibition of NF-κB activation.

48

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Figure 6.4. Inhibition of eosinophil numbers in the nasalscrapings (A) and IL-4 levels in the nasal lavage fluid (B)after 2 weeks of treatment. (Values are mean ± SD).

p=0.029 versus after levocetirizine

p<0.041 versus after levocetirizinep<0.044 versus after desloratadine

7.1. Clinical studies in seasonalallergic rhinitis (SAR)

The first seasonal allergic rhinitis study with levocetirizine wasof multicentre, randomised, double-blind, placebo-controlled,parallel-group design26 in which patients were randomised toreceive levocetirizine 5 mg (n=116) or placebo (n=119) oncedaily for 2 weeks. The change in T4SS over the entire studyperiod was compared, using two distinct categories; withouttaking into account weather conditions or under dry-onlyweather conditions.

Symptom relief with levocetirizine treatment was noticeablefrom the first day of treatment and was sustained over the total study duration. Compared with the placebo group,the improvement from baseline in T4SS was found to besignificantly higher in the levocetirizine group (Figure 7.1).Analysis of T4SS under dry weather conditions revealed an even more favourable treatment effect of levocetirizine (58% change in T4SS compared with placebo). This is veryimportant since pollen numbers during dry periods are higherand symptoms are much more severe necessitating higherantihistamine activity.

The observed effects were not only statistically significant but,more importantly, clinically relevant. The incidence of adverseevents with levocetirizine treatment was comparable with thatof placebo.

In conclusion, levocetirizine was highly effective in reducingsymptoms in patients with seasonal allergic rhinitis with higherefficacy in higher pollen days usually associated with moresevere symptoms.

The ability of levocetirizine and desloratadine to providesymptom relief, improvement in nasal airflow and anti-inflammatory activity was investigated in patients withseasonal allergic rhinitis. A randomised, double-blind,placebo-controlled, parallel-group study35 enrolled 30 patientswith a documented history of the disease within the previous 2 years who were subdivided in 3 groups of 10 patients and were assigned to receive either levocetirizine 5 mg,desloratadine 5 mg or placebo, for 2 weeks during the pollen season. All the patients were symptomatic at baseline.The clinical efficacy of the two drugs was assessed by a change in the mean Total Symptom Score (TSS) at the end of the 2 weeks compared with the baseline values.The TSS consisted of the symptoms: nasal obstruction,sneezing, rhinorrhoea, and itching of the nose. The effect of the two treatments on the nasal obstruction was objectively(rhinomanometry) documented by the change in the nasalairflow at the end of the study, compared with the baselinevalues. The number of inflammatory cells (eosinophils andneutrophils) in the nasal scrapings and the IL-4 and IL-8 levelsin the nasal lavage fluid were examined as markers of allergicinflammation at the beginning and the end of drug treatment.

50

7. Clinical efficacy of levocetirizineIm

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Levocetirizine 5 mg(dry weather conditions)

p=0.0001 versus placebo

Figure 7.1. Levocetirizine improvement over placebo in change from baseline of T4SS (adjusted means),during the whole study period and under dryweather conditions.

51

The inter-group analysis revealed a significant differencebetween levocetirizine and desloratadine groups (p=0.0023),between levocetirizine and placebo groups (p=0.0009) andbetween desloratadine and placebo groups (p=0.03) (Figure 7.2A). Levocetirizine significantly improved the nasalairflow (p=0.038) at the end of 2 weeks treatment, while bothdesloratadine and placebo showed no effect on this parameter(Figure 7.2B).

In conclusion, levocetirizine provided significant symptomaticrelief in patients with seasonal allergic rhinitis with significantlybetter efficacy than desloratadine. Not only did levocetirizineimprove the symptoms of allergic rhinitis, but it also increasednasal airflow; an effect that was not demonstrated withdesloratadine. This functional effect might result from an anti-inflammatory drug effect on the inflammatory componentof nasal obstruction. This was corroborated by the anti-inflammatory findings already discussed in chapter 6.

7.2. Clinical studies in perennialallergic rhinitis (PAR)

The clinical efficacy of levocetirizine in patients with perennial allergic rhinitis was assessed in a multicentre,double-blind, placebo-controlled, parallel-group study37.A total of 294 patients with documented disease wererandomised to receive either levocetirizine 5 mg (n=150) orplacebo (n=144) for 6 weeks during the winter season.Changes from baseline of the mean Total 4 Symptom Score(T4SS = sneezing, rhinorrhoea, nasal and ocular pruritus) werecompared between the treatment groups over the first week,the first 4 weeks and the total 6-week period. Nasal congestionwas also recorded and scored individually.

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p=0.0009 versus placebop=0.0023 versus desloratadinep=0.03 versus placebo

p=0.038 versus baseline

Figure 7.2. Improvement in total symptom score (A)and nasal airflow (B) from baseline after 2 weeks of treatment.

T4SS was significantly improved with levocetirizine comparedwith placebo over all treatment periods (Figure 7.3A).Levocetirizine achieved an 86% relative improvement in T4SS over placebo (p<0.001) already over the first week oftreatment. Nasal congestion was also significantly reducedfrom baseline in the levocetirizine group compared with theplacebo group over the whole treatment period (p-valuesranging from 0.002 to <0.001 for all study periods) (Figure 7.3B).

In conclusion, levocetirizine was effective in the treatment ofperennial allergic rhinitis, with a highly significant and rapidtreatment effect, which was reported from the very first controlvisit and maintained throughout the 6 weeks of the study.In addition to the symptoms usually relieved by antihistamines,levocetirizine also significantly reduced nasal congestion, whichwas also observed during the first control visit and maintainedthroughout the 6 weeks.

7.3. Clinical studies in persistantallergic rhinitis (PER)

Levocetirizine was the H1-antihistamine chosen by a renownedgroup of specialists for the first study that evaluated theimplications of long-term antihistaminic treatment in persistentallergic rhinitis as defined by the new ARIA classification.The study is called XPERT™ (Xyzal in Persistent AllergicRhinitis Trial)38. A total of 551 patients diagnosed withpersistent allergic rhinitis who were sensitised to both housedust mites and pollens were enroled in this double-blind,placebo-controlled, parallel-group, multicentre study.Patients were randomised to receive either levocetirizine 5 mg(n=278) or placebo (n=273) for a 6-month period (Figure 7.4).The primary end-points of the study were the impact oftreatment on the symptom outcome evaluated as the change in Total 5 Symptom Score (T5SS = sneezing, rhinorrhoea,nasal pruritus, ocular pruritus and nasal congestion) and on the patients’ quality of life evaluated by the RhinoconjunctivitisQuality of Life Questionnaire (RQLQ) over a period of 4 weeks.Secondary parameters included T5SS and RQLQ assessmentsmade at week 1 and over 3, 4.5 and 6 months of treatment.In addition, summary scores from the general health statusquestionnaire (SF-36), a pharmacoeconomic assessment,incidence of co-morbidities and safety over all treatmentperiods were also evaluated.

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Figure 7.3. Improvement in mean T4SS score (A) andnasal obstruction score (B) from baseline in the twostudy groups over 1-week and 6-week period.

Figure 7.4. XPERT™ study design. Levocetirizine wasadministered over 6 months in patients suffering frompersistent allergic rhinitis.

53

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Levocetirizine treatment resulted in a significant (p<0.001)improvement of rhinitis symptoms (T5SS) compared with placeboover all treatment periods (week 1 to month 6). Although atbaseline persistent symptoms were of moderate severity,significant improvement was noticed already at the first visit of thestudy, and was maintained for the 6-month duration of the study(p<0.001) (Figure 7.5)39. The difference between the 2 arms ofthe study was larger than the minimum clinically relevant scoredifference of 1 versus placebo that was pre-specified by theboard of experts. There was also a statistically significantdifference for the individual symptoms of rhinorrhoea, sneezing,and nasal and ocular pruritus. Levocetirizine 5 mg significantlyimproved nasal congestion after 4 weeks of treatment, and thiswas generally maintained for the duration of the study. From thepoint of view of the patients, nasal congestion was improvedfrom ‘disturbing’ at baseline (score; 1.94±0.69) to mild or less,ie, ‘present but not disturbing’ (score 0.92±0.88), followingtreatment with levocetirizine (Figure 7.6; data on file).

Furthermore, over the primary study period of the first 4 weeks,cromoglycates (both nasal and ocular) were more frequentlyused by the placebo (62.6%) than the levocetirizine patients(49.3%); p=0.002. Over the entire 6-month period, a trend formore rescue medication use in the placebo group was observedfor prednisolone (13.6% versus 10.8%; p=0.362) and forcromoglycates (75.8% versus 69.4%; p=0.104).

Considering the 6-month duration of the study, levocetirizineappeared to be a particularly safe and well-tolerated treatment having a comparable rate of adverse effects with placebo; 70.7% of placebo-treated and 69.1% of the

levocetirizine-treated patients reported at least one adverseevent at some point during the 6-month period.

The most common adverse events were, for placebo versuslevocetirizine, respectively, headache (23.2% versus 24.5%),pharyngitis (20.5% and 19.8%), influenza-like symptoms (13.9% versus 14.0%), fatigue (7.0% versus 8.6%), somnolence(1.8% versus 6.8%), and gastroenteritis (5.1% versus 2.9%).

The overall frequency of co-morbidity events (such as asthma,upper respiratory viral infections and sinusitis) was significantlylower in the levocetirizine group than in the placebo group (54 versus 71 events/100 patients), over all 6 months (Figure 7.7).

Figure 7.5. Comparative evolution of T5SS over the 6 months of the study39.

Levocetirizine (n=278), placebo (n=273)p<0.05 versus placebo (Weekly) p<0.05 versus placebo (Monthly)

Figure 7.6. Improvement in nasal congestion.

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Most of the co-morbidity events were upper respiratory infectionevents, and represented 74% and 77% of all co-morbidityevents in the placebo and levocetirizine groups, respectively.For asthma events, respective figures were 18% and 13% forplacebo and levocetirizine groups. Except for sinusitis events,all co-morbidity event categories occurred more frequently inthe placebo group.The quality of life and pharmacoeconomicresults are reported in chapters 8 and 9, respectively.

In conclusion, levocetirizine is a fast acting, efficacious andwell-tolerated medication suitable for use in the long-termtreatment of persistent allergic rhinitis. Significant benefits onboth nasal symptoms and patient quality of life were noticed asearly as 1 week after the beginning of treatment and weremaintained over an extended period of 6 months. Long-termtreatment with levocetirizine had a sustained and significanteffect, not only on the classical histamine related symptoms,but also on nasal obstruction, an effect that demonstrates theanti-inflammatory potential of levocetirizine with regular dailyuse. Effective long-term treatment with levocetirizine was alsoassociated with an important reduction in the overall economicburden due to allergic rhinitis. When used for a long timelevocetirizine has the potential to reduce asthma-related co-morbid events as well as medication use for asthma.

7.4. Clinical studies in chronicidiopathic urticaria (CIU)

A randomised, double-blind, placebo-controlled, parallel-group,multicentre study evaluated the impact of levocetirizinetreatment on pruritus, wheal and quality of life in patients withchronic idiopathic urticaria40. The study included 166 patientssuffering from chronic idiopathic urticaria (no identifiable cause)for at least 6 weeks during the last 3 months. Patients wererandomly allocated to two groups to receive either levocetirizine 5 mg (n=81) or placebo (n=85) for 4 weeks.

The primary criterion for evaluation was the evolution of pruritusseverity score over the first week as well as over the total studyduration. Other parameters, such as the number and size ofwheals, pruritus duration, quality of life (assessed by DLQI),patients’ global evaluation of the disease outcome and theeconomic impact (additional treatment costs and overall loss ofproductivity) were also compared between the two study groups.

During the first week of treatment, the mean severity of pruritusdecreased significantly in the levocetirizine group comparedwith placebo (p<0.001) (Figure 7.8). There was a significantimprovement over placebo as early as day 2. The therapeuticeffect of levocetirizine remained significant during the entiretreatment period (p<0.001). The mean pruritus severity scoredecreased in the levocetirizine group from moderate (disturbing)to mild (non-disturbing). In addition, the duration of pruritus wassignificantly shorter in the levocetirizine group during the firstweek as well as over the total treatment period (p<0.001).In total, 52% of the patients treated with levocetirizine reported a marked improvement in their condition. The number of placebo-treated patients was half of that.

Investigators estimated that only 3.8% of the levocetirizine-treated patients had severe pruritus 1 week after drug intakecompared with 21.4% in the placebo group. After 4 weeks oftreatment, 85.3% of levocetirizine patients had no or mildpruritus compared with 66.7% in the placebo group.

54

46% 54%46% 54%29%

Placebo patients withassociated co-morbidities

Placebo patients withoutassociated co-morbidities

71%

Levocetirizine patients withassociated co-morbidities

Levocetirizine patients withoutassociated co-morbidities


Figure 7.7. Incidence of co-morbidities in the two study groups38.

Prur

itus

scor

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prov

emen

tfr

omm

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Week 1 Week 4


1.2

0.8

0

0.2

0.4

1.0

0.6

Figure 7.8. Improvement of pruritus severity score(means) with levocetirizine over the first week that wasmaintained over all 4 weeks of the study.

The mean number and size of the wheal scores were alsosignificantly improved in the levocetirizine group compared withplacebo (p<0.001) both after 1 week and over the total studyperiod (Figure 7.9).

Importantly, over the treatment duration, the use ofconcomitant medications for urticaria was 10 times higher in the placebo group (25.9) compared with only 2.5 medication events per 100 patients with levocetirizine(p<0.001). No patient in the levocetirizine treated group used corticosteroids.

The quality of life and pharmacoeconomic results are reportedin chapters 8 and 9, respectively.

In conclusion, levocetirizine is an effective treatment forchronic idiopathic urticaria providing rapid and sustained relief for the most worrisome symptoms (pruritus and wheals)as assessed by both objective and subjective criteria.Levocetirizine treatment is also associated with a significantdecrease in overall loss of work productivity and in the use of additional medications.

7.5. Clinical studies in paediatricsThe efficacy and safety of levocetirizine in children has beenevaluated in both seasonal and perennial allergic rhinitis.In addition, specific pharmacokinetic and pharmacodynamicstudies have been performed, which complete the profile of this medication providing data on its use in the paediatric population.

Levocetirizine has been evaluated in a multicentre,randomised, double-blind, placebo-controlled study41 enrolling177 children 6 to 12 years of age with a documented historyof seasonal allergic rhinitis for at least 1 year. Patients wererandomised to receive either levocetirizine 5 mg (n=89) orplacebo (n=88) for 6 weeks.

The primary objective of this study was to assess the efficacyof levocetirizine in reducing seasonal allergic rhinitis symptoms measured by the changes in the Total 4 SymptomScore (T4SS = sneezing, rhinorrhoea, nasal and ocularpruritus), over the first 2 weeks of treatment. Among thesecondary objectives evaluated were: efficacy on symptomsover 4 and 6 weeks of treatment, effect on nasal congestionand on health-related quality of life as measured by thePRQLQ and the global evaluation of illness evolution.

Impr

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Over the first week

11.5%

32.9%

15.3%

38.8%

25.0%

46.4%

31.0%

52.0%

Over the first 2 weeks Over the whole 6 weeksOver the first 4 weeks

3

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p=0.001 versus placebo

Whe

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1.5

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0.5

1.0

Whe

alsi

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1.5

0

0.5

1.0

Figure 7.9. Mean number and size (± SE) of whealsscores over the entire duration of the study.


Figure 7.10. Improvement of SAR symptoms in children treated with levocetirizine during all study periods.

After 2 weeks of treatment, levocetirizine alleviated significantlythe symptoms of seasonal allergic rhinitis (p<0.001) with a 94.1% relative improvement in T4SS from baseline overplacebo. The efficacy of levocetirizine remained significant(p<0.001) during all the 6 weeks of treatment (Figure 7.10).Evaluation of the individual rhinitis symptoms also showedsignificant improvements in the levocetirizine group comparedwith placebo throughout all the study periods. In addition, nasalobstruction was improved in children treated with levocetirizinereaching a maximum relative improvement over placebo, duringweek 3, of 77.5% (p<0.05). The disease evolution was rated asslightly-to-markedly improved with levocetirizine treatment byrespectively 84.3%, 80.9%, and 80.9% of the investigators,the parents and the children themselves. The respective figuresfor placebo were 54.5%, 60.2%, and 53.4%.

Incidence of treatment-emergent adverse events was similar inboth groups (33.7% with levocetirizine; 30.7% with placebo).No child in the levocetirizine group discontinued treatmentbecause of adverse events.

PRQLQ results are reported in chapter 9.

In conclusion, levocetirizine 5 mg daily is very well tolerated inchildren. It significantly improves all symptoms of seasonalallergic rhinitis in children 6 to 12 years of age. In agreementwith studies in adults, levocetirizine is clinically effective andwell tolerated in children as young as 6 years of age and canbe administered over the entire season to ensure a good overallsymptom control and increased quality of life.

Another randomised, double-blind, placebo-controlled,parallel-group study42 in children assessed the effectiveness oflevocetirizine in relieving the symptoms of perennial allergicrhinitis in children 6 to 12 years of age. A total of 306 childrenwere randomly distributed to receive either levocetirizine 5 mg(n=154) or placebo (n=152) for 4 weeks. The study efficacyvariables were the change in Total 4 Symptom Score (T4SS = rhinorrhoea, sneezing, nasal and ocular pruritus) frombaseline over the first 2 weeks of the study, as well as over the entire study period. The effect on the health-related qualityof life was assessed by the PRQLQ over week 1, 2 and all 4 weeks of treatment.

With regard to improvement in T4SS, treatment withlevocetirizine led to a significant improvement of the perennialsymptoms in children over all study periods. The relativeimprovement seen with levocetirizine compared with placebowas highly significant over the first 2 weeks (90.09%, p=0.001)and remained significant (p=0.008) over all 4 weeks of the

study (Figure 7.11).

Levocetirizine was well tolerated and no serious adverseevents occurred in any of the study patients. The incidence oftreatment-emergent adverse events judged as related to thestudy medication was similar between the groups (7.8% in the levocetirizine versus 5.9% in the placebo group).

PRQLQ results are reported in chapter 9.

In conclusion, this study confirms that levocetirizine 5 mgsignificantly improves the symptoms and the health-relatedquality of life in children with perennial allergic rhinitis in a relatively short period of time, and, therefore, can beconsidered to be a preferred treatment option for children as young as 6 years of age.

A study designed to assess the pharmacokinetics and safetyof levocetirizine in very young children (1 to 2 years of age) ata single dose of 0.125 mg/kg and with continuous therapy for 3 months at the same dose twice daily was performed inorder to confirm the dose intended for infants31. The study also evaluated the potency of levocetirizine in this age groupvia a pharmacodynamic histamine-induced wheal and flare(see chapter 5.5). Fifteen infants (11 boys and 4 girls,age range 13 to 25 months and weight range 9 to 15 kg)were recruited. Before the initiation of treatment, each childhad a physical examination, blood and urine tests to detectany disease or concurrent treatment that might interfere withthe pharmacokinetic and pharmacodynamic assessments.

56

p<0.001 versus placebop=0.008 versus placebo

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Over 2 weeks Over 4 weeks


2.0

1.0

0

1.5

0.5

Figure 7.11. Improvement of perennial allergic rhinitissymptoms (T4SS score) in children treated withlevocetirizine.

On the morning of the first day of the study, the infants had a histamine (10 mg/ml) skin prick test to determine baselinewheal and flare responses. They then received a single doseof 0.125 mg/kg levocetirizine and a complete pharmacokineticprofile was determined in 11 of the 15 infants. Thereafter,the same treatment was administered twice daily for 90 days.On days 3 to 6 and day 90 the children were examined andblood levels of levocetirizine determined. At day 90, blood andurine tests were also performed. To determine the inhibition ofhistamine-induced wheal and flare, histamine skin prick-testswere performed at days 3 and 90 and the results werecompared with the baseline values.

The overall safety profile of this 3-month open study wasexcellent. No clinical adverse events were reported, apart fromtwo cases of isolated, marked increases in alkaline phosphatase(one on day 3 and one on day 90), the first of which led topremature withdrawal from the study. No clinically relevanthaematological or biochemical abnormalities were observed.

Table 7.1 shows that the pharmacokinetic characteristics oflevocetirizine in infants are similar to those in adults with theexception of plasma half life (t1⁄2), which was approximately 4 hours, a value about two times lower than in adults.The CL/F, when adjusted to body surface area, was similar to that reported in adults.

As presented in chapter 5, levocetirizine achieved an almosttotal inhibition of the wheal and flare in the studied children(both at day 3 and day 90).

In conclusion, this study confirms the good pharmacokinetic/pharmacodynamic and safety profile of levocetirizine using

the intended dosing regimen of levocetirizine 0.125 mg/kg inchildren aged 12 to 24 months. It also shows that levocetirizinehas a potent inhibitory activity of histamine-induced wheal and flare responses, comparable with the inhibition observed in adults and superior to the inhibition reported with cetirizinein a population of a similar age46.

EPAAC™

The only study designed to evaluate the efficacy of anantihistamine on the prevention of asthma symptoms inchildren with a family history of atopy suffering from atopicdermatitis, and sensitised to grass pollen and/or house dustmite allergens, is the EPAAC™ (Early Prevention of Asthma in Atopic Children) trial using levocetirizine as the activetreatment. EPAAC™ is a double-blind, placebo-controlled,randomised, parallel-group trial enrolling asthma-free atopicchildren from 12 countries. The efficacy and safety oflevocetirizine 0.125 mg/kg administered twice daily for 18 months will be evaluated in preventing the onset of asthmain 1 to 2 year-old children. The results of this large study areexpected in 2006.

Approximately 2500 children have been screened and 500 children with a high risk of developing asthma enrolled forthis study. In addition to assessing the effects of levocetirizine,this trial offers also a unique opportunity to performepidemiological investigations in, for example, the associationbetween hygiene-related risk factors and early sensitisation,severity of dermatitis and biological markers in a high-riskgroup of infants.

ParameterLevocetirizine

Cmax (ng/ml) 286 (68) 270 (40)

tmax (h) 1.00 (1.0–6.0) 0.8 (0.5)

AUC (ng x h/ml) 1955 (186) 2310 (500)

T1/2 (h) 4.1 (0.67) 7.0 (1.5)

CL/F (ml/min/kg) 1.05 (0.10) 0.57 (0.18)

VZ/F (l/kg) 0.37 (0.06) 0.33

Serum protein binding 89.3 ± 1.0% 91%

57

Table 7.1. The pharmacokinetic characteristics of levocetirizine in children aged 1 to 2 years.

Data are expressed as mean ± standard deviation except tmax for children expressed as median (minimum to maximum).Comparative adult data are from43, 44, 45. CL/F: apparent oral body clearance; VZ/F: apparent volume of distribution.

Children (0.125 mg/kg) Adults 5 mg

Summaryn Levocetirizine 5 mg once a day is highly effective in

relieving the symptoms of seasonal (SAR), perennial (PAR)and persistent (PER) allergic rhinitis even under dryweather conditions when levels of airborne allergen are likely to be high

n Levocetirizine is the first and only antihistamine to datewith confirmed clinically relevant efficacy in persistentallergic rhinitis (PER) within the first week of treatmentand sustained for the whole 6-month study period

n Levocetirizine is an effective treatment for perennialallergic rhinitis (PAR) with relative efficacy over placebo of 86% within the first week of treatment

n Levocetirizine has been shown to significantly reducenasal congestion in perennial allergic rhinitis (PAR)patients within the first week after intake; an effectmaintained over the full 6-week duration of the study

n Levocetirizine 5 mg is an effective treatment for chronicidiopathic urticaria (CIU) as assessed by both objectiveand subjective criteria

n Levocetirizine provides rapid, strong and sustained relieffrom the most worrisome symptoms of chronic urticaria:pruritus and wheals

n Levocetirizine can be used for long-term regular treatmentof children 6 to 12 years of age with seasonal allergicrhinitis (SAR) and perennial allergic rhinitis (PAR)

n Levocetirizine shows more potent anti-inflammatoryeffects and is significantly more active in relievingsymptoms of seasonal allergic rhinitis (SAR) thandesloratadine

n Levocetirizine can improve nasal airflow, an effect notdemonstrated with desloratadine in the same setting.

Further reading

n Scadding GK & Church MK (2000). Rhinitis. In Allergy 2nd Edition

(Eds: Holgate ST, Church MK, Lichtenstein LM), pp. 55–76.London: Mosby).

n Lightman S & Buckley RJ (2000). Conjunctivitis. In Allergy 2nd Edition


n Allergic Rhinitis and Its Impact on Asthma. ARIA guidelines.

Available at: http://www.whiar.com.

n Grattan CEH & Charlesworth EN (2000). Urticaria. In Allergy 2nd Edition


58

The impact of levocetirizine on health-related quality of life hasbeen evaluated in several clinical trials using well-validated andwidely used instruments. The quality of life in all approvedindications (including persistent allergic rhinitis and CIU) ispresented below.

8.1. Improvement in quality of life in adults

In addition to the traditional efficacy parameters (see chapter 8.3) the large XPERT™ study38 also evaluated the effects of treatment on health-related quality of life,general health status and costs of persistent rhinitis.

XPERT™ used two widely accepted, well-validated and reliablequestionnaires, the Rhinoconjunctivitis Quality of LifeQuestionnaire (RQLQ) and the Short Form-36 questionnaire(SF-36) in order to assess the treatment effects oflevocetirizine on QoL. Significant improvements were foundwith levocetirizine 5 mg over the entire 6-month treatmentperiod for all scores of both questionnaires. Highly significantdifference (p<0.001) was observed over placebo for the overallscore of the disease-specific RQLQ. This improvementremained statistically significant in favour of levocetirizine forthe entire 6 months of the study period (Figure 8.1), and wasalso apparent as early as week 1 (p<0.001). The Improvementof the overall score was confirmed also for each of the RQLQdomains (all p<0.001 at 4 weeks).

The relative improvement in the RQLQ overall score withlevocetirizine over placebo for the whole treatment period was 36.4%. It ranged from 31.3% to 40.8% for the RQLQdomain scores and was the largest (>40%) for the sleep,nasal and eye symptom domains (Figure 8.2). Improvements in RQLQ domain and overall scores were considered clinically significant since they exceeded the 30% predefined thresholdfor clinical significance.

60

8. Contribution of levocetirizineto improvement inpatients’ Quality of Life



Chan

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-1

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Nasalsymptoms

Practicalproblems

SleepEmotions

-2.5

0

-1.0

-2.0

-3.0

-1.5

-0.5

Figure 8.1. Improvement of the health-related quality oflife with levocetirizine treatment as observed by thechanges from baseline in overall RQLQ score39.

Figure 8.2. Improvement of the RQLQ overall and domain scores with levocetirizine treatment over the 6-monthtreatment period39.

61

Regarding the more general SF-36 questionnaire, improvementsin scores with levocetirizine treatment (Figure 8.3) wereparticularly large for the role-physical and role-emotional scales,which largely followed the trend of the RQLQ. Statisticallysignificant improvements with levocetirizine treatment weredemonstrated over 3 and 4.5 months for the mental componentsummary (MCS) scores (both p<0.01) and over 4 weeks and 3,4.5, and 6 months for the physical component summary (PCS)scores (all p<0.01).

8.2. Improvement in quality of life:Urticaria

Chronic urticaria is often associated with impairment of daily activities and health-related quality of life (HRQoL).Since data in this domain is relatively scarce, the effect oflevocetirizine has been evaluated in a clinical study40 using thevalidated DLQI (Dermatology Life Quality Index) questionnaire,which has been developed to assess the impairment of HRQoLassociated with various dermatological conditions.

A particular interest of the study was the assessment of howalleviation of improvement in symptoms translates intoperceptible improvement of patients’ quality of life andreduction of the burden to society.

In this 4-week study, 166 patients suffering from CIU wererandomized to receive either levocetirizine 5 mg, or placebo.Quality of life scores paralleled the symptom evolution with a larger improvement in the levocetirizine group (overall score reduction with 7.3 units in the levocetirizine groupversus 2.4 units in the placebo group) (Figure 8.4A).Patients’ subjective evaluation of the disease outcome at the end of the study showed a higher proportion of patients reporting a marked improvement in the levocetirizinegroup compared with the placebo group (52% versus 27% respectively) (Figure 8.4B).

p<0.001 versus placebop<0.01 versus placebop<0.05 versus placebo

Impr

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PCS MCS Bodily pain Generalhealth

Vitality Socialfunctioning

Mentalhealth

Role-physical

Role-emotional

Physicalfunctioning

25

0

10

20

30

15

5

Figure 8.3. Improvement in SF-36 scales and component summary scores with levocetirizine treatment over the 6-month treatment period39.

8.3. Improvement in quality of life in children

QoL improvements with levocetirizine treatment have also beenevaluated in paediatric population studies.

In a randomised, double-blind, placebo-controlled study42,children aged 6 to 12 years suffering from perennial allergicrhinitis of at least one year’s duration were enrolled, providedthey were confirmed to be sensitive to house dust mite.The children were randomized to receive levocetirizine 5 mgonce per day or placebo for 4 weeks.

A special paediatric QoL questionnaire (PRQLQ), designed tobe completed by children themselves with the aid of a trainedinterviewer, was chosen to assess the health-related quality of life since it has already been successfully validated and used elsewhere.

Levocetirizine improved QoL at all assessment visits comparedto placebo. The evolution of the overall PRQLQ score (Figure 8.5)demonstrated that levocetirizine improved consistently, over allthe 4 weeks of treatment, the quality of children’s lives.It also improved the five PRQLQ domains: nose symptoms,eye symptoms, practical problems, other symptoms and activitylimitations. The primary efficacy improvements in T4SS showedstatistically significant correlations with the PRQLQ results,as would be expected in a largely symptom-driven disease.

Another paediatric study41, using the same PRQLQ instrument,evaluated the efficacy of levocetirizine and its effect on qualityof life in children between the ages of 6 and 12 years inclusive,with confirmed and documented seasonal allergic rhinitis.177 were randomised to treatment (88 to placebo and 89 tolevocetirizine). The majority of the children (98.3%) weresensitised to grass pollen (a positive or a very positive RASTtest or a positive skin test for grass pollen).

62

Figure 8.4. Quality of life scores (A) and proportion ofpatients who self-rated their disease outcome asmarkedly improved (B).

Figure 8.5. Improvement in overall PRQLQ score withlevocetirizine treatment over all study periods.

Impr

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63

Already at the first study visit (after 2 weeks of treatment),children treated with levocetirizine presented an overall PRQLQscore improvement over baseline larger with levocetirizineversus placebo (0.85 versus 0.51 respectively) (Figure 8.6A).The improvement observed in the levocetirizine group after 4 and 6 weeks of treatment remained larger than in theplacebo group at all time points, both for the overall score (1.19 and 1.55 respectively) and for the individual domains.In the global evaluation of disease evolution, there was a highconcordance of assessments made independently byinvestigators, parents and children. The results showed thatmore than 80% of the children in the levocetirizine group hadan improvement in their disease evolution compared withapproximately 50% in the placebo group (Figure 8.6B).With regards to the incidence of reported adverse events,similar numbers were found in both levocetirizine and placebo groups.

Impr

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Nose symptoms Eye symptoms Other symptoms Activity limitationsOverall score Practical problems

0.8

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15.7%

30.9%

23.2%

40.6%

18.2%

36.1%

19.4%

28.5%

33.5%

19.2%

33.7%

22.5%

Figure 8.6. Improvement in the individual domains scoreof PRQLQ from baseline (A) and global evaluation ofdisease evolution (B).

[3 H]M

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Disease improvement

Investigators

Global evaluation of disease evolution

Patients

Parents

Placebo Levocetirizine

No disease improvement

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16%84%45%

55%

19%81%

19%81%

47%53%

40%60%

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Summaryn Quality of life in patients suffering from persistant allergic

rhinitis (PER) is improved with levocetirizine as early asweek 1 after intake; an effect that is maintained as longas treatment continues

n The most significant QoL-related improvements withlevocetirizine treatment can be achieved in the domains of nasal and eye symptoms and disturbed sleep due tothe disease

n A significant improvement of the general health status,especially in role physical, role emotional and generalhealth, is achieved with levocetirizine treatment

n Co-morbidity events (eg, asthma) associated withpersistent rhinitis are lower with levocetirizine

n Improvements in QoL with levocetirizine have beenobserved in children suffering from seasonal allergicrhinitis (SAR) or perennial allregic rhinitis (PAR),a finding confirmed also by improvements in the patient’sassessment of the disease evolution.

64

9.1. Health-economic savings inallergic rhinitis

In addition to the efficacy and quality of life measurements,the XPERT™ study evaluated the costs incurred by society andpatients due to persistent allergic rhinitis and assessed whether levocetirizine was able to reduce these costs47.Both direct cost and time lost measures were collected inXPERT™. These parameters were associated with bothpersistent rhinitis and its co-morbidities. Healthcareexpenditures (additional medications and unscheduledphysician visits) were considered as direct medical costs.The time lost parameters refer to the productivity lost at work, ie, absenteeism (full days off work) and presenteeism(productivity lost while at work) and time lost in usual dailyactivities (leisure activities and other usual activities such ashousework) because of persistent rhinitis or its co-morbidities.

Overall cost parameters showed an improvement in thelevocetirizine group compared to no treatment. When convertedto monetary value, using French costing data, it appeared that, from a societal perspective, the total mean monthly cost per patient in the levocetirizine group was €202.12 (95% CI: 171.84 to 243.21) compared to €355.06 (95% CI: 300.68 to 428.41) in the no-treatment group.

This corresponded to a gain of €152.93/patient/month(p<0.001) or a 43% cost reduction over the costs of persistentrhinitis with no treatment (Figure 9.1). From an employerperspective, which excludes medication costs and physicianvisits, the gain was €64.70 per working patient per month(p<0.001). From a societal perspective, direct medical costslinked to persistent rhinitis were larger in the levocetirizinegroup (€16.39/patient/month) than in the no-treatment group(€5.32/patient/month), however, it should be noted that thedirect medical costs (paying for the levocetirizine treatment)constituted only 2% of the total costs. Using only French datawas not considered a limitation since, when the analysis wasrestricted to the French patients, the difference obtainedbetween the two groups (€200.94) was within the 95% confidence interval of the difference obtained afterpooling patients from all countries.

66

9. Contribution of levocetirizine to improvement inhealth-economics savings

€/pa

tient

/mon

th

Direct cost Work days lost

Levocetirizine(n=278)

No-treatment(n=196)

No-treatment(n=273)


No-treatment(n=273)

+2.78 [1.45; 3.87]

-64.70 [-111.89; -25.27]

-152.93[-231.83; -84.86]


Employer perspective Societal perspectiveSocial security perspective

300

0

250

200

150

100

50

450

400

350

Usual daily activites lost

Figure 9.1. Savings in the direct and indirect costs related to persistent allergic rhinitis achieved with levocetirizinetreatment from social security, employer and societal perspectives.

67

9.2. Health-economic savings inchronic idiopathic urticaria

In addition to the efficacy and quality of life measurements inCIU, a health-economics analysis has been performed withlevocetirizine treatment based on 2 clinical studies48. A total of294 patients suffering from CIU received either levocetirizine 5 mg or placebo administered once daily in the evening,for 4 weeks. Direct costs and productivity costs, in addition to efficacy and safety parameters were collected at baselineand during the treatment period.

Use of concomitant medications for relieving urticaria symptomsover all 4 weeks was 10 times higher for patients treated withthe placebo than for those treated with levocetirizine.The placebo group had a mean number of medication events at baseline of 1.4 per 100 subjects that increased to 35.4 over4 weeks (Figure 9.2). The mean number of medication eventsin the levocetirizine group increased from 2.1 at baseline to 2.7 over the evaluation period, which was more than 10 timeslower compared to the placebo group (p<0.001). Medicalprocedures for urticaria were only reported in the placebogroup. When standardised to 100 subjects, this correspondedto 0.67 medical procedures per 100 subjects for placebo andzero for levocetirizine.

Interestingly, while the placebo treated patients saw adecrease in productivity, patients treated with levocetirizineincreased their productivity over the study period. Up to 31.1%of the subjects in the placebo group experienced productivityloss for a mean of 2.24 days per subject. Subjects receivinglevocetirizine had a lower overall mean productivity loss(p<0.05). Overall productivity improved in the levocetirizinegroup (Figure 9.3).

Using a French societal perspective (2002 valuation) for allstudy patients and standardising all costs to a 30-day month,cost savings of €91.93/patient/month (p<0.05 vs placebo)were achieved with levocetirizine treatment when all costs(direct, absenteeism and presenteeism) were taken intoaccount (Figure 9.4). This was also true for the individual costcomponents with cost savings of €51.92/patient/month forabsenteeism and €39.64/patient/month for presenteeism.

Num

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1.0

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Figure 9.2. The number of co-medication events/100 patients (use of co-medications) after 4 weeks of treatment with levocetirizine or placebo.


Figure 9.3. The overall work productivity after treatment with levocetirizine increased over the wholestudy duration.

The results of this cost analysis provides evidence that subjectswith CIU can benefit from considerable cost savings if treatedwith levocetirizine. Although direct costs could be slightly higher with the active treatment due to the cost for the drug,savings are made primarily due to the decreased absenteeismfrom or presenteeism at work. Levocetirizine is a highly cost-effective treatment for CIU, which is in addition to its verygood symptom control.

Summaryn Levocetirizine decreases the costs for disease

management associated with persistent rhinitis by as much as 43%; savings of around €150 per patient per month

n The direct medical costs associated with levocetirizinetreatment comprise only 2% of the total diseasemanagement costs for persistant allergic rhinitisi (PER)

n Levocetirizine treatment is associated with a significantdecrease in work productivity loss and in the use ofadditional medications

n Treatment of urticaria with levocetirizine is associated with 10 times less medication events compared to no treatment

n CIU subjects treated with levocetirizine have a lowerproductivity loss and a lower absenteeism from work

n Savings in the treatment of urticaria of around €90 perpatient per month can be made if chronic idiopathicurticaria (CIU) patients are treated with levocetirizine.

68

Mea

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0

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40

180

160

140

120

Direct cost

Placebo Levocetirizine

PresenteeismAbsenteeism

Figure 9.4. Savings in the direct and indirect CIU relatedcosts made with levocetirizine treatment over theevaluation period (€ per 30 treatment days).

Levocetirizine has been administered numerous times and overextended periods with a favourable tolerability profile. Patient’sexposure is estimated under the hypothesis that a patientwould be treated for a period ranging from 20 to 60 days peryear. Based on UCB sales records49, the cumulative exposuresince the launch of levocetirizine (Feb 2001 to Nov 2004) isestimated to range from 5,637,880 (20 days) to 16,913,639(60 days) treatment periods.

10.1. Undesirable effectsIn therapeutic studies in women and men aged 12 to 71 years,15.1% of the patients in the levocetirizine 5 mg group had atleast one adverse drug reaction compared to 11.3% in theplacebo group50; 91.6 % of these adverse drug reactions weremild to moderate. In therapeutic trials, the drop-out rate due to adverse events was 1.0% (9/935) with levocetirizine 5 mgand 1.8% (14/771) with placebo. Clinical therapeutic trials withlevocetirizine included 935 subjects exposed to the drug atthe recommended dose of 5 mg daily. From this pooling,the following incidence of adverse drug reactions was reportedat rates of 1% or greater (common: >1/100, <1/10) underlevocetirizine 5 mg or placebo (Table 10.1):

Further uncommon incidences of adverse reactions(uncommon >1/1000, <1/100), such as asthenia or abdominalpain were also observed.

In addition to the adverse reactions reported during clinicalstudies and listed above, isolated cases of the followingadverse drug reactions have been reported in post-marketingsurveillance.

Data are at present insufficient to support an estimate of theincidence of adverse drug reactions in the population to betreated50, however, the common adverse drug reactionsexperienced were as follows:

n Immune system disorders: hypersensitivity includinganaphylaxis

n Respiratory, thoracic, and mediastinal disorders: dyspnoea

n Gastrointestinal disorders: nausea

n Skin and subcutaneous tissue disorders: angioneuroticoedema, pruritus, rash, urticaria

n Investigations: weight increased.

10.2. CNS safetyComparative clinical trials have revealed no evidence that levocetirizine (at the recommended dose) impairs mental alertness, reactivity, or the ability to drive.Nevertheless, some patients could experience somnolence,fatigue and asthenia whilst on therapy with levocetirizine.Therefore, patients intending to drive, engage in potentiallyhazardous activities or operate machinery should take theirindividual response to the medicinal product into account51.

In a five-way, double-blind, crossover study52, 20 healthyvolunteers were randomised to receive either levocetirizine 5 mg, cetirizine 10 mg, loratadine 10 mg, promethazine 30 mg and placebo once daily for 4 days. During eachtreatment period, subjects were assessed using a battery ofpsychometric tests—critical flicker fusion (CFF), choice reactiontime (CRT), a continuous tracking task (CTT) and line analoguerating scales for sedation (LARS)—as well as a pinprick wheal and flare response to 100 mg/ml histamine solution atbaseline and at 1, 2, 3, 4, 6, 8, 10 and 12 hours after dosageon days 1 and 4.

The results showed that levocetirizine, cetirizine and loratadine,unlike the positive control drug, promethazine, were notdistinguishable from placebo in any of the objective orsubjective tests at any time point. In the skin, levocetirizineinhibited both the wheal and flare responses by more than80% on day 1 after dosing. Loratadine showed only a weakinhibitory activity on wheal and flare that completelydisappeared by day 4.

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10. Safety

Preferred Term Placebo Levocetirizine 5 mg(WHOART) (n=771) (n=935)

Headache 25 (3.2%) 24 (2.6%)

Somnolence 11 (1.4%) 49 (5.2%)

Mouth dry 12 (1.6%) 24 (2.6%)

Fatigue 9 (1.2%) 23 (2.5%)

Table 10.1. Incidence of adverse drug reactions.

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In a three-way cross-over study53, levocetirizine 5 mg,diphenhydramine 50 mg (positive control) or placebo wasadministered once daily for five consecutive days to 19 healthymale volunteers. A battery of psychometric tests including CFF,CRT, body sway, learning memory test and subjectiveassessments of alertness, were performed on day 1 and again on day 5. The results showed that, at all time points,levocetirizine did not produce any deleterious effect on cognitiveor psychometric functions compared with placebo at any time.

The question of sedation following antihistamine use poses adanger to ambulant patients involved in daily activities such asdriving. Consequently, the effects of levocetirizine 5 mg werecompared with diphenhydramine 50 mg (positive control) andplacebo on driving ability during normal traffic in 48 healthyvolunteers in a double-blind, placebo-controlled, randomisedtrial54. Treatments were administered on days 1, 2, 3 and 4,exactly 1.5 hours before the start of the driving test performedon days 1 and 4 (Figure 10.1). The test measured standarddeviation from the lateral position (SDLP; cm) at a constantspeed of 95 km/h. The results showed that levocetirizine wasequivalent to placebo while diphenhydramine differedsignificantly from placebo on both days. These data suggestdriving performance is not significantly impaired by 5 mglevocetirizine once daily.

In a further study55, the effects of levocetirizine 5 mg anddiphenhydramine 50 mg (positive control) were compared with placebo on memory and psychomotor performance:word-learning test, the Sternberg Memory Scanning Test,tracking tests, and a divided attention test (tracking andmemory scanning simultaneously); after acute (day 1) and sub-chronic (day 4) daily administration in 48 healthy volunteersin a double-blind, placebo-controlled, randomised trial.

While diphenhydramine significantly affected divided attentionafter acute administration, levocetirizine did not significantlyimpair any laboratory test performance, showing that memory,attention and tracking performances are unaffected after acuteand sub-chronic administration of 5 mg levocetirizine.

10.3. Cardiac safetyPreclinical data revealed no effects on the QT interval in dogsafter 3 months’ oral administration of levocetirizine. No effectson left ventricular intramyocardial monophasic action potentialduration, dispersion or QT duration, and no arrhythmias ortorsades de pointes have been produced in dogs afterintravenous perfusion of high doses51.

Two studies have been performed5, which provide data on the cardiac safety of levocetirizine; one in healthyvolunteers (n=36) randomly receiving either levocetirizine 30 mg (6 film-coated tablets of 5 mg) or placebo, and theother in patients (n=111). From the cardiac safety data,as well as from the general safety information gathered in thesix-fold therapeutic dose treatment with levocetirizine, it isconcluded that no relevant effect of levocetirizine on QT/QTcinterval and other cardiac safety parameters could be shown.

10.4. Interaction with other medicinal products and otherforms of interaction

No interaction studies have been performed with levocetirizine(including no studies with CYP3A4 inducers); studies with the racemate compound, cetirizine, demonstrated that there were no clinically relevant adverse interactions (withpseudoephedrine, cimetidine, ketoconazole, erythromycin,azithromycin, glipizide and diazepam). A small decrease in the clearance of cetirizine (16%) was observed in a multipledose study with theophylline (400 mg once daily), while thedisposition of theophylline was not altered by concomitantcetirizine administration50.

Figure 10.1. Volkert’s driving test.

Summaryn The overall incidence of adverse drug reactions with

levocetirizine is very similar to that of placebo (15.1% versus 11.3%, respectively)

n 91.6% of the adverse drug reactions observed withlevocetirizine are mild to moderate

n Various batteries of psychometric tests (eg, CFF, CRT,a continuous tracking task, subjective rating scales forsedation, etc) demonstrate levocetirizine indistinguishablefrom placebo in any of the objective or subjective tests atany time point

n Levocetirizine does not impair memory and psychomotor functioning.

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1. Name of the medicinal productXyzal® 5 mg film-coated tablets.

2. Qualitative and quantitativecomposition

Each film-coated tablet contains 5 mg levocetirizinedihydrochloride. For excipients, see 6.1.

3. Pharmaceutical formFilm-coated tablet.White to off-white, oval, film-coated tablet with a Y logo on one side.

4. Clinical particulars4.1 Therapeutic indications

Symptomatic treatment of allergic rhinitis (includingpersistent allergic rhinitis) and chronic idiopathic urticaria.

4.2 Posology and method of administration

The film-coated tablet must be taken orally, swallowedwhole with liquid and may be taken with or without food. It is recommended to take the daily dose in onesingle intake.

Adults and adolescents 12 years and above: The dailyrecommended dose is 5 mg (1 film-coated tablet).

Elderly:Adjustment of the dose is recommended in elderly patientswith moderate to severe renal impairment (see Patientswith renal impairment below).

Children aged 6 to 12 years:The daily recommended dose is 5 mg (1 film-coatedtablet). For children aged less than 6 years no adjusteddosage is yet possible.

Patients with renal impairment:The dosing intervals must be individualized according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient’s creatinine clearance (CLcr) inml/min is needed. The CLcr (ml/min) may be estimatedfrom serum creatinine (mg/dl) determination using thefollowing formula:

Dosing Adjustments for Patients with Impaired Renal Function:

Patients with hepatic impairment:No dose adjustment is needed in patients with solelyhepatic impairment. In patients with hepatic impairmentand renal impairment, adjustment of the dose isrecommended (see Patients with renal impairment above).

Duration of use:The duration of use depends on the type, duration andcourse of the complaints. For hay fever 3–6 weeks, and incase of short-term pollen exposure as little as one week, is generally sufficient. Clinical experience with 5 mglevocetirizine as a film-coated tablet formulation iscurrently available for a 6-month treatment period. For chronic urticaria and chronic allergic rhinitis, up to one year's clinical experience is available for theracemate, and up to 18 months in patients with pruritusassociated with atopic dermatitis.

4.3 Contraindications

History of hypersensitivity to levocetirizine or any of theother constituents of the formulation or to any piperazine derivatives.

Patients with severe renal impairment at less than 10 ml/min creatinine clearance.

4.4 Special warnings and special precautions for use

The use of Xyzal is not recommended in children aged lessthan 6 years since the currently available film-coatedtablets do not yet allow dose adaptation.

Precaution is recommended with intake of alcohol (seeInteractions). Patients with rare hereditary problems ofgalactose intolerance, the Lapp lactase deficiency orglucose-galactose malabsorption should not take this medicine.

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Summary of product characteristics

Group Creatinine Dosage andclearance (ml/min) frequency

Normal ≥80 1 tablet once daily

Mild 50–79 1 tablet once daily

Moderate 30–49 1 tablet once every 2 days

Severe <30 1 tablet once every 3 days

End-stage renal <10 Contra-indicateddisease––Patientsundergoing dialysis

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4.5 Interaction with other medicinal products and otherforms of interaction

No interaction studies have been performed withlevocetirizine (including no studies with CYP3A4 inducers);studies with the racemate compound cetirizinedemonstrated that there were no clinically relevant adverse interactions (with pseudoephedrine, cimetidine,ketoconazole, erythromycin, azithromycin, glipizide anddiazepam). A small decrease in the clearance of cetirizine(16%) was observed in a multiple dose study withtheophylline (400 mg once a day); while the disposition of theophylline was not altered by concomitant cetirizineadministration.

The extent of absorption of levocetirizine is not reducedwith food, although the rate of absorption is decreased.

In sensitive patients the simultaneous administration ofcetirizine or levocetirizine and alcohol or other CNSdepressants may have effects on the central nervoussystem, although it has been shown that the racematecetirizine does not potentiate the effect of alcohol.

4.6 Pregnancy and lactation

For levocetirizine no clinical data on exposed pregnanciesare available. Animal studies do not indicate direct orindirect harmful effects with respect to pregnancy,embyonal/fetal development, parturition or postnataldevelopment. Caution should be exercised whenprescribing to pregnant or lactating women.

4.7 Effects on ability to drive and use machines

Comparative clinical trials have revealed no evidence thatlevocetirizine at the recommended dose impairs mentalalertness, reactivity or the ability to drive. Nevertheless,some patients could experience somnolence, fatigue andasthenia under therapy with Xyzal. Therefore, patientsintending to drive, engage in potentially hazardousactivities or operate machinery should take their responseto the medicinal product into account.

4.8 Undesirable effects

In therapeutic studies in women and men aged 12 to 71 years, 15.1% of the patients in the levocetirizine 5 mggroup had at least one adverse drug reaction compared to11.3% in the placebo group. 91.6 % of these adversedrug reactions were mild to moderate.

In therapeutic trials, the drop out rate due to adverseevents was 1.0% (9/935) with levocetirizine 5 mg and1.8% (14/771) with placebo.

Clinical therapeutic trials with levocetirizine included 935 subjects exposed to the drug at the recommendeddose of 5 mg daily. From this pooling, following incidenceof adverse drug reactions were reported at rates of 1% orgreater (common: >1/100, <1/10) under levocetirizine 5 mg or placebo:

Further uncommon incidences of adverse reactions(uncommon >1/1000, <1/100) like asthenia orabdominal pain were observed.

The incidence of sedating adverse drug reactions such assomnolence, fatigue, and asthenia was altogether morecommon (8.1%) under levocetirizine 5 mg than underplacebo (3.1%).

In addition to the adverse reactions reported duringclinical studies and listed above, very rare cases of thefollowing adverse drug reactions have been reported inpost-marketing experience.

n Immune system disorders: hypersensitivity includinganaphylaxis

n Respiratory, thoracic, and mediastinal disorders:dyspnoea

n Gastrointestinal disorders: nausea

n Skin and subcutaneous tissue disorders: angioneuroticoedema, pruritus, rash, urticaria

n Investigations: weight increased.

4.9 Overdose

a) Symptoms

Symptoms of overdose may include drowsiness in adultsand initially agitation and restlessness, followed bydrowsiness in children.

b) Management of overdoses

There is no known specific antidote to levocetirizine.

Should overdose occur, symptomatic or supportivetreatment is recommended. Gastric lavage should beconsidered following short-term ingestion. Levocetirizineis not effectively removed by haemodialysis.

Preferred Term Placebo Levocetirizine 5 mg(WHOART) (n=771) (n=935)

Headache 25 (3.2%) 24 (2.6%)

Somnolence 11 (1.4%) 49 (5.2%)

Mouth Dry 12 (1.6%) 24 (2.6%)

Fatigue 9 (1.2%) 24 (2.5%)

5. Phamacological properties5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antihistamine for systemicuse, piperazine derivative, ATC code: R06A E09.

Levocetirizine, the (R) enantiomer of cetirizine, is a potentand selective antagonist of peripheral H1-receptors.

Binding studies revealed that levocetirizine has highaffinity for human H1-receptors (Ki = 3.2 nmol/l).Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/l). Levocetirizine dissociatesfrom H1-receptors with a half-life of 115 ± 38 min.

Pharmacodynamic studies in healthy volunteersdemonstrate that, at half the dose, levocetirizine hascomparable activity to cetirizine, both in the skin and in the nose.

In vitro studies (Boyden chambers and cell layerstechniques) show that levocetirizine inhibits eotaxin-induced eosinophil transendothelial migration throughboth dermal and lung cells. A pharmacodynamicexperimental study in vivo (skin chamber technique)showed three main inhibitory effects of levocetirizine 5 mg in the first 6 hours of pollen-induced reaction,compared with placebo in 14 adult patients: inhibition of VCAM-1 release, modulation of vascular permeabilityand a decrease in eosinophil recruitment.

The efficacy and safety of levocetirizine has beendemonstrated in several double-blind, placebo controlled,clinical trials performed in patients suffering from seasonalallergic rhinitis or perennial allergic rhinitis.

A 6-month clinical study in 551 patients (including 276 levocetirizine-treated patients) suffering frompersistent allergic rhinitis (symptoms present 4 days a week for at least 4 consecutive weeks) and sensitized to house dust mites and grass pollen demonstrated that levocetirizine 5 mg was clinically and statisticallysignificantly more potent than placebo on the relief fromthe total symptom score of allergic rhinitis throughout thewhole duration of the study, without any tachyphylaxis.During the whole duration of the study, levocetirizinesignificantly improved the quality of life of the patients.

Pharmacokinetic/pharmacodynamic relationship:

5 mg levocetirizine provide a similar pattern of inhibition of histamine-induced wheal and flare than 10 mg cetirizine. As for cetirizine, the action on histamine-induced skin reactions was out of phase withthe plasma concentrations.

ECGs did not show relevant effects of levocetirizine on QT interval.

5.2 Pharmacokinetic properties

The pharmacokinetics of levocetirizine are linear withdose- and time-independent with low inter-subjectvariability. The pharmacokinetic profile is the same whengiven as the single enantiomer or when given as cetirizine.No chiral inversion occurs during the process of absorptionand elimination.

Absorption:Levocetirizine is rapidly and extensively absorbedfollowing oral administration. Peak plasma concentrationsare achieved 0.9 h after dosing. Steady state is achievedafter two days. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg o.d. dose, respectively. The extent ofabsorption is dose-independent and is not altered by food,but the peak concentration is reduced and delayed.

Distribution:No tissue distribution data are available in humans, neither concerning the passage of levocetirizine throughthe blood-brain-barrier. In rats and dogs, the highesttissue levels are found in liver and kidneys, the lowest in the CNS compartment.

Levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is restrictive, as thevolume of distribution is 0.4 l/kg.

Biotransformation:The extent of metabolism of levocetirizine in humans isless than 14% of the dose and therefore differencesresulting from genetic polymorphism or concomitantintake of enzyme inhibitors are expected to be negligible.Metabolic pathways include aromatic oxidation, N- and O- dealkylation and taurine conjugation.Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multipleand/or unidentified CYP isoforms. Levocetirizine had noeffect on the activities of CYP isoenzymes 1A2, 2C9,2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose.

Due to its low metabolism and absence of metabolicinhibition potential, the interaction of levocetirizine withother substances, or vice-versa, is unlikely.

Elimination:The plasma half-life in adults is 7.9 ± 1.9 hours. The meanapparent total body clearance is 0.63 ml/min/kg. The major route of excretion of levocetirizine andmetabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only12.9% of the dose. Levocetirizine is excreted both byglomerular filtration and active tubular secretion.

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Renal impairment:The apparent body clearance of levocetirizine is correlatedto the creatinine clearance. It is therefore recommendedto adjust the dosing intervals of levocetirizine, based oncreatinine clearance in patients with moderate and severerenal impairment. In anuric end stage renal diseasesubjects, the total body clearance is decreased byapproximately 80% when compared to normal subjects.The amount of levocetirizine removed during a standard4-hour hemodialysis procedure was <10%.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology,repeated dose toxicity, toxicity to reproduction,genotoxicity or carcinogenicity.

6. Pharmaceutical particulars6.1 List of excipients

Core:Microcrystalline cellulose Lactose monohydrateColloidal anhydrous silicaMagnesium stearateCoating:Opadry® Y-1-7000 consisting of:Hypromellose (E464)Titanium dioxide (E 171)Macrogol 400

Oral drops, solution:Sodium acetateAcetic acidPropylene glycolGlycerol 85%Methyl parahydroxybenzoatePropyl parahydroxybenzoateSaccharin sodiumPurified water

Oral solution:Sodium acetateAcetic acidMethyl parahydroxybenzoatePropyl parahydroxybenzoateGlycerol 85%MaltitolSaccharin sodiumTutti frutti flavor 501103APurified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Three years.

6.4 Special precautions for storage

No special precaution for storage.

6.5 Nature and contents of container

Aluminium – OPA/aluminium/PVCblister Pack sizes of 1 , 2 , 4 , 5 , 7 , 10 , 2 x 10 , 10 x 10, 14 , 15 , 20 , 21 , 28 , 30 40 , 50 , 60, 70 , 90 , 100.Not all pack sizes may be marketed.

6.6 Instructions for use and handling

No special requirements.

7. Date of revision of the text

3/3/2005

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