TRAINING MANUAL

CONTENTS

CONTENTS

PART I: GENERAL CONCEPTS

1. INTRODUCTION TO ALLERGY...... 3 1.1 Definition...... 3 1.2 History ...... 3 1.3 Epidemiology...... 4 2. ANATOMY OF THE RESPIRATORY SYSTEM...... 6 2.1 Upper respiratory tract...... 6 2.2 Nose and paranasal sinuses...... 7 2.3 Pharynx...... 7 2.4 Larynx...... 8 2.5 Ear...... 8 3. ANATOMY OF THE SKIN AND FUNCTIONS...... 9 3.1 Introduction...... 9 3.2 Skin structure and functions...... 9 3.2.1 Epidermis...... 10 3.2.2 Dermis...... 10 3.2.3 Hypodermis...... 11 3.2.4 Skin adnexa...... 11 3.2.5 Sensory receptors in the skin...... 11 3.2.6 Blood distribution in the skin...... 11 3.2.7 Biological functions of the skin...... 11 4. SKIN LESIONS AND INFLAMMATION...... 13 4.1 Introduction...... 13 4.2 Inflammatory process in the skin...... 13 4.2.1 Vascular mechanisms of skin inflammation...... 13 4.2.2 Cellular mechanisms of skin inflammation...... 13 4.2.3 Lesion repair...... 14 4.3 Skin lesions...... 15 4.3.1 Primary lesions...... 15 4.3.2 Secondary lesions...... 16 5. THE IMMUNE SYSTEM...... 20 5.1 Non-specific immunity...... 20 5.2 Specific immunity...... 20 5.2.1 Humoral immunity...... 21 5.2.2 Cell mediated (cellular) immunity...... 21 5.2.3 Primary and secondary immune response...... 22 6. THE REACTION (ALLERGY)...... 24 6.1 Types of allergic reactions...... 24 6.1.1 Early allergic reaction...... 24 6.1.2 Late allergic reaction (allergic inflammation)...... 25 7. ALLERGIC RHINITIS...... 27 7.1 Traditional classification ...... 27 7.2 ARIA classification...... 29 7.3 Allergic rhinitis and quality of life...... 30 7.4 Allergic rhinitis diagnosis...... 32 7.4.1 Clinical history and physical examination...... 32 7.4.2 Physical examination...... 33

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7.4.3 Allergy tests...... 33 7.5 Treatment of allergic rhinitis...... 34 7.5.1 avoidance...... 34 7.5.2 ...... 35 7.5.3 Drug therapy...... 35 7.5.3.1 First-generation ...... 36 7.5.3.2 Second-generation antihistamines...... 37 7.5.3.3 Adverse reactions of antihistamines...... 40 8. URTICARIA...... 42 8.1 EAACI/GA2LEN/EDF/WAO definition...... 42 8.2 EAACI/GA2LEN/EDF /WAO classification ...... 43 8.2.1 Acute urticaria...... 43 8.2.2 Chronic urticaria...... 43 8.3 Treatment of urticaria...... 45 8.3.1 Identification and elimination/avoidance of the stimulus...... 45 8.3.2 Symptomatic pharmacological treatment...... 45 8.3.3 Treatment of urticaria according to EAACI/GA2LEN/EDF/WAO guidelines...... 45 9. OTHER ALLERGIC SKIN CONDITIONS – INSECT BITE PRURIGO...... 47

PART II: PRODUCT PROFILE

1. PHARMACOLOGICAL PROPERTIES OF ...... 53 1.1 Chemical structure...... 53 1.2 Pharmacodynamics...... 53 1.2.1 Mode of action...... 54 1.2.2 activity...... 54 1.2.3 Anti-PAF activity...... 58 1.2.4 Anti-inflammatory and antiallergic activity...... 63 1.2.5 Anticholinergic effects...... 65 2. RUPATADINE PHARMACOKINETIC PROPERTIES...... 66 2.1 Absorption and distribution...... 67 2.2 Metabolism and excretion...... 67 2.3 Pharmacokinetics in children...... 67 2.4 Elderly population ...... 68 3. RUPATADINE EFFICACY PROFILE IN ALLERGIC RHINITIS...... 70 3.1 Seasonal allergic rhinitis (SAR)...... 71 3.1.1 Dose-finding studies...... 71 3.1.2 Comparative efficacy studies...... 71 Rupatadine 10 mg versus 10 mg...... 72 Rupatadine 10 mg versus ebastine 10 mg and placebo...... 73 Rupatadine 10 mg and 20 mg versus loratadine 10 mg...... 74 Rupatadine 10 mg and 20 mg versus loratadine 10 mg...... 75 Rupatadine 10 mg versus desloratadine 5 mg and placebo...... 75 Rupatadine 10 mg versus 10 mg...... 76 3.2 Perennial allergic rhinitis (PAR)...... 77 3.2.1 Dose-finding study: rupatadine 10 mg and 20 mg versus placebo...... 78 3.2.2 Comparative efficacy studies...... 78 Rupatadine 10 mg and 20 mg versus cetirizine 10 mg and placebo...... 78 Rupatadine 10 mg and ebastine 10 mg versus placebo...... 79 Rupatadine 10 mg and 20 mg versus loratadine 10 mg and placebo...... 79 3.3 Persistent allergic rhinitis (PER)...... 80 Rupatadine 10 mg versus cetirizine 10 mg and placebo for 12 weeks ...... 80

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3.4 Nasal challenge studies...... 82 3.4.1 Vienna Challenge Chamber (VCC) Study...... 82 3.4.2 Acoustic rhinometry study...... 83 3.4.3 PAF nasal provocation study ...... 84 3.5 Quality of life (QoL)...... 85 3.6 Meta-analysis in allergic rhinitis ...... 87 4. RUPATADINE EFFICACY PROFILE IN URTICARIA...... 90 4.1 Chronic spontaneous urticaria (CSU)...... 91 4.1.1 Dose-finding study: rupatadine 5 mg, 10 mg and 20 mg versus placebo ...... 91 4.1.2 Rupatadine 10 mg and 20 mg versus placebo...... 92 4.1.3 Responder analysis: pooled data from efficacy studies...... 95 4.1.4 Rupatadine 10 mg versus levocetirizine 5 mg...... 96 4.2 Cold urticaria...... 97 4.3 Long-term treatment follow-up in urticaria...... 99 4.4 Other urticaria skin lesions: -bite allergy...... 100 4.5 Quality of life...... 102 5. RUPATADINE SAFETY PROFILE...... 103 5.1 Pharmacokinetic interactions...... 103 Effect of known CYP3A4 cytochrome inhibitors on rupatadine...... 103 Effect of rupatadine on alcohol and CNS depressants...... 104 Effect of food on rupatadine...... 104 Effect of grapefruit juice on rupatadine...... 104 Co-administration with azitromycin: effect on rupatadine...... 104 Co-administration with fluoxetine: effect on rupatadine...... 105 5.2 Central nervous system (CNS) effects...... 105 5.3 Cardiac safety...... 106 5.4 Long-term safety...... 107 5.5 Adverse drug reactions in clinical trials...... 108 5.6 Post-marketing safety...... 110 6. REFERENCES...... 111 7. SUMMARY OF PRODUCT CHARACTERISTICS...... 117

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PART I: ALLERGY GENERAL CONCEPTS

1

PART I: ALLERGY GENERAL CONCEPTS

1. Introduction to allergy

1.1 Definition

Allergy can be defined as a hypersensitivity reaction of our organism against the invasion of external substances or organisms that we name antigens or . Some of these allergens are well known, including plant pollen, home dust, animal dandruff, mites or certain foods. However, hypersensitivity reactions can also be produced in contact with certain metals (contact dermatitis), in cases of dermographism (tattoos), under cold exposure, due to insect bites or physical exercise, among others. Usually, our organism protects against them with no symptom manifestations (innate or natural immunity). However, subjects with hereditary predisposition (atopic) and sensitized by previous and repeated exposure to allergens can experience an exaggerated immune response (allergic reaction) of varying severity, that sometimes impedes daily life or can produce tissue lesions. In extreme conditions, the severity of this reaction can cause death. This is what we know as anaphylactic shock. The concept of “Allergic disease” includes several pathologies such as respiratory allergy (allergic rhinitis or rhinoconjunctivitis and asthma), food allergy, drug allergy, allergy to hymenoptera and skin allergy (urticaria and atopic dermatitis). Urticaria is one of the most frequent skin diseases. It is characterized by pruritic wheal and flare-type skin reactions with or without that usually persist for at least 24 h.

1.2 History

The term “allergy” was first used in 1906 by Clemens von Pirquet1 to describe the symptoms experienced by some patients who had received horse serum antitoxin to treat diphtheria. The word “allergy” comes from the Greek “allos,” meaning “change in the original state” and “érgon” that means reaction or reactivity. was first described in 1902 in an article by Portier and Richet2. However, the first reported case of anaphylactic reaction dates back to Ancient Egypt in 2600 BC, where the Pharaoh Menes died from a wasp sting, even though recent authors consider this story to be the obscure fiction of a historian3. Also in Ancient Egypt, detailed descriptions of repeated sneezing caused by incense or floral scents can be found, as well as the first descriptions of asthma. In the Roman Empire, Britannicus, son of Emperor Claudius and Messalina, suffered from a strange horse allergy, so he had to decline the honor of leading the patrician horse parade in favor of his adoptive brother Nero. This opened the door to Nero becoming the infamous Roman emperor, responsible for the great fire of Rome4. The first detailed treatise on an allergic disease was that of Maimonides, a 12th century Arabic physician. The English king Richard III, who was allergic to strawberries, used that condition to get rid

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of Lord William Hastings, accusing the nobleman of having poisoned him: Richard III had some strawberries prior to granting him an audience. That “dirty trick,” based on a barely known and highly exotic disease at the time, allowed him to put his enemy on the scaffold and also inspired Shakespeare’s play Richard III 4. Many isolated descriptions of , and of the first allergens, appeared from the 15th to the 18th centuries. The first drug allergy, to ipecac root imported from Brazil, was described in 1648. In 1700, the first occupational allergy, “baker’s asthma”, was described. The modern times of allergy began in 1819 with John Bostock’s description of the first case of “hay fever”. Bostock described his own disease and nine years later extended his work with the description of 28 patients5. In 1869, Charles Blackley performed the first skin-prick test to explore his own hay fever, and this led him to identify pollen as the cause of the disease. Although there were already numerous precedents, more or less empirical, this author was the first to conduct systematic research on the role of pollen in hay fever etiology6. was synthesized as a chemical curiosity before its physiological function was discovered. It was not until 1927 that it was isolated from liver extracts and it became known that this substance, whose pharmacological properties had already been investigated in 1910 by Dale and Laidlaw, had a natural origin. Also in 1927, Lewis identified a substance he called H substance, which was released by skin cells in response to certain stimuli, although he did not suspect that it was histamine. The first antihistamine, pyrilamine, was synthesized in 1937 by Daniel Bovet and the first corticoid in 1948 by Edward Kendall and Philip Hench. Until 1953 it was not known that histamine is produced in mast-cell granules. This was discovered because of a mastocytoma in Geoffrey B. West’s dog and he reported the discovery with James F. Riley. IgE was not described until 1966 by K. and T. Ishizaka. Finally, in the 1980s, Bengt I. Samuelsson won the Nobel Prize in Medicine for discovering the leukotrienes4. Since 1981, several second-generation antihistamines have been approved and marketed and have replaced first-generation antihistamines. Second-generation antihistamines are as effective as the first-generation antihistamines in controlling both allergic rhinitis and urticaria symptoms, but present better pharmacokinetics and a safety profile with fewer side effects and better tolerability.

1.3 Epidemiology

It is estimated that 20-30% of the worldwide population experience allergic diseases. An estimated 100 million people in Europe, and 500 million globally, have allergic rhinitis, one of the most prevalent allergic conditions, and this is associated with a social cost of about €3 billion per year in Europe alone (€1.3 billion, direct costs; €1.7 billion, indirect costs)7-9. In Europe, the prevalence of allergic rhinitis ranges from 16.9% in Italy to 28.5% in Belgium8. Environmental agents such as pollen, animal dander, household dust, moulds or certain foods are the most common causes of allergic reactions known as allergic rhinitis and urticaria10. The prevalence of allergic rhinitis is also high in children, ranging from 0.8 to 14.9% in 6-7 year olds (in the USA up to 42% in children aged up to 6 years), and from 1.4% to 39.7% in children aged 13- 14 years11,12,13. According to the American Academy of Allergy, Asthma and Immunology (AAAAI), people with allergic rhinitis miss 3.8 million days of work and school per year.

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The incidence of allergies has increased alarmingly in the last three decades, reaching epidemic proportions, and it is expected that the number of cases will double by 2020 in developed countries14. Recent insights from the fields of genetics, epidemiology and molecular biology seem to confirm that allergy is not simply a collection of symptoms but actually a systemic disease with localized clinical manifestations in one or several organs. The finding of a common genetic pool for asthma, rhinitis, urticaria and eczematous dermatitis confirms this hypothesis15. The term atopic allergy means a hereditary tendency toward those disorders, appearing either alone or in combination. However, patients with no atopic background may also develop hypersensitivity reactions, especially urticaria and anaphylaxis associated with the same (IgE) seen in atopic patients. It is known that 20-40% of patients with rhinitis have asthma and 70-90% of asthmatic patients have rhinitis, regardless of the diagnostic setting, thus leading to the concept of “one airway, one disease”16. The chances of having an allergic child are 30% if one of the parents, especially the mother, suffers from an allergy, and increase to 70% if both parents have the same allergic disease17. Urticaria is more common than previously thought and may be increasing. Up to one in four of the total population experience urticaria once in their lifetime. At any single time, 0.5–1.0% of the population is suffering from chronic spontaneous urticaria (CSU). Although all age groups can be affected, the peak incidence is seen between 20 and 40 years of age. The duration of the disease is generally 1–5 years but is likely to be longer in more severe cases with concurrent angioedema, in combination with physical urticaria, or with a positive autologous serum skin test (autoreactivity)18. Urticaria can occur in all age groups. Acute spontaneous urticaria is common in infants and young children, particularly in atopics. For example, it was experienced by 42% of the placebo-treated children in the 18-month EPAAC study19. The underlying causes of CSU do not appear to be different between children and adults. In general, further epidemiological studies in children are needed. However, it is becoming apparent that the differences between the underlying causes of urticaria in children and adults are only small, indicating that, with the possible exception of infants, the diagnostic approach should be the same as in adults.

Allergens Pollution Heredity

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2. Anatomy of the respiratory system

The respiratory system carries oxygen (O2) to the blood cells and eliminates the carbon dioxide (CO2) produced by the tissues. This exchange takes place in the lungs as we breathe. We inhale air rich in oxygen and exhale carbon dioxide.

2.1 Upper respiratory tract

By upper respiratory tract we mean four main structures: nose, mouth, pharynx and larynx.

Conchae

Soft palate

Pharynx

Epiglottis

Tongue

• Nose The main route of air entrance into the respiratory system. Its three main functions are warming, moistening and filtering the air. By warming it, both its temperature and the body’s temperature become similar, and local reactions by mucosal exposure to the cold are produced by moistening it, ensuring that the mucosa does not dry out and, by filtering it, potentially detrimental foreign particles are kept out.

• Mouth An additional air entrance. It is less effective than the nose when it comes to moistening and warming the air, and cannot fulfil the filtering function, but the mouth allows for a higher in flow, and so it is used when air is in high demand (e.g. during exercise, short-breath).

• Pharynx A tubular structure, approximately 10 cm long, extending from the back of the nose and mouth to the larynx. 6 For internal use only PART I: ALLERGY GENERAL CONCEPTS

• Larynx Also a tubular structure, housing the vocal cords and over which the epiglottis drops like a hinged lid.

2.2 Nose and paranasal sinuses

As previously indicated, the main air entrance into the respiratory system is the nose. Its functions are: • To warm the air • To moisten the air • To filter the air going into the lungs The nose also lodges the receptors responsible for olfaction, that is, the cells specialised in the sense of smell. Linked with the nasal cavity are the paranasal sinuses, cavities in the bones surrounding the nose which are linked with it through a number of small openings in the side-wall. The paranasal sinuses are lined along the mucous membrane of the nose, and their functions are: • To contribute to the warming and moistening of the incoming air. • To act as a resonance chamber for the voice. • To alleviate the weight of the bones they are part of. • To reduce the weight of the head.

Nasal bones Frontal sinus

Ethmoidal sinus Nasal septum

Conchae Sphenoidal sinus

Nasal spine Maxillary sinus

2.3 Pharynx

By inhaling through the nose or the mouth the air reaches the pharynx or gullet. In terms of its functions, the pharynx has three parts: nasopharynx (back of the nose), used only for breathing, the oropharynx (communicating with the mouth), a passage for both air and food, and the laryngopharynx (behind the larynx), used only for swallowing.

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2.4 Larynx

Located between the pharynx and the trachea, the larynx houses the vocal cords behind the thyroid cartilage, whose length and tension determine the pitch of the voice.

Epiglottis Vestibule

False vocal Thyroid cords cartilage

Trachea True vocal cords

2.5 Ear

The organ of hearing, and also of balance, is connected to the airways by means of the Eustachian tube. Its main parts are: • Outer (external) ear • Middle ear • Inner ear The outer ear consists of the auricle or pinna (a core of elastic cartilage covered by skin) and the external auditory meatus. The middle ear is a cavity in the temporal bone. Its outer wall is the tympanic membrane. It is linked with the outer air by means of the Eustachian tube. It transmits air vibrations (sounds) to the inner ear, where nervous impulses are produced for transmission to the brain. This transmission depends on the three tiny bones bridging the cavity: incus, stapes and malleus. Mechanical stimuli are transformed into nervous impulses in the inner ear, which includes two different organs, one for hearing and the other for balance. All these organs, in one way or other, may be involved in the allergic reaction, playing a role in its clinical signs and symptoms.

Inner ear

Middle ear

Eustachian tube

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3. Anatomy of the skin and functions

3.1 Introduction

The skin is the largest organ of the human body. It is the layer that separates the body from the external environment and acts both as a barrier and as a liaison between the outside world and the internal organs. The skin’s surface area covers between 1.5 to 2 m2 and is roughly equivalent to a sixth of our body weight. Skin thickness varies with age and sex. In childhood the skin is very thin, whereas in adulthood it thickens and in old age it becomes even thinner. Adult skin does not have a uniform thickness in every body area; it is thicker on the palms of the hands, the soles of the feet and the elbows. On the skin’s surface there are wrinkles and creases (the lines on the palms, the creases in joint areas, etc.), orifices (from the pore ducts of sweat and sebaceous glands), and protrusions (interpapillary ridges). The structure of wrinkles and creases on the skin is unique to each individual and is thus used to identify people (fingerprints).

3.2 Skin structure and functions

There are three layers of tissue in the skin. From the outermost to the innermost these are: • Epidermis (superficial dermis) • Dermis or corium (deep dermis) • Hypodermis or subcutis (subcutaneous tissue) The skin adnexa (nails, hair and glands) are situated on these layers.

Pore Hair

Dermal papilla Epidermis

Cold receptor Dermis Heat receptor Sebaceous gland Hair erector muscle Blood vessels Sweat gland Connective tissue Subcutaneous layer Nerve Fat cells

Representation of the skin layers and adnexa (hair, nails and glands).

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3.2.1 Epidermis

The epidermis is a resistant, flexible and very thin layer; it is colorless and transparent due to the absence of blood irrigation. The epidermis is the outermost skin layer that forms the actual protective covering against environmental influences. Its mean thickness is 0.1 mm; on the face, the thickness is just 0.02 mm whereas, on the soles of the feet, it ranges from 1 to 5 mm. The main function of the epidermis is to protect tissues from the environment.

Stratum corneum

Stratum lucidum Stratum granulosum Langerhans cells

Stratum spinosum

Melanocyte Stratum basale

Basal membrane

Epidermal strata.

3.2.2 Dermis

The dermis is somewhat thicker than the epidermis; it has a pinkish or reddish color, as it is a highly vascularized layer. It consists of fibrous tissue, which renders it a very resistant layer, difficult to tear and highly elastic. The main functions of the dermis are providing nutrition, supporting the epidermis and protecting the hypodermis. The dermis forms a well-defined border with the epidermis on the inner side of the basal membrane. Its thickness varies depending on the body region, and it can be up to 5 mm thick on the soles of the foot. The dermis provides the skin with strength and elasticity. The fixed cellular components in dermis are: • Fibroblasts. These are the most numerous cells, and they synthesize collagen and elastin fibers as well as ground substance. • Histiocytes. They phagocytize melanin and produce melanophages. • Mast cells. They are formed by granules containing heparin (a substance that inhibits blood coagulation and is involved in the inflammatory process) and histamine (a substance that causes dilation of skin capillaries and enhances their permeability). Mast cells are very important in inflammatory reactions of allergic origin.

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3.2.3 Hypodermis

The subcutaneous tissue, or hypodermis, is a yellowish layer due to its high fat content. It is made up of blood vessels and fibrous tissue arranged in bundles, thus separating fat tissue in lobules. Its thickness varies depending on the body region and, naturally, on each individual’s diet, as one of the functions of the hypodermis is fat storage. It also acts as an isolating factor and as a cushion. The specific functions of the subcutaneous tissue are: • Thermal isolation (fat is a poor heat conductor) • Protection against blows to the skin • Acting as an energy reserve

3.2.4 Skin adnexa

The skin adnexa comprise the hair and nails as well as sebaceous glands, sweat glands and odoriferous glands.

3.2.5 Sensory receptors in the skin

The skin is innervated by different independent nerve endings and receptors which record stimuli that allow the skin to fulfill its sensory function. Merkel cells located in the epidermis allow for the perception of prolonged contact. The Meissner corpuscles, arranged in rows throughout the dermal papillary body, act as tactile receptors of the most subtle pressure sensations. For this reason they are very abundant on the fingertips. Krause corpuscles are important in the perception of cold, and Ruffini corpuscles, located in the hypodermis, act as heat receptors. Independent nerve cells are located near the skin surface and transmit pain sensations. Vater-Pacini corpuscles, located on the deeper region of the dermis, react to deformations and mechanical vibrations.

3.2.6 Blood distribution in the skin

The gradual distribution of blood vessels in the skin corresponds to the flattened and stratified shape of this organ. Many vessels depart from the arteries and veins located under the epidermis, forming a cutaneous plexus between the hypodermis and the dermis. The blood vessels are closely interlaced in those areas where skin is exposed to sudden changes. From the cutaneous plexus and forming a perpendicular line to the outside, individual arterioles lie at the base of the capillary layer, which enter into the subcapilar plexus and ramify there. From there, fine loop-shaped capillaries extend to the inner part of the dermal papillae, assuring the maintenance of the avascular epidermis. The papillary layer is densely populated with blood vessels, unlike the reticular layer. Catabolite elimination is carried out via the corresponding venous networks and, in part, through the system of lymphatic vessels.

3.2.7 Biological functions of the skin

So far we have covered some of the functions carried out by the different skin structures. However, we feel it is necessary to further analyze this aspect and consider a series of skin functions, looking at the skin as a whole.

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In general terms, it may be said that the skin has a protective function against external environmental aggressions. But, like any other organ, the skin also performs certain functions relative to the environment and metabolic functions: • Body temperature regulation • Body fluid maintenance • Protection from microorganisms and external environmental agents • Protection from external environmental agents • Protection of internal organs • Sensory functions • Metabolic functions

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4. Skin lesions and inflammation

4.1 Introduction

In this chapter we will briefly introduce the inflammatory process in dermatology and the types of basic skin lesions that accompany the different diseases.

4.2 Inflammatory process in the skin

Inflammation is a defensive reaction by the skin and, as such, life would be impossible in its absence. The main goal of inflammation is basically to defend and to subsequently reconstruct affected tissues. Inflammatory processes in the skin always occur in the dermis. In this layer, a series of vascular and cellular mechanisms will be activated as a result of the inflammation. Cellular mechanisms can be both of plasma origin or be triggered by the skin cells themselves.

4.2.1 Vascular mechanisms of skin inflammation

Vascular changes begin with an increase in the lumen of dermal blood vessels (dermal vasodilation), which results in a significant blood volume increase (hyperemia) in the affected area. While blood flows to the injured area in large quantities, the capillary, owing to the importance of blood-transported substances for the affected area, increases its permeability to allow for a rapid release of plasma and cells into the tissues.

4.2.2 Cellular mechanisms of skin inflammation

There are two types:

1) Plasmatic cellular mechanisms White blood cells, or leukocytes, which carry out a defensive function, exit the blood circulation when they go through the capillary. First, white blood cells become adhered to the vessel wall and subsequently penetrate through the capillary and migrate to the lesion. Once there, the different types of white blood cells take action. Neutrophils are the most decisive cells and, as soon as they suspect there is an anatomical region affected, they are the first to arrive at the scene. Neutrophils phagocytize (“eat”) the foreign particles and the necrotic cellular debris. are the most representative cells in subacute and chronic inflammation because of their role in the immune response.

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Finally, eosinophils are involved in controlling inflammation intensity and duration, inactivating some of the chemical mediators in the inflammatory response. Their presence is more relevant in inflammation caused by allergic reactions or parasites.

2) Dermal cellular mechanisms These changes correspond to the dermal cells which are in, or near to, the lesion. Histiocytes are the first cells to get to the lesion focus and begin the process; they digest any foreign body they find that is related to the lesion. These cells act so quickly and voraciously that they get to the lesion even before the blood cells responsible for defense (neutrophils, lymphocytes, etc.). Soon enough, the battle field is full; on the one hand, the invading cells and on the other the defensive cells (dermal cells – histiocytes – and blood cells – neutrophils, lymphocytes, etc.). The dermal and blood defensive cells and the plasma, with a high protein content, present in the lesion form the inflammatory exudate. Mast cells are in charge of commencing the complete inflammation process, releasing histamine and heparin. Histamine dilates the capillaries and increases blood flow; heparin attracts the leukocytes and facilitates their escape and subsequent release from the capillaries into the inflammatory area. As can be seen, the function of these cells in terms of their participation in the reaction is not clear but is, however, crucial to the body’s defense. The inflammatory process in the skin (summary)

1) Vascular mechanisms

• Vasodilation → hyperemia • Increased capillary permeability • Leukocyte adherence to the capillary wall • Leukocyte migration to the lesion focus

2) Cellular mechanisms

• Mast cells → histamine and heparin • Neutrophils → phagocytosis • Histiocytes → phagocytosis

3) Lesion repair

• Fibrocytes → fiber formation

4.2.3 Lesion repair

After the inflammatory process has developed completely, it is time to restore the affected area. This is the task of the fibrocytes, which become very active and start multiplying quickly, thus originating fibroblasts. These cells are responsible for the formation of collagen, elastin and reticular fibers that form connective tissue.

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4.3 Skin lesions

Skin lesions present more or less distinct characteristics depending on the pathological process. They can be uniform or present different sizes, shapes and colors and appear at different stages of evolution or involution. The original lesion is known as basic or primary. The lesion may be present until it has fully developed or it can undergo changes as a result of regression, trauma or other external factors. This altered form is known as a secondary lesion.

4.3.1 Primary lesions

Maculae (spots) These are skin color changes, circumscribed and having different sizes, shapes and colors, but without skin elevation or depression.Their size varies and they tend to be round in shape, although some are ovoid or irregular.

Papules (pimples) These are solid elevations of the skin, circumscribed, with no visible fluids, of up to 1 cm in diameter, caused by an increase in cells or solid substance deposit. When they are large and affect the subcutaneous tissue, they are called nodules.Their shape and color can vary.

Vesicles (small blisters) Small skin elevations circumscribed to the epidermis containing clear liquid. They may be yellowish (sero­ purulent content) or reddish (blood content) in color. Occasionally they may present an intensely red areola. Vesicles may be discrete, with irregular distribution or arranged in groups and rows.

Blisters These are large vesicles. They are very fragile and they can burst easily because they are located on the superficial epidermis and their walls are very thin. When their location is deeper, they can form ulcerations and scars. They can be round or irregular in shape, with a serous or seropurulent liquid content.

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Pustules These are small skin elevations containing pus. Because of their shape, they are similar to vesicles. Usually, they are off-white or yellowish in color, or reddish if they contain blood.

Wheals These consist of flat skin elevations, swelling, varying in size, with an off-white central area and a reddish ring around it. They disappear quickly. They may be discrete or accumulate to form plaques that are solid, round, irregular or linear in shape secondary to scratching. They develop quickly and disappear a little more gradually. Itching is almost always present.

4.3.2 Secondary lesions

Flakes (skin desquamation, exfoliations) These are epidermal laminated masses, dry or oily, formed by dead areas that have lost all connection with the epidermal layers. Their size varies according to each disease, as does their color, which ranges from off-white to yellowish or brown.

Excoriations (abrasion, erosion or scrape) These result from the loss of epidermal tissue caused by a mechanical effect. Erosions are caused by nail scraping, other mechanical traumas and by constant friction. Usually these are small lesions, linear and dark in color.

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Fissures (clefts) Linear cracks in the epidermis, and even in the dermis, caused by disease or trauma. The edges are well-defined. They usually appear on the fold areas in which inflammation has resulted in skin thickening and loss of elasticity. They tend to be painful.

Ulcers Rounded or irregular excavations caused by substance loss due to gradual . They may affect both the dermis and the hypodermis. Lesion healing is slow and leaves a scar.

Scars Masses of newly-formed connective tissue that replace substance loss in the dermis or deeper layers. Scars represent a part of the normal healing and repair process. They are permanent, although with time they may decrease in size. Thick and voluminous scars are called keloids.

Scabs Dried masses made up of serum, blood or pus and epithelial and bacterial debris covering erosions and ulcers. Their size and thickness depends on the lesion type and extension.

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SUMMARY Definition of Allergy The term “allergy” was first used in 1906 by Clemens von Pirquet. It comes from the Greek “allos,” meaning “change in the original state” and “érgon” which means reaction or reactivity. The concept of “Allergic disease” includes: • Respiratory allergy (allergic rhinitis or rhinoconjunctivitis and asthma) • Food allergy • Drug allergy • Insect bite prurigo • Skin allergy (contact and atopic dermatitis)

Definition of Urticaria Urticaria is a mast-cell driven disease and one of the most frequent skin diseases. It is characterized by pruritic wheal and flare type skin reactions with or without angioedema that usually persist for at least 24 h.

Epidemiology • Allergic diseases: 20-30% of worldwide adult population. 100 million people in Europe and 500 million globally have allergic rhinitis, one of the most prevalent allergic conditions. • Allergic rhinitis in children: 0.8 to 14.9% in 6-7 year olds; 1.4% to 39.7% in children aged 13-14 years. • 20-40% of patients with rhinitis have asthma and 70-90% of asthmatic patients have rhinitis. • Urticaria: up to one in four in the total population suffers from urticaria once in their lifetime. • It can occur in all age groups.

Respiratory System

• Carries oxygen (O2) to the blood cells and eliminates the carbon dioxide (CO2) produced by the tissues. • Upper respiratory structure: nose, mouth, pharynx and larynx. • Nose: main route of air entrance into the respiratory system (warming, moistening and filtering the air). • Mouth: additional air entrance, less effective than the nose in moistening and warming the air. • Pharynx: tubular structure, approximately 10 cm long. Nasopharynx (breathing function); oropharynx (communicates with the mouth: passage air and food); laryngopharynx (swallowing function). • Larynx: tubular structure housing the vocal cords. • Ear: the organ of hearing (outer, middle and inner ear).

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Skin structure and functions • Epidermis (superficial dermis): the most superficial layer, it is not vascularized and is primarily made up of keratinocytes; it has several strata (corneum, lucidum, granulosum, spinosum and basale). • Dermis or corium (deep dermis): it is formed by vascularized connective tissue and contains numerous nerve endings. It is divided into two regions or strata (papillary and reticular). • Hypodermis or subcutis: subcutaneous tissue, mainly consisting of fat cells. It contains blood and lymph vessels and nerves. • Adnexa: Hair, nails, glands (sebaceous, sweat: eccrine and apocrine). • Sensory receptors. • Blood vessels. • Biological skin functions: body temperature regulation; body fluid maintenance; protection (from microorganisms, from external environmental agents, of internal organs), sensory functions, metabolic functions (vitamin D synthesis).

Skin lesions and Inflammation • Inflammation: defensive reaction by the skin; skin inflammatory processes (always occur in the dermis); vascular and cellular mechanisms involved:

1) Vascular mechanisms

• Vasodilation → hyperemia • Increased capillary permeability • Leukocyte adherence to the capillary wall • Leukocyte migration to the lesion focus

2) Cellular mechanisms

• Mast cells → histamine and heparin • Neutrophils → phagocytosis • Histiocytes → phagocytosis • Skin lesions: primary (maculae, papules, vesicles, blisters, pustules, wheals); secondary (flakes, excoriations, fissures, ulcers, scars, scabs). • Lesion repair: fibrocytes (fiber formation).

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5. The immune system

The human body protects itself from invading foreign disease-causing agents by using both general and specific defense mechanisms. This natural resistance to is called immunity.

5.1 Non-specific immunity

The general or basic means of defence are developed naturally by all living beings in order to contend with natural enemies: pathogens or foreign agents. This is what we call natural or non-specific immunity. These general mechanisms of defence include: • Mechanical or anatomical barriers (i.e. the skin and mucoses) • Chemical factors (i.e. in tears) • Inflammation • Phagocytes (cells able to engulf and destroy bacteria, dead cells etc.)

5.2 Specific immunity

The specific means of defence constitute what we actually know as immunity. The immune system consists of a variety of specialized cells and chemical compounds that identify and deal with foreign matter. One of the basic characteristics of the immune system is its ability to distinguish its own substances from foreign ones and to act against the latter without harming the body’s own cells. Some of the substances able to produce clinically-important immune reactions are: • Microorganisms (such as viruses, bacteria and moulds) • Air-suspended particles (such as pollen, dust, dandruff, mites) • Certain medicines (such as penicillin antibiotics) • Blood components administered by transfusion • Transplanted organs and tissues • Transformed cells (such as cancer cells). There are two types of specific immunity: humoral immunity (mediated by ) and cellular immunity (mediated by cells).

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5.2.1 Humoral immunity

This type of specific immunity depends on protein cells (antibodies) that bind onto foreign agents (antigens) stimulating their production.

The result of the humoral immune response is the production of antibodies.

The antibodies bind onto the corresponding specific antigens just like pieces of a puzzle, thus forming immune complexes. The process is mediated by a special class of white blood cells or leukocytes called lymphocytes. These lymphocytes can be either B lymphocytes or T lymphocytes. B lymphocytes play a special role in humoral immunity, since they are programmed to recognize and respond to specific antigens by producing antibodies. After the antigenic stimulus, that is, following the first contact with the antigen, the original B divides into two new types of cells: plasma cells and memory cells. The plasma cells produce antibodies able to recognize and form an with the same antigen that had bound on to the original B lymphocyte. These antibodies are released from the plasma cell and circulate throughout the body, in the blood-stream to form immune antigen-antibody complexes. The memory cells are B lymphocytes that recall or recognize the antigen that caused them to exist.

5.2.2 Cell mediated (cellular) immunity

This is the other type of specific immunity, and is mediated by T lymphocytes. The role of T lymphocytes in the immune system is more complex than that of B lymphocytes. The most interesting T lymphocytes are the cytotoxic T cells (killer T lymphocytes) whose function is to destroy foreign cells.

Cellular immunity. Type of specific immunity involving T lymphocytes. The cytotoxic T cells directly adhere to antigen-carrying cells and secrete a chemical substance that is lethal to the antigen. No antibodies are released during the cell-mediated immune response.

Some T lymphocytes adhere directly to antigen-carrying foreign cells, such as bacteria or viruses, and secrete toxic substances (chemical mediators called ) which are lethal to the bacteria attacked. This is known as cellular or cell-mediated immunity, as the cells interact with one another. Other types of T cells can also influence (either by supressing or augmenting) the ability of B lymphocytes to secrete antibodies (helper or cytotoxic T lymphocytes).

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5.2.3 Primary and secondary immune response

The immune system recognizes and remembers the foreign substances (antigens) it has been in contact with, and so is prepared to reject further invasions by the same antigen. When body cells face a given antigen for the first time, the ensuing response is the primary immune response, which “programs” the leukocytes to act against this invading specific antigen. Consequently, the ability of an animal to recognize and respond to an antigen consequently increases with exposure, this new response being the secondary immune response. Memory cells are generated by the B lymphocytes during the humoral immune response. A memory cell can remember or recognize the true antigen that caused its production. The memory cells generated during an initial infection can circulate in the blood or lymph for years, allowing the body to respond faster to further .

PRIMARY immune response It takes place for the first time when our body faces an antigen and causes the lymphocytes to become programmed to act against this antigen the next time it tries to enter our organism.

SECONDARY immune response It takes place during subsequent exposure to the same antigen, recognition being coupled with the ability to provide a faster and amplified response.

Vaccination is an example of artificially-acquired active immunity, as it meets the criteria of primary and secondary immune responses. It is based on a relatively innocuous form of antigen which, once injected, stimulates the production of antibodies. Initial inoculation promotes a primary specific response free from the severe symptoms of the disease. The body defences become “alert”, and any further contact with the same antigen (a very malignant or highly infectious form) provokes a secondary immune response with a faster and richer production of antibodies against the infection.

ARTIFICIALLY ACQUIRED IMMUNITY Vaccination induced immunity

Immunity acquired by exposure to a NATURAL IMMUNITY living pathogen

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Pathogens Humoral immunity

Maturation Secretion

Antibodies Bacteria

B lymphocyte Viruses

Plasma cell Viruses Moulds

Cellular immunity

Foreign Maturation proteins

“Killer” T lymphocyte T lymphocyte Infected cell

Helper T lymphocyte

Lymphokines Lysis

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6. The hypersensitivity reaction (allergy)

Immune responses normally protect us against the invasion of foreign organisms or substances. Yet, they can be harmful when the response to the antigen is exaggerated. This unduly magnified reaction, which can injure the tissue and provoke a varied symptomatology, is known as hypersensitivity reaction or allergy. An antigen causing an allergic reaction is called an allergen. The most common allergens in the environment are plant pollen, home dust, animal dandruff and mites, which, in the susceptible (allergic) individual, can trigger allergic reactions and result in , hay fever or asthma of varied degrees of severity. Certain types of allergens, such as some medicines or insects’ stings, can generate a violent, potentially fatal reaction known as anaphylactic shock.

The hypersensitivity An allergen or allergic reaction is an antigen producing an is an exaggerated response allergic reaction. Common to an antigen causing tissue allergens in the environment are injury and symptoms. plant pollen, animal dandruff, mites, home dust, etc.

6.1 Types of allergic reactions

On account of their practical interest, we shall distinguish between early allergic reaction and late allergic reaction.

6.1.1 Early allergic reaction

The allergen’s initial contact is with the antigen-presenting cell, whose task is to introduce the antigen to the helper T lymphocyte. This secretes cytokines that stimulate the B lymphocyte to become a plasma cell, which, in turn, secretes the immunoglobulin E (IgE) specific to the allergic process. The antibodies bind to specialized cells called mastocytes, and make them sensitive, that is, “programmed” in such a way that they react in a specific way when they come in contact again with the allergen. When this new contact with the same allergen takes place, the antibodies bound to the mast cells combine with the allergen, thus promoting an allergen-antibody reaction that releases certain chemical substances (such as ) from the mast cells and basophils.

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Allergen

Cytokines IgE synthesis

Free IgE Allergen T lymphocyte B lymphocyte Plasma cell Antigen-presenting cell

Inflammation-mediators release

HISTAMINE When exposed to an allergen, our body produces histamine to fight off the allergen. Histamine binds to the peripheral H1 receptors of the target cells, causing: • Excessive secretion • Stimulation of nerve-endings • Vascular dilation • Increase of capillary permeability allowing fluid to leak from various tissues • In the nose: itching, sneezing, rhinorrhea and obstruction (acute allergic rhinitis) • On the skin: reddening, swelling and hives (urticaria) • In the eyes: tear-shedding and itching (allergic conjunctivitis) • In the bronchia: constriction of the smooth bronchial tube muscles and excessive mucus production, with ensuing breathing difficulty (allergic bronchial asthma)

6.1.2 Late allergic reaction (allergic inflammation)

Upon contact with the allergen, mastocytes release not only vasoactive mediators, but also the so- called pro-inflammatory mediators, that is, substances promoting swelling and causing the late allergic inflammatory reaction that extends the activation of binding molecules and perpetuates the disease: • Leukotrienes (LT) • Prostaglandins (PG) • Platelet-activating factor (PAF)

• Tumor necrosis alfa factor (TNFα) • Gamma interferon (IFNγ)

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These pro-inflammatory mediators activate binding molecules, i.e. receptors on the surface of membranes which thus express or activate themselves, and ultimately result in inflammation of the tissues involved. Each of these mediators is responsible for the clinical symptoms of the allergic reaction: • Leukotrienes constrict the smooth bronchial tube muscles and activate the binding molecules on the surface of the bronchial smooth muscle cell. • Prostaglandins, depending on the type, constrict (PGF2 and PGD2) or dilate (PGE2). • PAF (Platelet-activating factor): activation of PAF, in part, initiates the vascular phase of the acute inflammatory response, by releasing numerous mediators that worsen the allergic reaction such as, for instance, a chemotactic mediator for eosinophils and neutrophils. Also, regardless of the histamine action, it causes vasoconstriction and increases vascular permeability. PAF could also be associated with bronchial hyperreactivity and the physiopathology of the anaphylactic shock. On the other hand, PAF and histamine seem to complement each other by mutual activation.

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7. Allergic rhinitis

Allergic rhinitis is an inflammation of the mucous membrane of the nose, characterized by symptoms like nasal congestion, rhinorrhea, sneezing and itch. Despite its mildness, it often causes psychological and social problems, and in the long run it may lead to bronchial asthma, chronic sinusitis, otitis media and nasal polyposis. Therefore, allergic rhinitis should not be dismissed as an insignificant disease. It is a very common disease which impairs patient’s quality of life and results in a great number of small financial, social and personal costs. In terms of the mechanism producing allergic rhinitis, the vasoactive chemical mediators (especially histamine) released by mast cells cause an early reaction characterized by: • Stimulation of mucous secretions causing rhinorrhea and watery eyes. • Stimulation of nerve endings causing nose and eye itching as well as moderate pain. • Blood vessel dilation causing erythema. • Increased capillary permeability, so that tissues present edema, thus leading to the presence of wheals and periorbital swelling. This early reaction may be followed by a late reaction with allergic inflammation and generalized symptoms, together with self-perpetuation of the process.

7.1 Traditional classification

According to the traditional classification, allergic rhinitis may be seasonal (hay fever or pollinosis) or perennial (year-round). As their names indicate, seasonal allergic rhinitis usually appears during specific months of the year, whereas perennial allergic rhinitis stays all year-round.

• Seasonal allergic rhinitis (SAR) Tree and bush pollen, as well as spring grass, are the allergens responsible for turning the spring season into Seasonal allergic an unpleasant time of the year for people with seasonal allergic rhinitis. Unfortunately, the pollens triggering this rhinitis kind of reaction are not limited to spring. Certain grass Recurrent disease and herb pollens in the summer and autumn are also associated with pollens responsible for seasonal allergic rhinitis. of trees and grasses Therefore, seasonal allergic rhinitis, as its name appearing at specific suggests, is a recurrent disease appearing at certain times of the year. times of the year, and its main triggers are tree (such as oak, elm, cedar) and herb pollens, or suspended fungal spores floating in the air.

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Seasonal allergic rhinitis is characterized by rhinorrhea, sneezing, nasal congestion, and nasal and eye itch. Watery eyes and conjunctivitis are also symptoms of seasonal allergic rhinitis.

• Perennial allergic rhinitis (PAR) In contrast to seasonal allergic rhinitis, the symptoms of perennial allergic rhinitis may appear throughout the year. Perennial allergic rhinitis is a common disorder caused by allergens normally found in the environment, such as household dust, animal dander, dust mites, feathers, fungi and moulds. Actually, household dust is everywhere, all year long, regardless of how clean you keep your home.

Perennial allergic rhinitis Common reaction that may appear all year-round associated with environmental allergens such as home dust, animal dandruff, feathers, fungi, mites, moulds and, at times, certain foods

Clinical symptoms of perennial allergic rhinitis are similar to those of seasonal allergic rhinitis, namely, rhinorrhea, itchy nose and eyes, nasal congestion, sneezing and watery eyes, but it may also involve chronic nasal obstruction. This occurs when the mucous membranes of the nasal cavity develop edema and obstruct the draining of mucous secretions of the sinuses, the spaces connected to the nasal cavity.

Edematous nasal mucosa

Post-nasal draining Watery rhinorrhea

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7.2 ARIA classification

In December 1995 a panel of experts gathered at the World Health Organization (WHO) headquarters in Geneva to develop a new set of guidelines for diagnosing and treating rhinitis and which would jointly address other interrelated inflammatory processes commonly associated with it, such as asthma. That is how ARIA - Allergic Rhinitis and its Impact on Asthma - was created20. One of the most important aspects of the ARIA document is its proposal for a new rhinitis classification into two new categories: “intermittent” and “persistent”. As mentioned above, rhinitis has been traditionally classified into two large groups, seasonal and perennial, and more recently a third group was added and defined as occupational rhinitis. This is still being used by many medical doctors, but the new ARIA document, and two recent updates by this group, strongly recommend the use of the new classification and the treatment options have been adapted accordingly21,22. The ARIA classification is clearly more satisfactory, better fits real-life clinical activity, and cannot be used interchangeably with the classical one.

• Intermittent allergic rhinitis (IAR) When the symptoms of rhinorrhea, nasal obstruction, nasal itching and sneezing occur for up to 4 days per week or for up to 4 consecutive weeks.

• Persistent allergic rhinitis (PER) When the above symptoms occur more than 4 days per week and for more than 4 consecutive weeks. Likewise, in terms of severity two main categories have been established: mild and moderate/severe. The following chart shows a scheme of the ARIA classification (Figure 1)21:

Types of allergic rhinitis

Intermittent Persistent Symptoms Symptoms < 4 days per week > 4 days per week, Or < 4 consecutive weeks and > 4 consecutive weeks

Mild Moderate/Severe all the items one or more items

Normal sleep Abnormal sleep Normal daily activities, Impairment of daily sports, leisure activities, sports, leisure Normal work and school Problems caused ot work No troublesome symptoms or school Troublesome symptoms

Figure 1. ARIA classification system for allergic rhinitis (adapted from Bousquet 21).

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7.3 Allergic rhinitis and quality of life

Unlike other diseases, such as cardiopathies or cancer, allergies are not usually life-threatening and rarely require hospitalisation. Symptoms are similar to those observed with colds or the flu, and are commonly treated with home remedies or products that do not need a prescription (over the counter) and, despite frequent use, are not too costly unless we are dealing with a recurrent or severe case which requires medical assistance. Yet, these ailments involving “itching and restlessness” can be misleading in terms of their ability to deteriorate an individual’s quality of life and result in increased costs, ultimately leading to significant economic and social costs (absence from work, decreased productivity, “psychological” or “affective cost” etc.). These chronic and debilitating diseases are hard to cure and, if not treated properly, can lead to complications. Thus, allergic rhinitis can be described as a common, usually mild disease, albeit recurrent, entailing many small costs at an individual level, which, although not representing a risk to life, greatly affects personal capacities not only among adults but also among school children (absence from school because of allergic rhinitis amounting to 2 million days/year in the USA). In addition to the physical symptoms described, allergic rhinitis goes hand-in-hand with a cohort of psychical symptoms often hindering the patient’s professional and social life: weakness, irritability, anxiety and depression, apathy, inability to carry out work and school tasks, deterioration of the affective condition and spirit, memory, capability of decision and psychomotor speed, lack of concentration, chronic fatigue, etc. More specifically, many patients with allergic rhinitis show introversion, restlessness and nonconformity with their own organic functions, all of which lead to a loss of self-esteem in the family and among friends and work partners. These affective conflicts create a vicious circle which, in turn, increases cognitive problems and performance loss caused by the disease itself. More important to the patient, and which must be taken into account, are those symptoms affecting normal daily life. Furthermore, patients are very interested in the possible adverse events of the treatment which are likely to be additive to the effects of the disease. Among the different definitions of “quality of life”, there is one which is closely related to allergic rhinitis, and is concerned with the functional effects of the disease and its treatment on the patient and how they are evaluated. Thus, quality of life includes 4 domains: • Physical and occupational function • Psychological condition • Social interaction • Somatic sensations From this perspective, quality of life can no longer be assessed according to conventional drug- efficacy rates, which reveal very little about the global impact on the patient’s daily life. Consequently, both generic and specific questionnaires have been developed in order to assess quality of life in cases of rhinitis rhinoconjunctivitis, and these have been shown to be simple, easy to complete (by the patient), sensitive and reliable.

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It has been demonstrated that allergic rhinitis, usually chronic, decreases quality of life and can cause acute behavioral problems. Indeed, allergic rhinitis hinders daily activities, causes the patient to wake up at night and so rest insufficiently, and causes annoying symptoms such as headache and nasal obstruction, rhinorrhea, etc. It can be psychologically disturbing. Studies on allergic rhinitis patients have shown that 80% of them report symptoms all year-round, 20% disturbed sleep, and 30% a clear deterioration of their quality of life. The different types of allergic reactions are generally categorized by what causes them, the part of the body most affected and other features. Based on the symptoms, the following categories can be stablished:

Sneezing and secreting • Paroxysmal sneezing • Watery anterior rhinorrhea • Nasal itching • Nasal obstruction • Worse by day than by night • Frequent conjunctivitis

Obstruction • Painful throat • Dryness of mouth and oropharynx • Nasal voice • Snoring • Hissing sound • Persistent coughing • Lack of night rest Another consequence of allergic rhinitis is the impact on social life: decreased self-esteem and nonconformity with one’s own body may cause introversion, isolation, irritability, depression and apathy, thus disturbing both family and friends. Also, allergic rhinitis may cause a chronic fatigue condition, a decrease of psychomotor reflexes and attention, cognitive disorders and so on, which increase the risk when operating machines or vehicles. This is further compounded by certain types of first-generation antihistamines which induce a certain degree of drowsiness. Much of this can be prevented with an adequate treatment, both prophylactic and symptomatic, thus preventing the inadequate management of allergic rhinitis from increasing the economic and social costs involved. Let us not forget the added danger associated with certain types of work, which may cause occupational allergic rhinitis to appear. Besides the quality and profitability of the manufactured products, what matters most is the well-being of the individuals and their relatives.

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In the USA, allergic rhinitis accounts for 64% of visits to general practitioners, who carry out 41% of all diagnostic tests and 92% of prescriptions. But this is only the tip of the iceberg. There are also countless patients visiting the pharmacist in search of counsel and consuming all sorts of remedies for “catarrh” or “colds”. And this happens in the USA, where one of the most cared about factors is patient education.

Trees

Grasses

Allergens

Bushes

Fungi

7.4 Allergic rhinitis diagnosis

The diagnosis of allergic rhinitis is based on a case-history containing numerous episodes of nose and eye symptoms, physical examination and positive results in immunological tests determining the presence of allergen-specific IgE antibodies. Thus, diagnosis shall be based on:

7.4.1 Clinical history and physical examination

As indicated above, the symptoms of rhinitis do not only affect the nose but usually also the face, ears, eyes and throat. The most often observed symptoms are nasal itching, sneezing, rhinorrhea and nasal congestion, which can appear either jointly or separately. Sore throat, coughing and snoring are less frequent, but lead to postnasal draining-induced pharyngeal and hypopharyngeal irritation. In fact, unsuspected postnasal draining is one of the most significant causes of chronic pain in the throat and of unexplained chronic coughing in non-smokers. Patients may also complain of facial pain and otitis secondary to sinusitis and blockage of the Eustachian tube, respectively. Actually many cases of middle ear inflammation in adults are caused by allergic rhinitis, and are clear evidence of this condition. Seasonal allergic rhinitis is characterised by recurrent symptoms, since it is an allergy to airborne allergens. Perennial (year-round) allergic rhinitis causes symptoms similar to those of seasonal allergic rhinitis, but they vary in severity, often unpredictably, throughout the year. Seasonal rhinitis, incorrectly called “hay fever”, is caused by pollens of trees, grasses and bushes, with well-defined pollen seasons, and so set allergen seasons.

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Perennial rhinitis is caused by 4 classes of well-defined airborne allergens present both at home and at the workplace: pets, dust mites, cockroaches and fungal spores. It is advisable to obtain a detailed history of the symptom-inducing triggering factors so as to have the necessary information for detecting causal allergens. The immediate cause of the appearance of symptoms has to be determined. For instance, those symptoms triggered when mowing the grass suggest grass pollen allergy. On the other hand, those present when the patient wakes up or triggered when cleaning the household are probably linked to dust mites. Symptoms which improve when the patient leaves the house and worsen on returning suggest an allergy linked to indoor allergens. When documenting the patient’s clinical history, it should be kept in mind that the absence of triggering factors does not eliminate the diagnosis of allergic rhinitis because the less obvious late symptoms prevail in many patients. A systematic history of environmental exposure has to be obtained, including relevant questions about the presence of pets (dogs, cats, birds, etc.), cockroach infestation, or the existence of wet or mossy areas in the house. Also, whether humidifiers are in use and what type of mattresses and pillows are normally used.

7.4.2 Physical examination

The physical examination of patients with suspected allergic rhinitis should focus on the eyes, ears, nose, throat and lungs. The inner eyelids and the white of the eyes may become inflamed (conjunctivitis), and there may be an exudation in the medial and lateral rim. As there is often nasal obstruction, the condition of the patient has to be evaluated according to his ability to inhale through each of the nasal passages. The lining of the nose may become characteristically swollen, leading to runny nose and stuffiness. In allergic rhinitis with no complications, nasal secretions are usually fluid and non-purulent. The appearance of purulence indicates concomitant infectious rhinitis. It is important to determine whether palpation of the maxillary, frontal, anterior ethmoidal (between the eyes) sinuses causes any pain. The mucous lining the back of the pharynx may look block-like. There may be secretion (postnasal draining) in the nasopharynx or posterior pharynx, on the distal part of the soft palate. A check of the tympani is advisable in order to find out whether there is any retraction or serous fluid. Also, the lungs require attention as there could be a hissing sound when breathing, since rhinitis often goes hand-in-hand with asthma.

7.4.3 Allergy tests

In combination with the person’s history of symptoms, skin tests can help the doctor to determine which specific IgE antibodies have reacted to the allergens causing the disease. Immediate positive skin reactions causing hives and eruptive skin rash (exanthema) indicate the presence of specific IgE antibodies to the introduced allergen that has bound to the skin mast cells. A positive skin test confirms the diagnosis of allergic rhinitis previously suggested by the symptoms of seasonal or perennial allergic rhinitis. Patients with suspected allergic rhinitis have to undergo a test including a battery of usually inhaled allergens (pollens of trees, grass, fungal spores, dust mites, cockroaches and animal dandruff). The selection of allergens to be used in these skin tests (Prick Test) must be individualized according to the patient’s history and geographic area.

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For patients who cannot stop taking antihistamines for 7-10 days or, in less frequent cases, show disseminated skin lesions preventing the use of skin tests, other tests can be carried out, such as the radioallergosorbent test (RAST), which measures blood levels of IgE antibodies specific to individual allergens. The determination of eosinophils in a nasal smear is sometimes useful, but hard to carry out in a normal medical office, and so is not very practical. Also, testing for pulmonary function should be reserved for patients with suspected asthma.

7.5 Treatment of allergic rhinitis

The management of allergic rhinitis includes allergen avoidance, medication, immunotherapy and patient education. Surgery may be used as an adjunctive intervention in a few highly-selected patients22.

7.5.1 Allergen avoidance

There are a number of general measures employed to avoid contact with allergens which trigger flares: staying away from areas with high concentrations of pollens during the annual periods of higher pollination, anticipating pollination and remaining inside with closed windows during the day and open windows only at night when the pollen count is low. However, the avoidance of pollens is often impossible due to their ubiquitous nature. Ventilation systems can be equipped with appropriate filters to avoid drawing pollen allergens into the house and the car. Other measures include controlling dust mites at home via vacuum cleaning, avoiding rugs, upholstery and carpets, and not keeping dogs, cats and other animals capable of producing allergens at home. These measures should be combined with patient education, which is very important, as patients should know what they can and should do and consume, maintain a good relationship with their attending physician and adhere to the treatments indicated.

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7.5.2 Immunotherapy

When an allergen cannot be avoided, allergen immunotherapy (subcutaneous, intranasal and sublingual) may provide an alternative solution, but it must be carried out carefully under constant supervision, because it can produce an allergic reaction. Anti-IgE monoclonal antibodies such as omalizumab have demonstrated a benefit in patients with allergic rhinitis. The antigen (IgE)-monoclonal antibody interaction decreases free IgE levels in the serum and, therefore, the interaction of IgE with mast cells and basophils, demonstrating dose- dependent clinical effectiveness in patients with allergic rhinitis22,23.

7.5.3 Drug therapy

The main objective of drug therapy used in the treatment of allergic rhinitis is the relief of disease symptoms (sneezing, rhinorrhea, nasal congestion, nasal itching and watery eyes). Therapies used in the treatment of allergic rhinitis symptoms include antihistamines, intranasal corticosteroids, leukotriene antagonists, decongestants, cromones and intranasal anticholinergic agents. In order to understand that antihistamines are the main drug therapy in the treatment of allergic rhinitis it is very important to understand the role of histamine as the main mediator, as well as other important mediatiors like PAF. Histamine is the most important bioamine in human basophils and mast cells and is a significant mediator of inflammation in allergic diseases with a powerful vasoactive and spasmogenic effect on the smooth muscle. Histamine exerts its biological and pathological effects through specific receptors, four of which have been identified so far (H1, H2, H3 and H4). The first one, H1, was identified in 1966, and is widely distributed in many human body tissues, in particular in the bronchial and intestine smooth muscle, as well as in the vascular wall. The most important effects of histamine when it interacts with the H1 receptor are vasodilation, constriction of the bronchial smooth muscle, and spastic constriction of the intestinal smooth muscle, among others. Two conformations of the H1 receptor (the active and the inactive forms) appear to be in equilibrium in the organism and this fact is very important for current understanding of the mode of action of antihistamine drugs, as we will see later on.

Some years later, another receptor, H2, was identified. H2 receptors are particularly important at the gastrointestinal level. Stimulation of this receptor results in increased gastric acid secretion. Several well known drugs used to treat peptic ulcers are antihistamines that block stomach H2 receptors, thus reducing the secretion of gastric acid. The term antihistamines generally refers to drugs that block the histamine H1 receptor, and are specifically used to treat allergies.

A new receptor, H3, was identified in the 1980s, and is basically associated with effects on the CNS.

Finally, another histamine receptor, H4, was discovered at the turn of the millennium. It is largely expressed in hemopoietic cells and its chemotactic properties strongly suggest a regulatory role in the immune system, offering an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders, including allergy and asthma.

Contrary to H2 and H3 receptors, H1 receptors play a significant role in the pathological processes related to allergy and inflammation, including increased vascular permeability, vasodilatation and constriction of smooth muscle. They also intervene in the release of inflammatory mediators in inflammatory cells.

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Drugs which act by inhibiting the activity of H1 receptors are called H1 antihistamines.

Receptor Cells Pharmacological action Bronchial constriction H Smooth muscle 1 Vasodilatation Endothelium ↑ Bronchial permeability Skin sensory nerves Stimulation Cardiac muscle Negative inotropic effect

Antihistamines are the drugs most commonly used for treating allergies. They interact with the

inactive form of the H1 receptor and stabilize this form, shifting the equilibrium toward the inactive state and thus diminishing the concentration of the active form. Consequently, the action of histamine, which is dependent on interacting with the active form of the receptor to exert its effects, is reduced.

Even though we traditionally classify these drugs as antihistamines that block H1 receptors, in fact we must consider them as “inverse agonists”, a term that reflects, more precisely, their mechanism of action. Typical antihistamines have a chemical structure featuring an ethylamine side chain (similar to histamine) bound to one or several cyclic groups. These chemical structural characteristics have led to considering them as various families: ethanolamides, alkylamides, ethylendiamides, phenotiazines and piperidines, each with a different active principle. Finally, it can be said that, according to European general consensus, antihistamines are the first choice or first-line treatment for rhinitis, both mild and moderate. PAF (Platelet Activating Factor) is a pro-inflammatory mediator of phospholipidic nature, present in humans, that has been associated with airway hyperreactivity, airway narrowing, high levels of eosinophils, and increased leaking from the bloodstream (vascular permeability). PAF has important roles in the development of allergic inflammatory conditions, mainly in the late phase of allergy, urticaria and anaphylaxis24-26. Even though histamine remains as the most important mediator in allergy, recent studies have stressed the increasing relevance of PAF in these pathologies and it has been suggested that the blockade by a drug of more than one mediator could be more efficacious than acting against only one of them.

7.5.3.1 First-generation antihistamines

The first histamine receptor antagonist was discovered by Staub and Bovet in 193727. The first antihistamines reached the market a few years later (promethazine, 1948), and in subsequent years. Before the appearance of modern antihistamines (in the 80s), over 40 compounds had been marketed with this indication. The first-generation antihistamines included active ingredients such as chlorpheniramine (launched in 1962) and promethazine. The side effects of first-generation antihistamines, in particular their sedating action, restricted their use and occasionally led to treatment being stopped. Moreover, their selectivity as histamine blockers was rather poor, and their activity equally affected cholinergic, alpha-adrenergic and triptaminergic (serotonin) receptors, thereby causing unwanted effects.

36 For internal use only PART I: ALLERGY GENERAL CONCEPTS

Due to their lipophilic character, they cross the blood-brain barrier, thus inducing numerous CNS adverse effects. Four different responses are possible at this level: stimulatory, i.e. food craving, muscular spasms, insomnia, restlessness, irritability; neuropsychiatric, i.e. anxiety, confusion, depression, and rarely hallucinations; peripheral, i.e. pupillary dilation, blurred vision, urine retention, constipation, impotence; and depressive, such as sedation, impaired alertness, etc. Some of these adverse effects could impact heavily on an individual’s daily life, for example when driving, and could lead to occupational accidents. They are implicated in civil aviation, motor vehicle and boating accidents, deaths as a result of accidental or intentional overdosing in infants and young children and suicide in teenagers and adults. Some exhibit cardiotoxicity in overdose. Consequently, the use of these drugs requires continuous attention.

Another inconvenience of these antihistamines was their short half-life, which imposed several doses per day in order to maintain their receptor-blocking efficacy. Yet, some “old” antihistamines are still useful in daily clinical practice and in some cases even preferable (e.g. to induce a very tired patient to sleep or to mitigate intense itching). Thus, hydroxyzine is very useful in chronic urticaria and atopic dermatitis, on account of its antipruriginous activity and sedating effects.

Another drug of this group, chlorpheniramine, is still administered Clemastine parenterally under certain circumstances, together with adrenalin, for treating anaphylaxis. Dexchlorpheniramine Diphenhydramine Therefore, due to the numerous adverse reactions, first- generation antihistamines are not recommended for treating Mequitazine allergic rhinitis patients28. Promethazine Hydroxyzine

7.5.3.2 Second-generation antihistamines

This anti-H1 group includes the so-called “new” or non-sedating antihistamines. This classification has to be revised, though, on account of the “antiallergic” characteristics of some of them. On the other hand, some of the antihistamines of this group, such as ketotifen or oxatomide, show

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antiserotonin and anticholinergic effects. The development of these compounds aimed to reduce or eliminate their sedating activity and anticholinergic adverse effects. Moreover, these agents can act on other mediators of the allergic reaction. The antihistamines of this group have been shown to have

the following characteristics: better H1 selectivity, no sedating effect, antiallergic properties and anti- inflammatory activity besides their antihistamine activity. The first antihistamines of this group were terfenadine and astemizole, launched in 1981. Next to reach the market were acrivastine, azelastine, cetirizine, ebastine, fexofenadine, levocabastine, loratadine, mizolastine, olopatadine and bepotastine. More recently marketed drugs were levocetirizine, desloratadine, rupatadine and bilastine.

These new antihistamines show high affinity for H1 receptors, and very little or no activity on other receptors. Moreover, they have a very long side chain and, by being barely liposoluble, do not cross (or do so very slightly) the blood-brain barrier, so that the adverse effects on the CNS disappear or decrease. They show a variable half-life and the receptor blocking activity is not directly related to the drug’s half-life. The distribution of the drug’s active metabolite in the tissues and the minimal reversibility of some of their binding to the receptor extend their clinical effects, regardless of serum concentration. Also, almost all of them are administered once a day and their activity lasts for 12-24 hours.

Most of the second-generation antihistamines have a Tmax of less than 1 hour indicating fast onset of action, a beneficial feature in acute cases. Terfenadine, the first “second-generation” antihistamine, was launched in Europe at the beginning of the 1980s. Its relative lack of sedative effects compared with its predecessors, made it the most

prescribed H1 receptor-blocker worldwide. After a while, terfenadine was associated with adverse cardiac effects (arrhythmias) and interactions with other concomitantly-administered drugs. Astemizole was launched as a second-generation antihistamine in the mid 1980s, its main advantage over terfenadine being that one single dose per day was enough, while still retaining its non-sedating effect. Yet, it was also shown to have cardiac side effects. However, due to the adverse cardiac effects of these drugs (induction of fatal arrhythmias as a consequence of alterations in the electrocardiogram (ECG): abnormal prolongation of the QTc parameter), both drugs were withdrawn from the market some years ago. The newer second-generation

anti-H1 compounds suchs as levocetirizine, desloratadine, rupatadine and bilastine have the advantage of cardiac safety with no abnormal QTc prolongation. Ebastine and loratadine are administered once daily, and have no sedating effect. At high doses, ebastine has occasionally shown effects on the ECG. Whereas ebastine is a prodrug needing liver metabolism to become active, this step makes loratadine inactive but is transformed into desloratadine, the main active metabolite which is largely responsible for the antihistaminergic effects of the parent compound. Mizolastine is an azelastine analog. Fexofenadine is terfenadine’s active metabolite and one of the incorrectly-named non-sedating antihistamines (in fact, they can all induce a certain degree of drowsiness, at least in some patients). It offers an alternative to terfenadine, but affords nothing new beyond the therapeutic potential of the remaining drugs of the same group. Cetirizine is a metabolite of hydroxyzine and seems to induce a certain degree of somnolence. Its mean elimination half-life ranges from 6.5 to 10 hours. No clinically significant mean increases in QTc were observed in cetirizine-treated subjects.

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Levocetirizine is the active enantiomer (R-form) of cetirizine and has been developed with the aim of obtaining a compound with fewer adverse events than its parent drug cetirizine. Desloratadine is an active metabolite of loratadine. One of its main characteristics is that its affinity for the H1 receptor is higher than loratadine. It has a fast onset of action and reduces nasal blockage. It is also non-drowsy, and does not increase QT. Bepotastine is a compound which is only available in Asian countries (Korea, Japan). It was launched in 2004 and is indicated for allergic rhinitis, urticaria and itching-associated skin diseases. Rupatadine is one of the latest new second-generation antihistamines and the main properties and advantages over other new second-generation antihistamines will be discussed in the Product Profile section. More recently a new drug has been introduced into the market: bilastine. This compound is structurally- related to fexofenadine with the same restrictions in terms of food and intestinal transport interactions. However, further clinical experience is needed to confirm its supposed advantages. At low strengths, all these drugs can block histamine’s binding to its receptor, thus reducing vascular permeability and itching, and relaxing the bronchial and intestinal smooth muscle. These agents also have additional activities which can contribute to their antiallergic effects. They interfere with the release of mediators from mast cells hindering calcium metabolism. They can also inhibit the allergic reaction’s late stage, acting on leukotrienes and prostaglandins or on platelet- activating factor. Furthermore, there is evidence that some of these new compounds have additional anti-inflammatory properties that may improve their antiallergic activity.

According to ARIA, several properties should be met by the new-generation H1-antihistamines: Pharmacological properties: Acrivastine • Potent and non-competitive H receptor blockage 1 Astemizole • Additive anti-allergic activities Azelastine • No interference of activity by foods Bepotastine Side effects: Bilastine • No sedation Cetirizine Desloratadine • No anticholinergic effect Ebastine • No weight gain Epinastine • No cardiac side effects Fexofenadine Pharmacokinetics: Ketiofen • Rapid onset of action Levocabastine Levocetirizine • Long duration of action, at least 24 hr Loratadine • Administration once a day Mizolastine • No development of tachyphylaxis Olopatadine Rupatadine Terfenadine

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Current guidelines strongly recommend second (new)-generation over first (old)-generation oral antihistamines (low-quality evidence). This recommendation places relatively high value on the reduction of adverse effects and relatively low value on uncertain comparative efficacy of new- 28 generation versus old-generation oral H1-antihistamines .

ARIA proposed pathway for treating allergic rhinitis

Check for asthma especially Diagnosis of allergic rhinitis in patients with severe and/or persistent rhinitis Intermittent Persistent symptoms symptoms

Moderate- Moderate- Mild severe Mild severe

In preferred order Not in preferred order intranasal CS oral H -blocker Not in preferred order 1 oral H -blocker H -blocker or LTRA or intranasal H -blocker 1 1 1 or intranasal H -blocker and/or decongestant and/or decongestant1 Review the patient or LTRA or intranasal CS after 2-4 weeks or LTRA (or cromone) Improved Failure If persistent rhinitis Review diagnosis review the patient Step-down Review compliance after 2–4 weeks and continue Query infections treatment or other causes for >1 month If failure: step-up If improved: continue for 1 month Blockage Add or increase Rhinorrhea add intranasal CS add ipratropium decongestant dose or oral CS (short term)

Failure referral to specialist Allergen and irritant avoidance may be appropriate

If conjunctivitis Add

oral H1-blocker or intraocular H1-blocker or intraocular cromone (or saline)

Consider specific immunotherapy

Figure 2. Algorithm for the management of allergic rhinitis (reprinted, with permission from Bousquet et al.)22

H1-blocker = antihistamine; CS = corticosteroid; immunotherapy = under-the-skin (subcutaneous) or under-the- tongue (sublingual) administration of a specific allergen extract; intranasal = administration directly into the nose; intraocular = administration directly into the eyes; LTRA = leukotriene-receptor antagonist; rhinorrhea = runny nose.

7.5.3.3 Adverse reactions of antihistamines

The ideal second-generation antihistamine should be a potent and specific H1 receptor antagonist, preventing histamine-mediated symptoms, and free from adverse effects. The main adverse reactions associated with antihistamines are the following: Nervous system: drowsiness, headache, food craving and weight gain. These adverse effects can be rated both subjectively and objectively. Sedation as a side effect is highly relevant for the safety of workers and drivers, as well as for school performance. Yet it is sometimes hard to rate sedation

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objectively. The FDA has classified astemizole, loratadine, fexofenadine and terfenadine as non- sedating anti-H1. Cetirizine 10 mg/day does not alter psychomotor performance; yet, both clinical experience and the patient’s subjective feeling demonstrate that it can produce somnolence; ketotifen has similar effects; thus both drugs are rated as sedating by the FDA. Stimulation of appetite and weight gain have also been demonstrated with astemizole, azelastine and ketotifen. Cardiovascular: some of these products have demonstrated adverse effects on the cardiovascular system. Although by the 1970’s some isolated publications had already pointed out the possible cardiotoxic effects (prolongation of the QT interval, arrhythmias) of some anti-H1 products (e.g. hydroxizine at high doses), it was from 1986 onwards that the cardiotoxic effects of certain second- generation antihistamines were fully described: for astemizole and terfenadine, and for ebastine at high doses. The unwanted effects of terfenadine and astemizole arise when they are concomitantly administered with certain macrolides (i.e. erythromycin) or oral antifungals (ketoconazole). Relevant studies show that it is not a class effect, since it has not been seen with first-generation antihistamines or with all the second-generation drugs. The described pathology defines a ventricular tachycardia called “torsade de pointes”, and it is known to be associated with certain drugs. The “torsade de pointes” appears only (and rarely) when the QT interval of the ECG is prolonged beyond normal. Teratogenicity: antihistamines cross the placental barrier, and some have been demonstrated to cause teratogenic effects in experimental animals. For this reason, the FDA has listed most of the anti-H1 agents in category C, meaning that they should only be used in cases of extreme necessity and when the benefits for the mother widely surpass their potential risk for the foetus. Some antihistamines, such as cetirizine and loratadine, are listed in category B as low risk drugs. All antihistamines are excreted in the breast milk. Some studies have shown suckling with irritability or somnolence symptoms due to the mother receiving first-generation antihistamines. Second-generation antihistamines have been found to be free from these effects. To summarize this section it is very important to highlight the ARIA safety requirements for new antihistamines: • No sedation or cognitive or psychomotor impairment • No anti-cholinergic effects • No weight gain • No cardiac side effects • Studies should be carried out in young children and elderly patients to assess safety • Prospective post-marketing safety analyses should be conducted

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8. Urticaria

Urticaria is one of the most frequent skin diseases. It is characterized by pruritic wheal and flare-type skin reactions with or without angioedema that usually persist for at least 24 h. Urticaria is more common than previously thought and may be increasing. Up to one in four in the total population suffers from urticaria once in their lifetime. Urticaria can occur in all age groups. Acute spontaneous urticaria is common in infants and young children, particularly in atopic individuals. For example, it was experienced by 42% of placebo-treated children in the 18-month EPAAC study19. At any single time, 0.5–1.0% of the population is experiencing chronic spontaneous urticaria (CSU). Although all age groups can be affected, the peak incidence is seen between 20 and 40 years of age. The duration of the disease is generally 1–5 years but is likely to be longer in more severe cases with concurrent angioedema, in combination with physical urticaria or with a positive autologous serum skin test (autoreactivity)29. The underlying causes of CSU do not appear to be different between children and adults. In general, further epidemiological studies are needed in children. However, it is becoming apparent that the differences between the underlying causes of urticaria in children and adults are only small, indicating that, with the possible exception of infants, the diagnostic approach should be the same as in adults.

8.1 EAACI/GA2LEN/EDF/WAO definition

The recently revised and updated (2013) guideline has defined urticaria as follows: “Urticaria is a disease characterized by the development of wheals (hives), angioedema, or both. Urticaria needs to be differentiated from other medical conditions where wheals, angioedema, or both can occur as a symptom, for example skin prick test, anaphylaxis, auto-inflammatory syndromes, or hereditary angioedema (bradykinin-mediated angioedema)”30. Clinical appearance “…The wheal is characterized by a central swelling of variable size, almost invariably surrounded by a reflex erythema. It is associated with itching or sometimes a burning sensation and has a fleeting nature, with the skin returning to its normal appearance, usually within 1–24 h. Sometimes wheals resolve even more quickly.”30 “...Angioedema is characterized by a sudden, pronounced erythematous or skin-colored swelling of the lower dermis and subcutis with frequent involvement below mucous membranes and sometimes pain rather than itching and frequent involvement below mucous membranes. Its resolution is slower than that for wheals and can take up to 72h”30. Urticaria and angioedema may appear separately or concomitantly as skin manifestations. Angioedema is localized and well-defined edema affecting the deep epidermal layers, including subcutaneous cell tissue.

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Pathophysiological aspects “…Urticaria is a mast-cell-driven disease. Histamine and other mediators, such as platelet-activating factor (PAF) and cytokines released from activated mast cells, result in sensory nerve activation, vasodilatation, and plasma extravasation as well as cell recruitment to urticarial lesions....”30. The pathogenesis of urticaria is complex and has many features in addition to the release of histamine from dermal mast cells31,32.

8.2 EAACI/GA2LEN/EDF /WAO classification

The wide diversity and number of different urticaria subtypes that have been identified reflect, at least in part, the increasing understanding of the causes and eliciting factors of urticaria and the molecular and cellular mechanisms involved in its pathogenesis. The aim of the EAACI/GA2LEN/EDF/ WAO 2013 revision30 is to provide an updated classification of urticaria on the basis of its duration, frequency and causes, thereby facilitating the interpretation of divergent data from different centers regarding underlying causes, eliciting factors, and therapeutic responsiveness of urticaria subtypes.

8.2.1 Acute urticaria

Acute urticaria is defined as the occurrence of spontaneous wheals, angioedema, or both for less than 6 weeks.

8.2.2 Chronic urticaria

The classification of chronic urticaria has been revised 30 (Table 1) based on the special nature of its eliciting physical factors. Other diseases previously related to urticaria for historical reasons, and other syndromes, are no longer considered to be subtypes of urticaria due to their distinctly different pathogenesis, and are listed in Table 2 for reference.

Table 1. Classification of chronic urticaria subtypes (presenting wheals, angioedema, or both)

Chronic urticaria subtypes Chronic spontaneous urticaria1 Inducible urticaria Symptomatic dermographism* Cold urticaria† Delayed pressure urticaria‡ Spontaneous appearance of Solar urticaria wheals, angioedema, or Heat urticaria§ both ≥6 weeks due to known Vibratory angioedema or unknown causes Cholinergic urticaria Contact urticaria Aquagenic urticaria

1 Chronic spontaneous urticaria is the new term adopted for chronic idiopathic urticaria (CIU). *also called urticaria factitia, dermographic urticaria; †also called cold contact urticaria; ‡also called pressure urticaria; §also called heat contact urticaria

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Chronic urticaria Cold contact urticaria Dermographic urticaria

Chronic spontaneous urticaria is a process in which urticaria outbreaks and/or angioedema lasts for 6 weeks or longer. The 6-week limit between chronic and acute urticaria has been set by medical consensus. A possible cause is identified in only 20% of cases, i.e. other medical processes or conditions statistically associated with chronic urticaria. However, in some very thorough studies, in which the patients selected have been clearly diagnosed with chronic urticaria, fewer than 5% of cases present a confirmed cause for urticaria. Physical urticaria. Urticaria lesions are triggered by certain environmental factors (rubbing or pressure, cold, heat, sunlight, contact with water, etc.) and may be experimentally reproduced somewhat easily. There are different types, among them the following: Cold urticaria. It features the onset of pruritus, erythema and edema located in areas exposed to low temperatures, especially in exposed areas on cold and windy days. Manipulation of cold objects may induce hand edema, and taking ice cream or cold drinks may produce lip swelling and, less commonly, swelling of the tongue and oropharynx, although respiratory compromise is very rare. Dermographic urticaria or dermographism. A wheal appears immediately after a moderate pressure or friction stimulus, such as the one produced by the seams in underwear. Its duration is very limited (20-30 minutes), which differentiates it from delayed pressure urticaria.

Table 2. Diseases related to urticaria for historical reasons and syndromes that present with hives and/or angioedema

• Maculopapular cutaneous mastocytosis (urticaria pigmentosa) • Urticarial vasculitis • Bradykinin-mediated angioedema (e.g., HAE) • Exercise-induced anaphylaxis • Cryopyrin-associated periodic syndromes (CAPS; urticarial rash, recurrent fever attacks, arthralgia or arthritis, eye inflammation, fatigue and headaches), that is, familial cold auto- inflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), or neonatal onset multisystem inflammatory disease (NOMID). • Schnitzler’s syndrome (recurrent urticarial rash and monoclonal gammopathy, recurrent fever attacks, bone and muscle pain, arthralgia or arthritis and ) • Gleich’s syndrome (episodic angioedema with ) • Well’s syndrome (Granulomatous dermatitis with eosinophilia)

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This guideline classification is the result of a systematic literature review using the ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is an update and revision of the previous EAACI/GA2LEN/EDF/WAO guidelines on urticaria33,34. There is clinical consensus and a strong recommendation that this 2013 updated version of the classification should be maintained in urticaria30.

8.3 Treatment of urticaria

The treatment of urticaria30 is often difficult and frustrating both for the physician and for the patient, particularly in the case of chronic urticaria where there are several factors that increase the number of outbreaks or their intensity, and current guidelines recommend aiming for complete symptom control in urticaria as safely as possible.

8.3.1 Identification and elimination/avoidance of the stimulus

The aim of the first treatment step is to prevent, as much as possible, the effect of any known unspecific histamine-releasing factors. Hot water, tight clothes, sun exposure during the most intense hours, certain drugs like aspirin or some foods (spicy foods, canned food, alcohol, etc.), increase histamine release by mast cells. Therefore, decreasing this possible effect is worthwhile, but, a strict diet is not advisable, as the results observed do not tend to be clearly satisfactory. Furthermore, patients can become obsessed with what they can or cannot eat, thus increasing their anxiety and sometimes worsening the evolution of the urticaria. However, if identified, specific food allergens need to be omitted as far as possible.

8.3.2 Symptomatic pharmacological treatment

The main outcome of therapies aimed at symptomatic relief is to reduce the effect of mast cell mediators such as histamine, PAF, and others on the target organs. Many symptoms of urticaria are mediated primarily by the actions of histamine on H1 receptors located on endothelial cells (the wheal) and on sensory nerves (neurogenic flare and pruritus). Antihistamines are particularly useful in controlling pruritus. The choice of antihistamine is based on urticaria severity and on the sleep tolerance reported by the patient. Continuous treatment with H1- antihistamines is of utmost importance in the treatment of chronic urticaria (safety data are available showing their continuous use for several years), supported not only by the results of clinical trials35,36 but also by the mechanism of action of these medications.

8.3.3 Treatment of urticaria according to EAACI/GA2LEN/EDF/ WAO guidelines

Antihistamines have been available for the treatment of urticaria since the 1950s. However, the older first-generation antihistamines have pronounced anticholinergic effects and sedative actions on the CNS, (e.g. they can interfere with rapid eye movement sleep and impact on learning and performance). Thus, the recent GA2LEN 2013 revision and update guideline30 does not recommend the use of these sedating (first-generation) antihistamines for the routine management of urticaria, except for

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the very few places worldwide where modern second-generation antihistamines are not available. This recommendation is based on strong evidence regarding potential serious side effects of old sedating antihistamines (lethal overdoses have been reported) and the worldwide availability, at low cost, of modern second-generation antihistamines, which not only lack these side effects but also have improved efficacy and duration of action.

In conclusion, the guideline recommends that modern second-generation H1-antihistamines, like rupatadine, are to be used as “first-line treatment” of urticaria, including chronic spontaneous urticaria (CSU), the most common type of chronic urticaria. “First-line treatment” is of “high quality evidence” (low cost, worldwide availability, very good safety profile and good efficacy)30. In addition, several studies have demonstrated that the majority of patients with chronic urticaria not responding to a single dose will profit from updosing of second-generation antihistamines at doses up to four-fold higher than the recommended doses. Updosing up to four-fold the dose of modern antihistamines, including rupatadine, is recommended by the guidelines as “second line or step” in the treatment algorithm30. Antihistamine updosing is also defined as being of “high quality evidence” (low cost, good safety profile, good efficacy)30. Finally, in the treatment algorithm for urticaria a “third line” is recommended in patients not responding to antihistamine updosing. When the symptoms persist after a further 1-4 weeks, the guideline recommends to add on to second-line treatment: omaluzimab (anti-IgE; strong recommendation/high level of evidence), (immunosupressant; strong recommendation/high level of evidence), or montelukast (leukotriene antagonist; weak recommendation/low level of evidence). A short course (maximum 10 days) of corticosteroids may also be used if exacerbations demand this as a “third line” option30. Regarding special populations like children, a strong recommendation was made by the panel to discourage the use of first-generation antihistamines in infants and children. Thus, in children, the

same first-line treatment and updosing (weight-adjusted) with modern second-generation H1- antihistamines is recommended as in adults30. Only medications with proven efficacy and safety in the pediatric population, such as rupatadine37, should be used.

First line: Modern second-generation antihistamines If symptoms persist after 2 weeks Second line: Increase dosage up to fourfold of modern second- generation antihistamines

If symptoms persist after 1–4 further weeks Third line: Add on to second line*: Omalizumab or Ciclosporin A or Montelukast Short course (max 10 days) of corticosteroids may also be used at all times if exacerbations demand this

Figure 3. Algorithm for the management of urticaria30. *The order of third-line treatments does not reflect preference.

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9.  Other allergic skin conditions – insect bite prurigo

In addition to urticaria, there are other common allergic skin conditions, such as • Atopic dermatitis • Contact dermatitis • Insect bite prurigo In the first two allergic skin diseases, antihistamines are only recommended as symptomatic treatment, mainly to reduce the intense pruritus. Insect bite prurigo (mosquito-bite-sensitive adults)

Definition and epidemiology Insect-induced prurigo is a benign and self-limiting disease. It is a cutaneous hypersensitivity reaction to the chemical substances that are transmitted by the bites and stings of ectoparasites, generally of the insectae class (mosquitoes, fleas, bedbugs, lice, etc.) either for feeding or for defensive purposes. The condition triggers immediate and late immunological mechanisms, which are expressed by chronic, pruriginous, recidivating papullae or papulovesicles. Insect-induced prurigo, also known as papular urticaria, is one of the most frequent manifestations of skin allergy.

Clinical manifestations The most important lesion is the pruriginous papula, which appears 24 to 48 hours after the bite, subsequent to the appearance of an erythema or wheal area that resolves quickly. Its topography is segmentary, and exposed areas such as the face, hands, thighs and legs tend to be more affected. Sometimes a blister appears on top of the papula owing to intense inflammatory infiltration: this is known as “ampullar prurigo”. For most people, bites and stings cause pain and discomfort, which usually last from a few hours to a few days. Symptoms in the affected area include reddening, inflammation and itching. Some people are allergic to insect bites and stings. This means that their immune system overreacts to the poison injected by an insect. After the first bite or sting, subjects produce an allergic substance, known as immunoglobulin E (IgE) antibody, which reacts to the insect’s poison and the symptoms stay longer. For the few people who are severely allergic to poison, bites and stings can be a matter of life and death. Severe allergic reactions to insect bites and stings may affect many organs and they develop rapidly. This reaction is called anaphylaxis. Anaphylaxis symptoms may include: urticaria affecting large body areas, inflammation of the throat or tongue, respiratory difficulties, dizziness, cramps, nausea or diarrhea. In extreme cases, a sudden blood pressure drop may result in shock and loss of consciousness. Anaphylaxis must be medically-treated immediately and can be lethal.

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Treatment Prevention is the best therapy: avoid wearing bright-colored clothes and perfumes outdoors. As the smell of meals attracts insects, care should be taken when cooking, eating or drinking sweet drinks, such as sodas or juice, and meals should be kept covered until they are served. Wear closed-toe shoes and avoid walking barefoot. Moreover, avoid wearing loose clothing, with which insects can be trapped between the fabric and the skin. The use of repellents is very important. When applied to the skin or clothes, they produce a vapor that is offensive both to the insects’ smell and taste.

Topical treatment Antipruritic drugs, cream or ointment, such as 0.5-1% phenol, 0.25-1.5% menthol and 5-10% camphor. Topical low-potency steroids (hydrocortisone, mometasone, fluticasone, etc.) should be used with caution, for short periods (less than 7-10 days) and only on the lesions. Application of ice to decrease inflammation.

Systemic treatment

Oral non-sedative H1-antihistamines (rupatadine) to relieve itching and decrease the wheals. Oral corticosteroids when there is exacerbation of persistent chronic symptoms. Epinephrine (in case of acute anaphylaxis) and parenteral antihistamines.

48 For internal use only PART I: ALLERGY GENERAL CONCEPTS

SUMMARY The Immune System Immunity is the natural resistance of the human body to infection: • Non-specific or general immunity: defence mechanisms (e.g. skin, mucosa, tears, inflammation). • Specific immunity (humoral immunity): mediated by antibodies and cellular immunity: mediated by T lymphocytes). Primary and secondary immune response The hypersensitivity reaction (allergy) • Exaggerated response to an antigen causing tissue injury and symptoms. • Early allergic reaction: response to the allergen’s initial contact to the antigen-presenting cell; production of histamine to fight off the allergen. • Late allergic reaction: late inflammation caused by leukotrienes, prostaglandins, platelet activating factor (PAF) and other pro-inflammatory mediators released by mast cells. Allergic rhinitis Inflammation of the nasal mucosa that causes nasal congestion, rhinorrhea, sneezing and itching. Affects almost 20% of population. Traditional classification • Seasonal allergic rhinitis: recurrent disease associated with pollens of trees and grasses appearing at specific times of the year. • Perennial allergic rhinitis: common reaction that may appear all year-round with environmental allergens. New classification (ARIA: Allergic Rhinitis and its Impact on Asthma) • Intermittent: symptoms of rhinorrhea, nasal obstruction, nasal itching and sneezing occur for up to 4 days per week or for up to 4 consecutive weeks. • Persistent: above symptoms occur more than 4 days per week and for more than 4 consecutive weeks. Treatment • Avoiding allergen • Allergen immunotherapy: under supervision and carefully • Systemic and local corticoids and nasal decongestants • Antihistamines (the most commonly used drugs): • First generation: old drugs; cross blood-brain barrier, sedating action. Not recommended by guidelines. • Second generation: non-sedating; no cardiac side effects of the newer drugs (e.g. desloratadine, rupatadine). Recommended by guidelines based on strong evidence.

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Urticaria Urticaria is characterized by the development of wheals (hives), angioedema or both. Types of urticaria: • Acute urticaria (less than 6-week duration) • Chronic urticaria (more than 6-week duration): • Chronic spontaneous urticaria • Inducible urticaria (symptomatic dermographism, cold urticaria, solar urticaria, delayed pressure urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticaria, aquagenic urticaria) Treatment of urticaria: • Identification and elimination/avoidance of the stimulus. • Symptomatic treatment (GA2LEN 2013 updated guideline):

• First-line treatment: modern second-generation H1-antihistamines at recommended doses in adults and children. • Second-line treatment: updosing up to four-fold the dose of modern antihistamines. • Third-line treatment: omaluzimab (anti-IgE) or immunosupressants or leukotriene antagonists or short course corticosteroids in patients not responding to antihistamine updosing. Other allergic skin conditions Insect bite prurigo • Reaction syndrome, usually with pruriginous papullae, owing to an insect bite. • Treatment: • Prevention • Topical (antipruritic drug, low potency topical corticosteroids, ice) • Systemic (oral non-sedative antihistamines, oral corticosteroids, adrenaline in case of acute anaphylaxis and parenteral antihistamines)

50 For internal use only PART II: PRODUCT PROFILE

51

PART II: PRODUCT PROFILE

1. Pharmacological properties of rupatadine

1.1 Chemical structure

Rupatadine (C26H26CIN3–C4H4O4) is an N-alkyl pyridine derivative that is classed as a novel second- generation antihistamine. Structurally, two chemical groups are important: a piperidinyl group responsible for antihistamine activity, and a lutidinyl group responsible for anti-PAF activity (Figure 1)38.

Lutidinyl group: anti-PAF activity CH3

N N N

HO2C CO2H

CI Piperidinyl group: anti-H1 activity

Figure 1. Chemical structure of rupatadine fumarate.

1.2 Pharmacodynamics

Rupatadine acts directly, with no prior metabolism, on the H1 and PAF receptors. This means it is not a prodrug, and thus it shows a fast onset of action, as clinical studies have demonstrated. Also, rupatadine binds the H1 receptor in a pseudo-irreversible way. This characteristic implies a prolonged link with the receptor, so that the clinical effects persist even when the product’s plasma levels are no longer detectable. Moreover, some rupatadine metabolites show a strong antihistamine activity. These characteristics confer a long-lasting effect on the product.

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1.2.1 Mode of action

Rupatadine interacts specifically with histamine H1 receptors and PAF receptors outside the CNS. It is therefore both an antihistamine and a PAF antagonist (Figure 2). As such, it has direct and indirect, ‘downstream’ effects on numerous inflammatory chemicals or mediators39. The innovative combination of these mechanisms of action endows rupatadine with high clinical efficacy, similar or even higher in certain cases than the latest second-generation antihistamines.

Role of Rupatadine in allergic inflammatory cascade

IMMEDIATE REACTION LATE REACTION Symptoms: Pruritus Symptoms: Sneezing, rhinorrhea Nasal congestion Skin wheal and flare Inflammatory reaction Tearing Urticaria Anaphylaxis Late responses ongoing asthma

= Rupatadine

Figure 2. Schematic representation of the allergic inflammatory cascade, highlighting the important role of PAF (and histamine) and showing the action of rupatadine on both the early and late phase of the allergic reaction.

1.2.2 Antihistamine activity

Receptor-binding studies

Rupatadine binds strongly (this is called affinity) to histamine H1 receptors compared with several first- and second-generation antihistamines, as has been shown in various binding-assay studies.

54 For internal use only PART II: PRODUCT PROFILE

For instance, in Chinese hamster ovary cells (CHOs), rupatadine bound more strongly than other second-generation antihistamines (levocetirizine, fexofenadine) to H1 receptors. Rupatadine was approximately 7 times stronger than levocetirizine, and about 29 times stronger than fexofenadine (Figure 3)40.

Comparative binding affinity of Rupatadine

Antihistamine power (1/ki x 1000 nM)

Rupatadine

Desloratadine

Levocetirizine

Fexofenadine

25 105 625 714

Figure 3. Antihistamine binding affinity of rupatadine compared with other second-generation antihistamines (adapted from Barron et al.40).

Rupatadine also binds preferentially (this is called selectivity) to H1 receptors in the peripheral (lung) rather than CNS (cerebellum). This has been demonstrated in an ex vivo binding study using tissues extracted from guinea-pigs that were previously treated by the oral route with 0.16 mg/kg rupatadine or with the same dose of hydroxyzine, a known CNS depressant agent, used as a reference. Rupatadine occupied 70% of H1 receptors in the lung compared with <10% of H1 receptors in the cerebellum; however hydroxyzine showed no selectivity for peripheral (lung) versus CNS (cerebellum) receptors, with more than 50% of central receptors blocked by the drug (Figure 4)39,41.

For internal use only 55 RUPAFIN TRAINING MANUAL – ALLERGIC RHINITIS AND URTICARIA

Selectivity of Rupatadine in peripheral H1 receptors 80

70

60

50

40

% blockage 30

20

10

0 Rupatadine Hydroxyzine

Central nervous system Peripheral

Figure 4. Preferential binding of rupatadine to H1 receptors in the peripheral (lung) rather than central nervous system (cerebellum)39,41.

In vitro pharmacological studies In vitro pharmacological experiments were conducted using muscle strips from guinea-pig ileum. Histamine was injected into the preparation to cause muscle contraction. Various antihistamines (test compounds) were previously incubated (5 minutes) and the histamine-induced contractions in the absence and in the presence of test compounds were recorded to determine the extent to which muscle contractions were inhibited. In these in vitro experiments, rupatadine was approximately 25 times more potent than cetirizine and approximately 75 times more potent than loratadine (Figure 5)42.

56 For internal use only PART II: PRODUCT PROFILE

Comparative activity in inhibiting histamine-induced muscle contractions

Rupatadine

Cetirizine

Loratadine

1.33 4.22 Relative inhibitory value (RIV)* 100

Figure 5. Rupatadine is more effective than cetirizine and loratadine in inhibiting histamine-induced muscle contractions in isolated muscle strips from guinea-pig ileum (adapted from Merlos et al42). *Data shown are the relative inhibitory values (RIVs) versus

rupatadine. RIV=IC50 rupatadine/IC50 compound × 100. IC50 value means the concentration

of test compound that inhibits muscle contractions by 50%. The smaller the IC50 value, the greater the inhibitory potency and the smaller the amount of the drug needed to inhibit the histamine-induced effects.

In vivo studies in animals Rupatadine was about 3–15 times stronger than loratadine in:

a) Inhibiting histamine-induced hypotension in normotensive rats (ID50= 1.4 mg/kg i.v. and 4.7 mg/kg i.v., respectively)42.

b) Inhibiting histamine-induced bronchospasm in guinea pigs (ID50=0.11 mg/kg i.v. and 1.6 mg/ kg i.v., respectively)42.

ID50 value means the dose of test compound that inhibits the histamine-induced effect (hypotension or bronchospasm) by 50%. The smaller the ID50 value, the greater the inhibitory potency and the smaller the dose of the drug needed to inhibit the histamine-induced effects. In dogs, rupatadine was significantly more effective than loratadine in inhibiting wheal formation after an intradermal injection of Ascaris suum extract solution (84% vs 66% inhibition; p<0.05)43. Wheal is a flat skin elevation, swelling, varying in size, with an off-white central area and a reddish ring around it. In other experiments, histamine drops were placed in the eyes of guinea-pigs to mimic allergic conjunctivitis. Rupatadine was approximately 20 times stronger than loratadine in reducing histamine- induced conjunctivitis44.

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Similar to other antihistamines, such as loratadine and cetirizine, rupatadine was a potent inhibitor of histamine-induced wheals in dogs at an oral dose of 1 mg/kg, with a maximum effect at approximately 4 hours after administration and a significant effect still observed after 24 hours (Figure 8)45.

In healthy volunteers Skin flares were produced by skin injection of histamine in healthy male volunteers. The effects of single-dose (10, 20 or 40 mg) and multiple-dose (20 or 40 mg once daily for 7 days) rupatadine were then evaluated. After single-dose rupatadine administration, flares were inhibited by a maximum of 69–93% (Figure 6)46. After multiple-dose rupatadine administration, skin flares were rapidly inhibited, and inhibition was maintained at 70–90% during the study 47. Flare can be defined as a diffuse area of redness on the skin around the point of application of an irritant (such as histamine), due to vasomotor reaction.

Wheal and skin area suppression after Rupatadine dose

50 600 40 400 30 20 200 Flare area (mm )

2 10 0 0 -10 -200 -20 -30 -400 -40 2

-50 -600 ) Wheal area (mm -60 -800 -70 -80 -1000 -90 -100 -1200 +1h +4h +8h +48h +56h basal +2h +6h +24h +72h +120h

Placebo Rupatadine 10 mg Rupatadine 20 mg Rupatadine 40 mg Rupatadine 80 mg

Figure 6. Rupatadine effectively reduces wheal and flare areas (produced by intradermal histamine) in healthy volunteers. All rupatadine doses produced significantly greater decreases than placebo for up to 96 h46.

1.2.3 Anti-PAF activity

PAF is a proinflammatory mediator of phospholipidic nature, present in humans, that has been associated with airway hyperreactivity, airway narrowing, high levels of eosinophils, and increased leaking from the bloodstream (vascular permeability). PAF has important roles in the development of allergic inflammatory conditions mainly in the late phase of allergy, asthma and anaphylaxis 24-26 (Figure 2) . A dual inhibitor of histamine-H1 and PAF receptors, such as rupatadine, may offer a clear advantage and superior clinical efficacy in the treatment of allergic rhinitis and urticaria over the

traditional compounds that only inhibit H1 receptors.

58 For internal use only PART II: PRODUCT PROFILE

Receptor-binding studies Rupatadine displayed similar strength as ginkgolide-B (BN-52021, a potent pure PAF-receptor antagonist) in binding to PAF receptors in rabbit platelet membranes. In this model, rupatadine 3 app competitively inhibited the binding of the agonist [ H]-WEB-2086 to PAF receptors with a Ki value of 550 nM that is approximately only twice lower than that of BN-52021, used as reference app 42 (Ki =221nM) (Ki is the inhibitory constant which is reflective of the binding affinity to the receptor: the smaller the Ki, the greater the binding affinity and the potency to block the receptor). This binding test demonstrates that the anti-PAF activity of rupatadine should be ascribed to its interaction with specific PAF receptors and not only to physiological antagonism.

In vitro pharmacological studies Anti-PAF activity was also demonstrated in a functional in vitro test in rabbit and human platelets (physiological antagonism). PAF antagonist potency is commonly assayed by taking advantage of the ability of this mediator to aggregate platelets from several species, including rabbits, due to the presence of PAF receptors in the platelet membrane48. Rupatadine was 160 times more potent than loratadine and >500 times more effective than terfenadine or ketotifen in inhibiting PAF-induced platelet aggregation in washed rabbit platelets (Table 1)41.

Table 1. Rupatadine is more effective than loratadine, terfenadine and ketotifen in inhibiting PAF-induced platelet aggregation in washed rabbit platelets

IC50 (µM) Rupatadine 0.2 Loratadine 32 Terfenadine >100 Ketotifen >100

IC50 = drug concentration that produces 50% inhibition of the PAF-induced effect.

Neutrophils play a major role in allergic reactions and in vitro studies have evaluated the effect of rupatadine on human neutrophil chemotaxis induced by PAF. In a comparison of rupatadine with other

H1 receptor antagonists, rupatadine was significantly more active (74.1%) than loratadine (34.5%), fexofenadine (7.9%) or cetirizine (which showed no inhibitory activity) (Figure 7)49.

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Inhibition of PAF induced chemotaxis in human neutrophils

Rupatadine

Loratadine

Fexofenadine p < 0.01 vs Rupatadine

Cetirizine (no inhibition) Relative inhibitiory value (RIV)

0 7.9 34.5 74.1 %

Figure 7. Percentage of inhibition of PAF-induced chemotaxis in human neutrophils (adapted from Ramis et al.49).

In vivo studies in animals Anti-PAF activity was also demonstrated in vivo in several experimental models in animals. Rupatadine, but not loratadine, was active in:

• Inhibiting PAF-induced hypotension in normotensive rats (ID50=0.44 mg/kg i.v.). Loratadine was

not active in this test at the maximum concentration tested of 5 mg/Kg i.v. (ID50> 5 mg/kg i.v.).

ID50 means the dose of the test compound that inhibits PAF-induced blood pressure decrease (hypotension) by 50%42

• Inhibiting PAF-induced bronchospasm in guinea pigs (ID50=0.0096 mg/kg i.v.). Loratadine was

not active in this test at the maximum concentration tested of 0.3 mg/kg i.v (ID50>0.3 mg/kg i.v.)42 Oral rupatadine (1 mg/kg) inhibited the wheal induced by intradermal administration of histamine or PAF in dogs whereas loratadine and cetirizine only inhibited the histamine-induced wheal. The maximum effect of rupatadine occurred after 4 h, and significant effects were still observed 24 h after single-dose administration of rupatadine, indicating a long-lasting effect (Figure 8)45.

60 For internal use only PART II: PRODUCT PROFILE

Rupatadine has powerful antihistamine and anti-PAF activity

Histamine PAF 60 80

60 40

40 20 20 % inhibition % inhibition

0 0

0 6 12 18 24 0 6 12 18 24 Time (h) Time (h)

Cetirizine Loratadine Rupatadine Web - 2086

Figure 8. Dual antihistamine and anti-PAF activity of oral rupatadine (1 mg/kg) in dogs.

In this in vivo model, rupatadine was as effective as cetirizine and loratadine in antagonizing increased vascular permeability provoked by histamine, but superior to these agents against PAF-induced increases in vascular permeability. Rupatadine was as effective as the pure PAF antagonist WEB-2086, used as a positive control (adapted from Queralt el al.45). In guinea-pigs with conjunctivitis produced by PAF, rupatadine effectively reduced symptoms. However, other antihistamines (levocabastine, loratadine) had no significant effect50. In mice, rupatadine protected against death due to high-dose PAF administration, whereas loratadine did not42.

In healthy volunteers Blood samples taken from healthy volunteers were used to evaluate PAF-induced platelet aggregation and the anti-PAF activity of rupatadine in this model. After single-dose rupatadine administration (40 or 80 mg orally) to volunteers, the effects of PAF on platelet aggregation were re-evaluated. The effect of rupatadine to inhibit platelet aggregation started at 2 h and peaked at 4 h, but was not significant at 24 h after rupatadine administration47. In a dose-ranging study, PAF was injected into volunteers’ skin to produce flares. Rupatadine markedly reduced the area of such flares. After a 20-mg dose, flare-reducing activity was maintained for up to 48 h postdose. After a 40-mg dose, flare area was reduced by 68% at 4 h, 87% at 6 h and > 60% at 72 h. Moreover, flare area was reduced for up to 96 h after administration of rupatadine 80 mg47. In another study in healthy volunteers51, it was shown that a single dose of rupatadine 40 mg was highly effective for up 72 h against PAF and histamine- induced dermal flares (Figure 9), and also inhibited platelet aggregation (Figure 10) in an ex vivo test in the same group of volunteers. These data further support the observation that rupatadine has the dual capability to block both H1 and PAF receptors in humans.

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Anti-PAF and antihistamine activity in humans: inhibition of flare areas by Rupatadine

100 20 ** ** ** ** 80 ** * 15 ** ** 40 ** 10 * * 20 * 5 Plasma rupatadine levels (ng/ml) Inhibition of flare response (%) 0 0

0 1 2 4 6 12 24 48 72 96 Time after oral dosage with 40 mg rupatadine (*): p < 0.01; (**): p < 0.001

Figure 9. Anti-PAF and antihistamine activity of rupatadine in humans51. Inhibition of flare responses induced by PAF (green) and histamine (orange). Plasma levels of rupatadine are shown by the pink shaded area.

Anti-PAF activity in humans: Inhibition of PAF-induced platelet aggregation by Rupatadine

80 82% inhibition p = 0.023

60

40

(AUC AUC]) [%ADP 20 PAF-induced aggregation PAF-induced

0 Before dosage 4h after dosage

Figure 10. Anti-PAF activity in humans. Inhibition of PAF-induced platelet aggregation by rupatadine 40 mg51.

62 For internal use only PART II: PRODUCT PROFILE

1.2.4 Anti-inflammatory and antiallergic activity

Unlike various first-generation antihistamines (e.g. hydroxyzine) and second-generation anti­ histamines (e.g. levocetirizine, loratadine), rupatadine is a competitive inhibitor of PAF receptors and blocks proinflammatory activity of this mediator. Rupatadine has a wide-range of anti-inflammatory and antiallergic activity against cells and chemicals involved in immediate and delayed allergic reactions, and it has been shown to inhibit:

Mast cell degranulation In pharmacological studies, rupatadine inhibited antigen-induced histamine release from canine 43 skin mast cells more effectively than loratadine (IC50=5.3 µM and 19 µM, respectively) . In addition, rupatadine inhibits histamine and (interleukins, TNFα) secretion from human mast cells in response to allergic, immune and neuropeptide triggers52. Finally, recent studies have shown that PAF stimulates human mast cell release of proinflammatory mediators (histamine, interleukin-8 and TNFα) and that this effect is inhibited by rupatadine53. All these activities endow rupatadine with unique properties in treating allergic inflammation and may have a beneficial effect on the late-phase allergic reaction (delayed hypersensitivity).

Cellular migration (recruitment/chemotaxis) of eosinophils and neutrophils Rupatadine inhibited the early symptoms (dyspnea, cyanosis, bronchospasm) and bronchoalveolar eosinophil recruitment in a guinea pig model of allergic asthma (ovalbumin-sensitized animals). Rupatadine was as effective as loratadine but significantly more effective than cetirizine54. Moreover, in eosinophils from eosinophilic donors or healthy volunteers, rupatadine 10–100 nM reduced eotaxin-induced eosinophil chemotaxis39.

In human neutrophils stimulated with PAF and LTB4, rupatadine dose-dependently inhibited chemotaxis and had a greater effect than other antihistamines such as cetirizine, fexofenadine, loratadine and mizolastine39,49.

Production of inflammatory mediators (cytokines) such as ILs 5, 6 and 8, and TNFα In vitro, rupatadine was the most potent of four antihistamines tested in inhibiting the production of IL-6 and IL-8 in histamine-stimulated human umbilical vein endothelial cells (HUVECs) (Figure 11). That is, in restricting IL-6 production, rupatadine was about twice as potent as desloratadine, approximately 48 times more potent than levocetirizine, and 460 times more potent than

fexofenadine (respective mean IC50 values were 0.046, 0.1, 2.2 and 21 nM). Similarly, in inhibiting IL-8 production, rupatadine was 3 times more potent than desloratadine, and 60 times more potent

than levocetirizine (corresponding mean IC50 values were 0.04, 0.12 and 2.4 nM). Interestingly, a

direct association was apparent between Ki values (i.e. binding affinity to H1 receptors) and the extent to which IL production was inhibited39,40 . In addition, rupatadine was significantly more effective than desloratadine in inhibiting the release of TNFα, IL-5 and IL-6 from human lymphocytes55.

Neutrophil adhesion molecules (CD11b and CDE18) and transcription factors (nuclear factor-kappaB; NF-κB) involved in inflammation39,56

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Rupatadine is a stronger inhibitor of inflammatory mediators (cytokines) than other antihistamines IL- 6 IL- 8 125 125

100 100

75 75

50 50 % inhibition % inhibition

25 25

0 0

-12 -11 -10 -9 -8 -7 -12 -11 -10 -9 -8 -7 Log (Concentration) M Log (Concentration) M

Rupatadine Levocetirizine Desloratadine Fexofenadine

Figure 11. Rupatadine is more potent than various other antihistamines in inhibiting cytokine release from HUVECs (human umbilical vein endothelial cells)39,49. IL-6 (interleukin-6); IL-8 (interleukin-8).

In addition, rupatadine inhibits cytokine release from activated human lymphocytes to a greater extension than desloratadine (Figure 12)55.

Rupatadine is a stronger inhibitor of inflammatory mediators (cytokines) than desloratadine

IL- 5 TNF - α GM - CSF

125 ## 125 125

100 100 ## 100 ** * * ** 75 *** 75 *** 75 50 50 50 *** *** *** ***

Control (%) 25 Control (%) 25 Control (%) 25

0 0 0 -7 -6 -5 -7 -6 -5 -7 -6 -5 Antihistamine [log M] Antihistamine [log M] Antihistamine [log M] IL- 6 IL- 8 125 125

100 ## 100 *** 75 75 *** ** 50 50 ***

Control (%) 25 Control (%) 25

0 0 -7 -6 -5 -7 -6 -5 Antihistamine [log M] Antihistamine [log M]

Rupatadine Desloratadine

*p < 0.05, **p < 0.01, ***p < 0.005 vs control, ## p < 0.001 vs rupatadine

Figure 12. Rupatadine inhibits cytokine release from activated human lymphocytes to a greater extent than desloratadine56. GM-CSF (granulocyte-macrophage colony-stimulating factor); IL-5 (interleukin-5); IL-6 (interleukin-6); IL-8 (interleukin-8); TNF-α (tumor necrosis factor-α).

64 For internal use only PART II: PRODUCT PROFILE

Overall, the extensive anti-inflammatory and antiallergic profile of rupatadine suggests that the compound may provide better symptomatic relief in disorders such as allergic rhinitis and urticaria39.

1.2.5 Anticholinergic effects

Several studies have been conducted to assess the anticholinergic effects of rupatadine. These adverse effects occur with many first-generation antihistamines. In several preclinical models, no anticholinergic effects were observed with doses ≤7 mg/kg (>40 times the dose for humans). Rupatadine did not exhibit peripheral anticholinergic activity with single doses from 10-80 mg in humans, with no effect on salivary flow 46,57,58.

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2. Rupatadine pharmacokinetic properties

In preclinical phases, the pharmacokinetic properties of rupatadine were examined in various laboratory animals, including mice, rats, dogs and monkeys. The results of those studies showed a rapid absorption and a high distribution volume which suggest good tissue distribution. In all species, total bioavailability was above 50% although active metabolites and pharmacokinetic parameters were species-dependent. Half lifes ranged from 1 h (mice) to 2-3 h (rats and dogs)58. A total of 17 phase I studies have been performed with a total sample of 334 atopic and healthy volunteers. The pharmacokinetic properties of oral rupatadine 10-40 mg once daily have been investigated in single- or multiple-dose studies47,59,60, including a study of 10 mg rupatadine once daily in younger (aged 18-35 years) versus older (aged 65-72 years) subjects47. The potential for pharmacokinetic interactions between rupatadine and other agents, including those that inhibit cytochrome P450 (CYP) isoenzymes, has also been assessed47,58,61.Where possible, this section will focus on data for rupatadine 10 mg once daily, the recommended therapeutic dose. The main pharmacokinetic parameters and profile of rupatadine 10 mg (therapeutic dose) after single and repeated dose treatment are summarized in Table 2.

Table 2. Main pharmacokinetic parameters and profile of rupatadine 10 mg

Once-daily dose Parameter Single Multiple

Cmax (ng/mL) 2.6 3.8

tmax (h) 0.75 0.75-1.0

AUC0-24h (ng/mL/h) 7.6 12.5 linear increase with single C /AUC max doses of 10-40 mg Effect of food intake minimal Protein binding 98-99% extensive hepatic Metabolism metabolism

Elimination t1/2 (h) 5.0 5.9 60.9% in feces, 34.6% in Elimination urine Effect of age little clinical relevance

66 For internal use only PART II: PRODUCT PROFILE

2.1 Absorption and distribution

Rupatadine is rapidly absorbed after oral administration, reaching peak plasma concentration (Cmax) of 2.6 ng/mL within an hour (45 min-1 h), which matches its clinical profile, as its antihistamine effects are detectable after 1-2 hours. After repeated administration, steady-state plasma concentrations of rupatadine were reached on days 3-5, with no abnormal accumulation, and a Cmax of 3.8 ng/mL. In the 10-40 mg dose range, linearity between dose and Cmax and area under the curve (AUC) was observed, suggesting dose-proportional pharmacokinetics over that dose range62. Rupatadine is extensively bound to plasma proteins (98-99%)47,59. It is well distributed in tissues indicating that the high degree of binding does not cause the compound to be retained in the circulating blood, allowing it to reach its target receptors. As rupatadine has never been administered to humans by the intravenous route, no data are available on its absolute bioavailability, but the oral bioavailability in animal studies (dogs) was >50%47.

2.2 Metabolism and excretion

Similar to other second-generation antihistamines, rupatadine shows a presystemic or first-pass hepatic metabolism, i.e., it can be metabolized by certain enzymes present in the intestinal tract and the liver. Rupatadine is transformed at the hepatic level mainly via CYP and specifically via the CYP3A4 isoenzyme. The main pathways identified for the biotransformation of rupatadine were different oxidative processes which end up conjugating inactively with the glucuronic acid of the biliary system. The amounts of unaltered active substance found in urine and feces were insignificant. This means that rupatadine is almost completely metabolised. Some of the metabolites retain antihistamine activity and may partially contribute to the global effect of the drug and its long duration of action. Roughly, the active metabolites desloratadine and other hydroxylated derivatives accounted for 27% and 48%, respectively, of the total systemic exposure of the active substances62. CYP3A4 has been identified in vitro as the main isoenzyme responsible for rupatadine’s biotransformation, and it is unlikely that there is a genetic polymorphism in its biotransformation.

Mean elimination half-life (t1/2) is approximately 6 hours after repeated-dose treatment, ranging from 4.3 to 14.3 hours47. It should also be noted that the half-life of the metabolite ranges from 13 to 41 hours, which contributes to maintaining antihistamine activity up to 72 hours. Excretion is both via urine and feces. In an excretion study in humans (40 mg of 14 C-rupatadine), 34.6% of the administered radioactivity was recovered from urine and 60.9% from feces collected for 7 days. Biliary excretion is the main elimination pathway of the drug. Rupatadine undergoes considerable systemic metabolism when administered orally. The amount of unaltered active substance found in urine and feces was very low58,62.

2.3 Pharmacokinetics in children

Pharmacokinetics in children receiving rupatadine oral solution 1 mg/mL, have been investigated in two phase II studies in children with allergic rhinitis: one study in children aged 2-5 years63 and the other study in children aged 6-11 years64.

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In both subgroups of children, rupatadine was rapidly absorbed. The respective mean Cmax, AUC and elimination half-time values are indicated in Table 3. All these values are similar to those obtained in adults and adolescents.

Table 3. Pharmacokinetic parameters of rupatadine in children at steady state

Parameter 2-5 years 6-11 years Mean (SD) n = 40 n = 11

Cmax (ng/mL) 1.96 (0.52) 2.54 (1.26)

AUC0-24 (ng/mL/h) 10.38 (4.31) 10.74 (6.80)

t1/2 (h) 15.94 (4.09) 12.28 (3.09)

A population pharmacokinetic model was developed using data from the two pediatric pharmacokinetic studies referred to above65. Overall, results from the population pharmacokinetic study confirmed that the pharmacokinetics of rupatadine depend on the body weight of children. A 2.5 mg dose of rupatadine 1 mg/mL oral solution in children with a body weight in the range 10 to 25 kg, and a dose of 5 mg in children with

a body weight above 25 kg, showed similar exposure (Cmax and AUC) to that obtained in adults and adolescents with rupatadine 10 mg (tablets). These results support the proposed posology of reducing the dose in children aged between 2-11 years by adjusting for body weight.

2.4 Elderly population

In elderly volunteers aged 65 or older who participated in the rupatadine trials, even lower systemic clearance values were observed compared with those of young subjects, probably due to a physiological decrease in presystemic metabolism. These differences were not observed in the metabolites analyzed. The mean elimination half-life of rupatadine in elderly and young volunteers was 8.7 and 5.9 hours, respectively. As rupatadine 10 mg was well tolerated in healthy elderly individuals, with no clinically relevant adverse effects, it was concluded that adjustments are not necessary when using a 10 mg dose in elderly patients58,62.

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SUMMARY Chemical structure Rupatadine is a modern second-generation antihistamine with a chemical structure designed to show two well-balanced activities in a single molecule: H1 receptor and PAF receptor antagonist activity. Pharmacodynamics • Rupatadine is a novel second-generation antihistamine with antihistamine and anti-PAF activity. • Rupatadine binds more strongly than various other second-generation antihistamines

(loratadine, fexofenadine, levocetirizine) to histamine H1 receptors. • Rupatadine produces a rapid and sustained reduction of skin flares (induced by injection of histamine into the skin) in healthy volunteers. • Rupatadine is a competitive inhibitor of PAF receptors. With regard to the inhibitory activity on the PAF receptor, rupatadine is clearly the only antihistamine that presents this activity and this is independent of its antihistamine activity. • Rupatadine markedly reduces skin flares (induced by injection of PAF into the skin) in healthy volunteers. • Rupatadine inhibited the wheal induced by intradermal administration of histamine or PAF in the dog, whereas loratadine and cetirizine only inhibited the histamine-induced wheal. • Rupatadine has wide-ranging anti-inflammatory activity against cells and mediators involved in immediate and delayed allergic reactions, as it has been shown to inhibit: • Mast cell degranulation. • Cellular migration (chemotaxis) of eosinophils and neutrophils.

• Production of inflammatory mediators (cytokines) such as ILs 5, 6 and 8, and TNFa. • Neutrophil adhesion molecules (CD11b and CDE18) and transcription factors (NF-kB) involved in inflammation. • The extensive anti-inflammatory and antiallergic ‘profile’ of rupatadine suggests better symptom relief than that provided by various other antihistamines in allergic rhinitis. Pharmacokinetics • Rupatadine is rapidly and well absorbed after oral administration with maximum plasma

concentrations (Cmax) of 2.6 ng/mL between 0.75 and 1 hour. • Rupatadine is extensively bound to plasma proteins (98-99%). The mean elimination half- life is approximately 6 hours. • Rupatadine is almost completely metabolized via cytochrome P450 (CYP3A4 isoenzyme). Some metabolites retain antihistamine activity. Excretion takes place both via urine (35%) and feces (61%). • Children (2-11 years old) receiving rupatadine oral solution (1 mg/mL; dose adjusted to

body weight), showed similar exposure (Cmax and AUC) to 10mg (tablets) in adults and adolescents. • In elderly patients, no dose-adjustments are necessary when using the therapeutic dose of 10 mg (tablets).

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3. Rupatadine efficacy profile in allergic rhinitis

The efficacy of rupatadine in the treatment of AR (allergic rhinitis) has been investigated in adults and adolescents (aged ≥12 years) in 15 clinical trials: 9 studies in SAR (seasonal allergic rhinitis), 4 studies in PAR (perennial allergic rhinitis) and 2 studies in PER (persistent allergic rhinitis), and most of them were carried out with a high level of scientific evidence (level 2: randomized, double blind, controlled clinical trials). A total of 3696 subjects were included in the phase II-phase III studies, and the population treated with rupatadine was 2367 patients, 1245 of whom were treated with the therapeutic dose of 10 mg, that was the preferred dose chosen from phase II dose-ranging studies (dose range: 2.5-20 mg) . Several studies were carried out in comparison with other antihistamines used for reference: cetirizine, levocetirizine, desloratadine, ebastine and loratadine. The target population was patients with moderate or severe AR. As the aim was to include patients in the acute phase of the disease, the subjects had to have a >5 score for nasal symptoms on a standardized scale at the time of enrollment. This guaranteed that only patients with an acute episode of at least mild intensity were included. A history of at least 2 years of AR, documented in clinical records, was required prior to study enrollment. The primary efficacy endpoints of those studies were based on the daily assessment of symptom intensity registered by the patients in their diaries. Mean daily total symptom score (DTSSm), the primary endpoint in SAR studies, was equal to mean daily symptom score registered for each of the assessed symptoms. The percentage of days with a score of severe symptoms ≤1 (Pdmax1; primary endpoint in PAR studies) corresponded to the percentage of days of the study period in which, for each patient, the most severe symptom score for each day was <1. In PER studies, the primary endpoint was the mean change from baseline in instantaneous total symptom score (i6TSS). Mean daily symptom score (DSSm) was a secondary endpoint which allowed for the determination of a given symptom’s mean score; it is the mean of all scores registered for a given symptom and for all days of the study. The global efficacy assessment was determined based on the score assigned by the investigator and by the patient in all studies using a conventional scale.

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3.1 Seasonal allergic rhinitis (SAR)

3.1.1 Dose-finding studies

Two dose-ranging, placebo-controlled trials47,66, were carried out in patients with SAR to select the optimal therapeutic dose (Table 4). This dose was further confirmed in a pooled analysis of phase II and phase III clinical trials67.

Table 4. Dose-ranging studies of rupatadine in SAR (PLA: placebo; RUP: rupatadine; od: once daily; m: multicenter; r: randomized; db: double-blind; pg: parallel groups)

Number of Study design and Treatment Duration Reference patients level of evidence PLA od 50 Izquierdo I. m, r, db, pg RUP 10 mg od 54 2 weeks Allergy 2000; level 2 RUP 20 mg od 45 55 (Suppl. 63): 27566 PLA od 74 RUP 2.5 mg od 76 Izquierdo I. m, r, db, pg RUP 5 mg od 79 2 weeks Drugs Today 2003; level 2 RUP 10 mg od 72 39: 451–46847 RUP 20 mg od 81

Rupatadine 2.5–20 mg once daily was clearly more effective than placebo in alleviating nasal and ocular symptoms of SAR in a dose-dependent manner. Overall, however, the 10 and 20 mg doses were the most effective and there was little difference between them in terms of symptom relief and patient/investigator global ratings. Based on balance between symptom relief, patient and investigator preference and tolerability/safety, rupatadine 10 mg once daily was choosen as the preferred option and is now the recommended therapeutic dose. A further pooled analysis (phase II and phase III clinical trials) involving 1368 patients with moderate to severe SAR, confirmed that rupatadine (2.5-20mg) was superior to placebo and that 10 and 20 mg were equally effective in reducing mean daily total symptom scores (mDTSS). A covariate analysis found no age- or sex-related differences67.

3.1.2 Comparative efficacy studies

The efficacy of rupatadine 10 and 20 mg, in comparison with other second-generation antihistamines, has been evaluated in 6 pivotal, well-controlled phase III clinical trials in patients with SAR. These studies are summarized in Table 5.

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Table 5. Efficacy of rupatadine in SAR patients. Comparative studies with cetirizine (CTZ), ebastine (EBA), loratadine (LOR), desloratadine (DES) and levocetirizine (LEV) (od: once daily, m: multicenter, r: randomized, db: double-blind, ol: open label; pg: parallel groups, sc: single centre)

Number of Study design and Treatment Duration Reference patients level of evidence Martinez Cócera C. RUP 10 mg od 124 m, r, db, pg 2 weeks JIACI 2005; 15: CTZ 10 mg od 117 level 2 22-968. PLA od 81 m, r, db, pg Guadaño EM. Allergy RUP 10 mg od 79 2 weeks level 2 2004; 59: 766-7169. EBA 10 mg od 83 RUP 10 mg od 112 m, r, db, pg, Saint-Martin F. JIACI RUP 20 mg od 111 2 weeks level 2 2004; 14: 34-4070. LOR 10 mg od 116 RUP 10 mg od 107 Izquierdo I. Drugs m, r, db, pg RUP 20 mg od 112 2 weeks Today 2003; 39: 451- level 2 LOR 10 mg od 112 46847. 122 Lukat KF. J Asthma RUP 10 mg od m, r, db, pg 119 4 weeks Allerg 2013; 6:31- DES 5 mg od level 2 118 3971 Maiti R. Arc RUP 10 mg od 30 sc, r, ol, pg Otolaryngol Head 2 weeks LEV 10 mg od 30 level 2 Neck Surg 2010; 136: 796-80072.

Overall, these studies have shown that rupatadine is at least as effective as other second-generation antihistamines such as cetirizine, ebastine, loratadine and desloratadine in relieving nasal and ocular symptoms and had a better safety and efficacy profile than levocetirizine in patients with SAR. A summary of these studies, with a focus on the main differences between rupatadine and these drugs, is presented below.

Rupatadine 10 mg versus cetirizine 10 mg A randomized, double-blind, parallel group clinical trial compared a daily dose of 10 mg of rupatadine for 14 days with cetirizine 10 mg in 249 patients68. The primary efficacy endpoint was the mean total daily symptom score (mTDSS) for nasal and non- nasal symptoms recorded in the patient’s diaries. The mTDSS was 0.7 for both treatment groups. In the investigator-assessed global efficacy evaluation, 93.3% of patients in the rupatadine group and 83.7% in the cetirizine group showed some improvement or a great improvement in their symptoms (p=0.022). On day 14 of treatment, the reduction of daily symptom severity from baseline was 56% for the rupatadine group and 50% for cetirizine, as seen in Figure 13 (mean changes –0.87 and –0.65, respectively). In both groups, the treatments were well tolerated.

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Daily Total Symptom Score

2.5

2.0 -50% -56%

1.5

1.0 * *

0.5

0 Baseline (day 1) Day 14 Baseline (day 1) Day 14

Cetirizine 10 mg (n = 117) Rupatadine 10 mg (n = 124)

Figure 13. Mean Daily Total Symptom Scores (mDTSS) and changes in mDTSS for cetirizine and rupatadine (* p<0.05).

After the first week of treatment, the investigator’s global assessment and the absence of “runny nose” were significantly better with rupatadine, suggesting a faster onset of action with this drug.

Rupatadine 10 mg versus ebastine 10 mg and placebo In this randomized, double-blind, parallel group, placebo-controlled clinical trial, a daily dose of rupatadine 10 mg for 14 days was compared with ebastine 10 mg and placebo in 243 patients69. Rupatadine 10 mg was significantly superior to placebo in reducing the mean daily total symptom scores (mDTSS) from baseline (33% and 13% reduction, respectively, p<0.05). Ebastine (22% reduction), did not reach a significant difference versus placebo (Figure 14). Similarly, and considering symptom-by-symptom scores, rupatadine produced a greater reduction in the severity of all assessed symptoms compared with placebo. These differences were statistically significant for the symptoms of sneezing, rhinorrhea, watery eyes and nasal itching. Although the difference between the two active drugs was not statistically significant rupatadine improved 4 symptoms of SAR compared with placebo, whereas ebastine only improved one individual symptom, showing a trend in favor of rupatadine (Figure 14).

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Mean daily symptom-by-symptom and total scores

Placebo Ebastine 10 mg Rupatadine 10 mg 2.5

2.0

1.5

† 1.0 * * * * 0.5

Mean symptom score * 0 Rhinorrhoea Nasal Sneezing Tear-shedding TOTAL pruritus

Figure 14. Mean daily symptom-by-symptom and total scores for rupatadine 10 mg, ebastine 10 mg and placebo. * = p < 0.05 Rupatadine 10 mg vs. placebo, † = p < 0.05 Ebastine 10 mg vs. placebo. Adapted and modified from Guadaño EM69.

Rupatadine 10 mg and 20 mg versus loratadine 10 mg A randomized, double-blind, parallel group, placebo-controlled clinical trial compared rupatadine 10 mg and rupatadine 20 mg versus loratadine 10 mg in 339 patients with SAR70. In the per-protocol analysis, rupatadine 10 and 20 mg, once daily for 14 days, proved to be better than loratadine 10 mg both in total symptom score (Figure 15) and particularly in sneezing and nasal itching assessed separately by the practitioners (p=0.01; clinical score of each symptom). No significant differences were found between the doses of rupatadine 10 and 20 mg in any of the analyses conducted.

Total Daily Symptom Score

* p < 0.05 between groups

2.0 *

1.5 -44.6% -47.5% -54.3% 1.0

Mean score 0.5

0 Baseline (1st day) Day 14

Loratadine 10 mg (n = 92) Rupatadine 10 mg (n = 86) Rupatadine 20 mg (n = 77)

Figure 15. Rupatadine versus loratadine in SAR patients (mTDSS after 2 weeks treatment; adapted from Saint-Martin F70).

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Rupatadine 10 mg and 20 mg versus loratadine 10 mg In a second comparative clinical study with loratadine in 331 patients, no significant differences were found between treatments. However, in terms of total symptom score there were significant differences between rupatadine and loratadine in some specific symptoms 47. The investigator’s global assessment was significantly better for the groups receiving both doses of rupatadine (10 and 20 mg) than for the loratadine 10 mg group (Figure 16).

Overall efficacy impression by investigator

Rupatadine 10 mg Rupatadine 20 mg 6% 5% 1% 11%

24%

55% 33% 65% Loratadine 10 mg 6% 24% ** * 47% Worsening of symptoms

No change ** p < 0.001 RUP 10 mg vs LOR 10 mg 23% Improvement of symptoms * p < 0.05 RUP 20 mg vs LOR 10 mg Marked improvement/no symptoms Data on file

Figure 16. Rupatadine 10 and 20 mg versus loratadine 10 mg in SAR patients. Efficacy evaluation by the investigator.

Rupatadine 10 mg versus desloratadine 5 mg and placebo A total of 379 patients were included in this study and randomized to one of the three treatment groups. Efficacy was assessed by the change from baseline in the total symptom score (TSS) over 4 weeks of treatment by means of a reflective (prior 12 hours; primary end point) or instantaneous (secondary end point) evaluation. Rupatadine 10 mg/day and desloratadine 5 mg/day were both significantly superior to placebo in reducing the baseline total symptom score (both p<0.05). Rupatadine, desloratadine and placebo reduced the reflective symptoms by 46%, 49% and 37%, respectively. Similar results were obtained when the instantaneous symptoms score was analyzed (Figure 17)71.

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Change from baseline in total symptom score

Reflective Instantaneous 0

-1

-2

-3

-4

-5 -4.49 -5.22 4 weeks -6 -5.83 -5.94 -6.35 -7 -6.69 * * * -8 * TSS mean change from baseline Placebo Rupatadine * p < 0.05 active treatments vs placebo Desloratadine -10

Lukat KF, et al. J Asthma Allergy. 2013:6;31-9

Figure 17. Mean change in Total Symptom Score from baseline after treatment with rupatadine 10 mg, desloratadine 5 mg or placebo, once daily for 4 weeks.

No statistically significant differences were seen between rupatadine and desloratadine. Both rupatadine and desloratadine improved patients’ and physicians’ perception of disease severity. As for the safety profile, no differences were observed between the two treatment groups and placebo.

Rupatadine 10 mg versus levocetirizine 10 mg This was a 2-week, single center, randomized, open, parallel group, comparative clinical study between rupatadine 10 mg and levocetirizine 10 mg in patients with SAR72. There was a significantly greater reduction in Total Nasal Symptom Score (TNSS) in the rupatadine group (36.7% vs 18.02%, p<0.001) as well as in the Rhinoconjunctivitis Quality of Life Questionaire (18.08% vs 9.94%, p=0.02) (Figure 18).

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Nasal symptom reduction and quality of life

Mean different vs first visit

Symptoms RQLQ (TNSS) 0 9.94% 18.08% -0.5 18.02% Levocetirizine -1 Rupatadine

-1.5 36.67% * -2 ** p < 0.001 -2.5 * p = 0.02

-3 ** Maiti R, et al. Arch Otolarvneol Neck Sug. 2010;136:796-800.

Figure 18. Change in Total Nasal Symptom Score (TNSS) and Rhinoconjunctivitis Quality of Life (RQLQ) over 2 weeks in study groups.

Differential leukocyte counts (neutrophils and eosinophils) and serum IgE levels were significantly reduced by both drugs compared to baseline values, but rupatadine was found to be superior to levocetirizine in the reduction of IgE serum levels (16% vs 7.5%, p=0.004) and eosinophil counts (p<0.001). The incidence of adverse effects was lower in the rupatadine group compared with the levocetirizine group (11.5 vs 23.3%). It is concluded from the results of this study that rupatadine is a better choice for SAR compared with levocetirizine because of its better efficacy and safety profile.

3.2 Perennial allergic rhinitis (PAR)

A dose-ranging phase II study47 and three phase III comparative studies with cetirizine, ebastine and loratadine73,74,75 were conducted in patients with PAR (Table 6). The primary endpoint of these studies was Pdmax1, corresponding to the percentage of days during the study period in which the score of the most severe symptom on each day was ≤1, for each patient. Furthermore, the change from baseline in the severity of total symptoms score (TSS) was also evaluated. Overall, rupatadine was at least as effective as cetirizine, ebastine and loratadine in relieving nasal and ocular symptoms in patients with PAR.

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Table 6. Studies in Perennial Allergic Rhinitis (PAR) in adults and adolescents (>12 years) (PLA: placebo; RUP: rupatadine, CTZ: cetirizine; EBA: ebastine; LOR: loratadine; m: multicenter; r: randomized; db: double- blind; pg: parallel groups; pc: placebo-controlled)

Total number Study design and Treatment Duration Reference of patients level of evidence

PLA od Izquierdo I. Drugs of m, r, db, pg, pc RUP 10 mg od 245 4 weeks Today 2003; 39: level 2 RUP 20 mg od 451-46847. PLA od 70 Marmouz F. J. Asthma RUP 10 mg od 65 m, r, db, pg, pc 4 weeks and Allergy 2011; 4: RUP 20 mg od 68 level 2 27-3573. CTZ 10 mg 66 PLA od 73 Molina M. Therapy m, r, db, pg, pc RUP 10 mg od 71 4 weeks 2010; 7(4): 426- level 2 EBA 10 mg od 79 42974. PLA od 69 Kowalski ML. Therapy RUP 10 mg od 73 m, r, db, pg, pc 4 weeks 2009; 6(3): 417- RUP 20 mg od 71 level 2 42575. LOR 10 mg od 70

3.2.1 Dose-finding study: rupatadine 10 mg and 20 mg versus placebo

A placebo, controlled, dose-ranging study was carried out to evaluate the efficacy and safety of rupatadine in patients with PAR. Outpatients were randomized to one of the three parallel treatment groups: rupatadine 10 or 20 mg or placebo, once daily for a 28 day period in a total of 174 evaluable patients47. The two doses of rupatadine provided better control of symptoms than placebo assessed by Pdmax1, and both doses were selected for further phase III comparative trials with other second- generation antihistamines.

3.2.2 Comparative efficacy studies

Rupatadine 10 mg and 20 mg versus cetirizine 10 mg and placebo A randomized, double-blind, parallel group, placebo-controlled clinical trial compared a daily dose of rupatadine 10 mg or 20 mg for 28 days versus cetirizine 10 mg and placebo in 273 patients73. The three active treatment groups differed significantly from placebo in terms of the primary endpoint (morning/evening reflective total symptom score; 5TSS), with no significant differences between them. Similarly, in terms of secondary endpoints (morning/evening reflective nasal total symptom score: 4TNSS) and individual symptom analysis (rhinorrhea, nasal itching, congestion and sneezing) both rupatadine 10 and 20 mg and cetirizine 10 mg showed significant differences with respect to placebo. In conclusion, the sustained 24-hour action of rupatadine 10 mg (the therapeutic dose) provides effective control of morning and evening symptoms in patients with PAR treated for up to 4 weeks.

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Rupatadine 10 mg and ebastine 10 mg versus placebo In this randomized, double-blind, parallel group, placebo-controlled clinical trial, a daily dose of 10 mg of rupatadine for 28 days was compared with ebastine 10 mg and placebo in 219 patients (intention to treat population)74. The percentage of days during the study period where the score of the most severe symptom on each day was less than or equal to 1 (main end point; Pdmax1), both at 2 weeks and at the end of the study period, was greater for rupatadine 10 mg and ebastine 10 mg compared with placebo, but was shown to be non significant (Table 7). Both total symptom score (5TSS) and total nasal symptom score (4TNSS) were significantly improved for rupatadine 10 mg users compared with placebo (p=0.019 and p=0.025, respectively). No significant differences were seen between active treatments (Table 7).

Table 7. ANCOVA results of the primary efficacy variable (Pdmax1), total symptom scores (5TSS) and total nasal symptom score (4TNSS) by treatment period (2 and 4 weeks) (*p<0.05; **p<0.01) (adapted from Molina M et al.74)

Outcome measure Rupatadine (n= 69) Ebastine (n=77) Placebo (n=73) Pdmax1 at 2 weeks 42.3 ± 40.3 47.5 ± 38.5 36.7 ± 34.7 Pdmax1 at 4 weeks 48.7 ± 37.9 50.8 ± 35.9 42.0 ± 34.2 5TSS at 2 weeks -5.17 ± 4.3* -5.16 ± 4.1** -4.28 ± 3.8 5TSS at 4 weeks -5.53 ± 3.9* -5.32 ± 4.0* -4.53 ± 3.8 4TNSS at 2 weeks -4.25 ± 3.3* -4.27 ± 3.2** -3.42 ± 3.0 4TNSS at 4 weeks -4.55 ± 3.0* -4.41 ± 3.1* -3.62 ± 2.9

As for investigators’ global clinical assessment, rupatadine and ebastine treatments were better than placebo (54%, 50% and 42 %, respectively), but only rupatadine demonstrated a statistically significant difference (p=0.03).

Rupatadine 10 mg and 20 mg versus loratadine 10 mg and placebo A randomized, double-blind, parallel group, placebo-controlled clinical trial compared a daily dose of rupatadine 10 mg and rupatadine 20 mg for 28 days versus loratadine 10 mg and placebo in 283 patients75. Both rupatadine (10 and 20 mg) and loratadine (10 mg) were significantly better than placebo in terms of mean reduction of total daily symptom score after 4 weeks of treatment, but only rupatadine 20 mg significantly improved the primary outcome Pdmax1 (52.2% ± 3.9 vs 36.4% ± 4, p<0.05). Significant reductions from baseline in total symptom score (5TSS) were achieved with rupatadine 10 mg (–4.00), rupatadine 20 mg (–3.96) and loratadine (–3.94) compared with placebo (p<0.01). It should be noted that rupatadine was significantly better than placebo for three separate symptoms, rhinorrhea, sneezing and ocular itching, while loratadine was significantly better than placebo in terms of rhinorrhea and nasal itching.

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In addition, patients’ subjective assessment of global clinical efficacy was significantly better for both rupatadine doses compared with placebo, while for the loratadine group this variable did not differ significantly from placebo and was even slightly worse. There were no significant between-group differences in the incidence of overall adverse events and no clinically significant QTc enlargements were detected. In conclusion, once-daily rupatadine (10 and 20 mg) is an effective and safe treatment for the management of patients with perennial allergic rhinitis.

3.3 Persistent allergic rhinitis (PER)

As noted earlier (see section 7.1. of Part I: Allergy general concepts), the classification of allergic rhinitis underwent a major change in 2001 following publication of the Allergic Rhinitis and its Impact on Asthma (ARIA) working group report20, updated in 200822. According to the new classification, allergic rhinitis was defined as intermittent and persistent. It is clearly more satisfactory, better fits real-life clinical activity, and can not be used interchangeably with the classical definitions of seasonal and perennial allergic rhinitis. Two studies have been performed with rupatadine in patients with PER according to the new ARIA classification (summarized in Table 8)76,77. The first study was a 12-week phase III, double-blind, randomized clinical trial which assessed the efficacy of rupatadine in comparison with placebo and cetirizine (discussed in this section).The second study was an open-label, Phase IV long-term (1 year) clinical trial to evaluate the safety and tolerability of rupatadine; this study is summarized in Section 5.4 of Part II: Product profile (Long-term safety).

Table 8. Studies of rupatadine in patients with persistent allergic rhinitis (PER) (PLA: placebo; RUP: rupatadine; CTZ: cetirizine; od: once daily; m: multicenter; r: randomized; db: double blind; o: open; pc: placebo-controlled)

Number of Study design and Treatment Duration Reference patients level of evidence PLA od 185 m, r, db, pc Fantin S. Allergy RUP 10 mg od 183 12 weeks level 2 2008; 63: 924-3176. CTZ 10 mg od 175

324 in the PLA od 6-month study Valero A. Drug Safety 12 months m, o for 1 year RUP 10 mg od 120 in the 2009;32(1):33-4277. 1-year study

Rupatadine 10 mg versus cetirizine 10 mg and placebo for 12 weeks in the treatment of patients with persistent allergic rhinitis In this clinical trial, 543 patients aged 12 years and older and diagnosed with moderate persistent allergic rhinitis were randomized to one of three treatment groups: rupatadine 10 mg (n=183), cetirizine 10 mg (n=175) and placebo (n=185), once a day for 12 weeks76.

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Rupatadine produced a statistically significant reduction in the baseline total symptom score (i6TSS, the primary efficacy endpoint) compared with placebo at 4, 8 and 12 weeks. However, when comparing cetirizine with placebo, the reduction of total symptom score was statistically significant at 4 and 8 weeks (p<0.05) but not statistically significant at 12 weeks (Figure 19).

Change from baseline in mean i6TSS at 4, 8 and 12 weeks of treatment

0

-10

-20 Placebo -30 Cetirizine 10 mg Rupatadine 10 mg -40 * ** % change from baseline * * -50 ** 4 weeks 8 weeks 12 weeks

* Active group vs placebo p < 0.05; ** Active group vs placebo p < 0.01

Figure 19. Change from baseline in mean instantaneous Total Symptom Score (i6TSS) at 4, 8 and 12 weeks of treatment period.

The change from baseline in the instantaneous total nasal symptoms score (iTNSS) (including nasal blockage) showed a significant reduction with both treatments in comparison with placebo, during the full 12-week treatment period (p<0.05). Nevertheless, only rupatadine exhibited a significant improvement in iTNSS at 6, 8, 9, 10, 11 and 12 weeks in comparison with placebo and cetirizine (p<0.05) (Figure 20).

iTNSS change from baseline

0

-0.5 Placebo Rupatadine 10 mg -1.0 * Cetirizine 10 mg -1.5 * -2.0 * * ** ** ** -2.5 ** ** ** -3.0

TNSS mean change from baseline -3.5

-4.0 1 2 3 4 5 6 7 8 9 10 11 12

Week of Treatment * p < 0.05 both groups vs placebo ** p < 0.05 rupatadine vs placebo

Figure 20. Serial time profile over 12 weeks of the instantaneous Total Nasal Symptom Score (iTNSS) mean change from baseline.

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Onset of action was observed at the first 24 h for both treatments (rupatadine vs placebo, p=0.013; cetirizine vs placebo, p=0.015). Study treatments were well tolerated, with no significant differences versus placebo. In summary, rupatadine 10 mg is an effective and safe antihistamine for the treatment of PER (ARIA classification) with a fast onset of action. Rupatadine, but not cetirizine, was significantly better than placebo in the reduction of symptoms after long-term treatment (12 weeks).

3.4 Nasal challenge studies

Nasal challenge studies were performed in allergic patients to determine the effect of rupatadine on allergen-induced nasal symptoms and obstruction (Vienna Challenge Chamber and Acoustic Rhinometry studies), its onset of action (Vienna Challenge Chamber study) or to demonstrate the effect of rupatadine against PAF-induced nasal symptoms in allergic rhinitis patients (proof of concept study).

3.4.1 Vienna Challenge Chamber (VCC) Study

The aim of this study was to evaluate the efficacy of rupatadine, 10 mg once daily, and placebo on allergen-induced symptoms (including nasal congestion), nasal airflow, nasal secretion and subjective tolerability in response to grass pollen in a controlled allergen-exposure chamber (VCC). With this model it was possible to determine the onset of action of rupatadine. This was a crossover, placebo-controlled, randomized, double-blind clinical trial involving 45 patients with a history of SAR who were treated with rupatadine 10 mg or placebo for 8 consecutive days in two different periods separated by a wash-out interval of at least 14 days. During each study period the last dose of rupatadine or placebo (day 8) was administered 60 minutes before the patient was exposed to pollen during 6 hours in a controlled exposure chamber. The administration of rupatadine 10 mg was associated with highly significant relief of allergic rhinitis symptoms, including nasal obstruction. In addition, rupatadine 10 mg showed a rapid onset of action that was already significant (p=0.001 vs placebo) from the first evaluation at 15 minutes after starting allergen exposure, and was maintained throughout the study at all further evaluation times (30 minutes, 45 minutes, 1 hour, 2 hours and 6 hours) (Figure 21)78. Subjective nasal congestion was also reduced significantly with rupatadine 10 mg compared with placebo, suggesting a potential decongestant activity.

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Mean Total Nasal Symptom Scores (mTNSSs)

9

8 ** ** ** ** 7 ** 6 5 * 4

Mean scores 3 * p = 0.001 vs placebo Rupatadine ** p < 0.001 vs placebo Placebo 2

1

0 0 50 60 80 120 150 180 220 240 270 300 330 360 Time (min)

FigureRupatadine 21. Effect showed of rupatadine a rapid in patientsonset of with action SAR exposed15 minutes to aeroallergens after allergen in the exposure Vienna Challenge Chamber.

In similar studies, the reported onset of action for loratadine and levocetirizine was 45 and 75 minutes, respectively79.

3.4.2 Acoustic rhinometry study

The reduction of nasal obstruction in SAR patients treated with rupatadine 10 mg, once daily for 3 consecutive days, or placebo, was measured by acoustic rhinometry at 2 and 24 hours after nasal allergen challenge, in a double-blind, crossover, randomized, placebo-controlled study80. At 2 hours post-nasal allergen challenge, there was a significantly greater reduction (47%) in nasal volume with placebo than after pretreatment with rupatadine (20.2 vs 14.1%; p<0.05) (Figure 22).

Acoustic rhinometry: Percentage change in volume

2 hours 24 hours - 0

-5

-10

Placebo

nasal obstruction -15 Rupatadine % change in volume * * p < 0.05 + -20

Figure 22. Percentage change in nasal volume, evaluated between the second and fifth -25 centimeters (Volume2-5) by acoustic rhinometry at 2 hours and 24 hours following allergen challenge in the placebo and rupatadine groups (NS: not significant; * p<0.05) (adapted from Valero et al.80).

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This study shows that rupatadine 10 mg can reduce nasal obstruction assessed by objective measures and is well tolerated in patients with allergic rhinitis.

3.4.3 PAF nasal provocation study

Platelet activating factor (PAF) is a potent mediator of inflammation and has important roles in the development of allergic inflammatory conditions, mainly in the late phase of allergy, asthma and anaphylaxis 24,25,26. However, its relevance in allergic rhinitis and its potential as a new therapeutic target in this pathology has been less well-studied and needs to be confirmed in controlled clinical trials. In a recent study it has been demonstrated, for the first time, that the instillation of PAF in the nasal cavities increased the individual and total nasal symptoms score in both healthy volunteers and allergic rhinitis patients, and that nasal obstruction was the most relevant and lasting nasal symptom affected 81. Using the same model, and based on the hypothesis and the concept that blocking both PAF and histamine effects might represent greater clinical efficacy than just blocking one of them82, a proof- of-concept placebo-controlled study was designed to assess, for the first time, the ability to block the nasal clinical response induced by PAF, both in healthy volunteers (HV) and SAR patients pretreated with rupatadine83. Levocetirizine was used for comparison. Healthy volunteers (HV, n=10) and asymptomatic seasonal allergic rhinitis (SAR, n=10) patients were treated out of the pollen season with either rupatadine 20 mg, levocetirizine 10 mg, or placebo once daily for 5 days prior to the PAF nasal challenge. Total 4-nasal symptom score (T4SS) and nasal

patency (Volume2-5, by acoustic rhinometry) were assessed from 0 to 240 minutes after repeated PAF challenge. In SAR patients, but not in HV, both rupatadine and levocetirizine showed a trend to decrease PAF-induced T4SS from 60 to 120 minutes. Rupatadine but not levocetirizine caused a significant reduction (p<0.05) of T4SS AUC compared to placebo. Rupatadine and levocetirizine caused no significant changes on nasal patency compared to placebo (Figure 23).

AUC of nasal symptoms

5 AUC Placebo = 570 ± 285 4.5 AUC Levocetirizine = 373 ± 235 4 AUC Rupatadine = 262 ± 256*

3.5

3

2.5

2

1.5

1 Mean differences from 30 min score Mean differences 0.5

0 0 min 30 min 60 min 90 min 120 min 240 min

Placebo Levocetirizine 10 mg Rupatadine 10 mg

Figure 23. Area under the curve of nasal symptoms (AUC: mean±SD, 30-240 min; Likert scale scores) of T4SS time-course adjusted by baseline values at 30 min.: *p<0.05 vs placebo.

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These results suggest that both rupatadine and levocetirizine showed a tendency to decrease nasal symptoms, but only rupatadine significantly reduced the overall nasal symptoms (AUC) induced by PAF in SAR patients.

3.5 Quality of life (QoL)

Allergic rhinitis (AR) is associated with impaired social life, sleep, school, and work. It is well known that the health-related quality of life (HRQoL) of patients can be altered by the severity and duration of rhinitis. The extent to which disease-associated problems affect HRQoL and the extent to which this is improved by the use of antihistamines such as rupatadine, should be assessed using specific AR quality of life tools. The ESPRINT-15 questionnaire (EsQ-15) is a Spanish validated specific instrument to assess HRQoL in AR84,85 and it has been used to assess the effect of rupatadine on QoL in AR patients after 4 weeks86 and 12 weeks76. A conventional disease-specific and validated Rhinoconjunctivitis Quality of Life Questionaire (RQLQ)87 was used to assess the effect of rupatadine on QoL in a 12-month (long-term) treatment study88. A prospective, multicenter, observational, longitudinal study was designed with the aim of evaluating treatment response after 4 weeks of treatment with rupatadine in a cohort of 360 patients with AR, in terms of changes in HRQoL, symptoms, and severity86. Eligible patients, aged 18 years or older, were categorized as having intermittent or persistent, mild, or moderate to severe AR according to the original ARIA Classification21. With regard to HRQoL, the EsQ-15 global score decreased significantly from baseline after 4 weeks of rupatadine treatment (mean[SD]=3.0 [1.2] vs 1.0 [0.9], p<0.0001). All EsQ-15 dimensions (symptoms, activities of daily living, sleep, psychological impairment, and general health) also showed significant improvements (p<0.0001) after 4 weeks of treatment with rupatadine. A decrease in the EsQ-15 global score represents an improvement in QoL (Figure 24).

Improvement of ESPRINT -15 domain scores in AR patients (n = 360) treated with Rupatadine for 4 weeks

5 * p < 0.0001 4

3

2 * 1 * * * *

0 Global score Symptoms Daily activities Sleep disturbances Psychological impact

Baseline 4-week treatment with rupatadine

Figure 24. Quality of life in allergic rhinitis (AR) patients after 4-week treatment with rupatadine.

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This study also demonstrated that rupatadine significantly reduced AR symptoms severity (p<0.0001) and mean [SD] total nasal symptom score (TNSS) (8.2 [1.8] vs 3.1 [2.1], p<0.0001). In a 12-week study in patients with PER, rupatadine 10 mg once daily significantly improved total RQLQ scores compared with placebo (p<0.05) as well as the domains of sleep (p<0.05), activities (p<0.01) and nasal symptoms (p<0.01)76, as shown in Figure 25.

Overall Activities Sleeping Non-allergic Practical Nasal Ocular Emotions symptoms problems symptoms symptoms

-0.5 t

-1.5 ov eme n r † * * Im p -2.5 * * * * * * Placebo (n = 185) -3.5 *p < 0.01 vs. baseline Mean change from baseline Rupatadine 10 mg od (n = 183) † p < 0.05 vs. baseline Cetirizine 10 mg od (n = 175) Adapted and modified from Fantin S. Allergy 2008; 63: 924-931

Figure 25. Rupatadine showed significant improvement in patients’ QoL after 12 weeks of treatment, in a 3-month placebo-controlled study vs. cetirizine in patients with PER.

The impact of rupatadine 10 mg on QoL in patients with PER was also assessed in an open label, prospective, long-term treatment (12 months)88. The disease-specific and validated Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was used to evaluate HRQoL in these patients and MID was defined as the “minimum important difference” which patients perceived as beneficial (MID values below 0.5 are considered with no clinical relevance)87. In Figure 26 it is shown that rupatadine produced significant improvements in the RQLQ (MID>1) throughout the 12-month study.

Treatment: effect on RQLQ overall scores at 12 months 0

-0.2 N = 266 N = 257 N = 252 N = 245 N = 243 N = 81 N = 78 -0.4 MID = 0.5 -0.6

-0.8

-1.0 MID = 1.0 Improvement -1.2

-1.4 MID = 1.5 -1.6

2 months 3 months 4 months 5 months 6 months 9 months 12 months Mean change from baseline: p < 0.0001

Figure 26. Effect of rupatadine 10 mg on QoL in a 12-month study in patients with persistent allergic rhinitis.

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In conclusion, several studies which used QoL questionnaires have demonstrated that rupatadine significantly improves patients’ overall QoL after short- (4 weeks), medium- (3 months) and long- term (12 months) treatment.

3.6 Meta-analysis in allergic rhinitis

The efficacy and safety of rupatadine for allergic rhinoconjunctivitis was assessed by a systematic review of randomized, double-blind, placebo-controlled studies with meta-analysis89. Using the most important databases, up to January 2013, this systematic review was aimed at identifying double- blind, placebo-controlled, randomized trials which administered rupatadine for allergic rhinitis. The following databases were used: CENTRAL, MEDLINE, OVID/EMBASE, DARE, SCI-Expanded, UK National Research Register, ISI-web, BIOSIS Previews, SCOPUS, NHS EED, Current Controlled Trials. No restriction was introduced for treatment duration and dose, study design, population age, allergen exposure and disease classification. The methodological quality of included studies and risk of bias were systematically assessed. Meta-analysis was performed, when possible, to summarize the information. Seventeen of 413 initially identified records were fully assessed for eligibility. Ten trials involving 2573 patients overall met the inclusion criteria and entered the analysis. In cases where different scoring systems were used to evaluate symptoms, Standardized Mean Differences (SMD) were adopted for the summary statistics. Eight trials assessed daily reflective overall allergy symptoms scores. Out of 1650 analyzed patients for this outcome, 820 received rupatadine 10 mg and showed a significant reduction compared with the 830 patients receiving placebo (SMD: –0.37, 95% CI –0.46 to –0.27; p<0.00001) (Figure 27).

Outcome: Total Symptom Score (Reflective assessment)

Rupatadine Placebo Std. Mean Difference Std. Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI Reflective assessment Guadano (27) 0.98 0.67 79 1.39 0.67 81 9.4% –0.61 [–0.93, –0.29] Kowalski (29) –4 2.04 73 –2.76 2.07 69 8.4% –0.60 [–0.94, –0.26] Marmouz (23) 4.04 2.09 65 5.52 3.01 70 8.0% –0.56 [–0.91, –0.22] Izquierdo (30) 0.86 0.54 54 1.07 0.53 50 6.3% –0.39 [–0.78, –0.00] Lukat (32) 7.42 3.7 117 8.79 4.13 122 14.5% –0.35 [–0.60, –0.09] Potter (31) 4.9 2.7 180 5.6 2.7 180 22.1% –0.26 [–0.47, –0.05] Molina (28) –5.53 3.9 69 –4.53 3.8 73 8.7% –0.26 [–0.59, 0.07] Fantin (25) 4.79 2.85 183 5.62 3.62 185 22.6% –0.25 [–0.46, –0.05] Subtotal (95 %) 820 830 100.0% –0.37 [–0.46, –0.27] Heterogeneity: χ2 = 8.00, df = 7 (P = 0.33); I2 = 12% Test of overall effect: Z = 7.34 (P < 0.00001)

–1 –0.5 0 0.5 1 Favours experimental Favours control

Figure 27. Forest plot for the reflective assessment of Total Symptoms Score (outcome). Rupatadine is superior to placebo (SMD: –0.37; p<0.00001).

Four trials performed an instantaneous assessment. The point-estimate for the 375 patients undergoing active treatment was significantly higher compared with the 382 receiving placebo (SMD: –0.41, 95% CI –0.71 to –0.11; p=0.007).

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Total nasal symptom reduction was higher in patients receiving rupatadine on the reflective (SMD: –0.36, 95% CI –0.48 to –0.25; p<0.00001) and instantaneous (SMD: –0.39, 95% CI –0.61 to –0.17; p<0.0004) evaluation in 1178 and 1117 subjects, respectively. Pooled data on reflective individual nasal and ocular symptoms were available from seven trials. Rupatadine performed better than placebo in reducing rhinorrhea (SMD: –0.30, 95% CI –0.41 to –0.19; p<0.00001), sneezing (SMD: –0.39, 95% CI –0.52 to –0.26; p<0.00001), nasal itching (SMD: –0.21, 95% CI –0.33 to –0.10; p< 0.0003) and nasal obstruction (SMD: –0.25, 95% CI –0.37 to –0.13; p<0.0001). Information about the occurrence of total AEs during treatment was derived from six trials which assessed a total of 1136 patients. No substantial difference in the frequency of total AEs was observed between rupatadine 10 mg (220 events) and placebo (204 events) (OR 1.23, 95% CI 0.95 to 1.59; p=0.12) (Figure 28).

Outcome: Risk of Adverse events

Rupatadine Placebo Odds ratio Odds ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Total of adverse events Molina (28) 41 69 42 73 16.2% 1.08 [0.55, 2.11] Fantin (25) 42 183 39 185 29.2% 1.12 [0.68, 1.83] Guadano (27) 52 79 51 81 16.8% 1.13 [0.59, 2.17] Lukat (32) 47 119 44 122 25.6% 1.16 [0.69, 1.95] Marmouz (23) 36 65 27 70 11.3% 1.98 [1.00, 3.93] Stuebner (26) 2 45 1 45 0.9% 2.05 [0.18, 23.41] Subtotal (95 %) 560 576 100.0% 1.23 [0.95, 1.59] Total events 220 204 Heterogeneity: χ2 = 2.42, df = 5 (P = 0.79); I2 = 0% Test of overall effect: Z = 1.56 (P = 0.12) 0.05 0.2 1 5 20

Figure 28. Forest plot for the risk of adverse events. Rupatadine showed no significant difference in the incidence of adverse events versus placebo (odds ratio: 1.23; p=0.12)

In conclusion, randomized, double-blind, controlled trials show a favorable risk–benefit ratio in rupatadine for the treatment of allergic rhinoconjunctivitis. This evidence is strengthened when data are pooled in the form of meta-analysis, where accurate and robust effect estimations are derived from a large population, reinforcing the potent efficacy of rupatadine in the control and management of allergic rhinitis.

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SUMMARY Seasonal Allergic Rhinitis (SAR) • The efficacy of rupatadine in SAR has been investigated and demonstrated in adults and adolescents (aged ≥12 years) in 9 clinical trials in comparison with: placebo, cetirizine, ebastine, loratadine, desloratadine and levocetirizine. • Rupatadine 10 mg once daily is the recommended dose for SAR. • Rupatadine, but not ebastine, significantly reduced the mean total daily symptoms score (mTDSS), compared with placebo. • Rupatadine showed better investigator global assessment ratings and a significantly greater absence of runny nose (p=0.03) than cetirizine. • Rupatadine shows better safety and efficacy than levocetirizine. • Rupatadine is at least as effective as loratadine and desloratadine. • Rupatadine shows a better safety and efficacy profile than levocetirizine. Perennial Allergic Rhinitis (PAR) • The efficacy of rupatadine in PAR has been investigated in adults and adolescents (aged ≥12 years) in 4 clinical trials in comparison with: placebo, cetirizine, ebastine and loratadine. • Rupatadine 10 and 20 mg were effective and safe in patients with PAR. • Rupatadine is at least as effective as cetirizine, ebastine and loratadine. Persistent Allergic Rhinitis (PER) • The efficacy and safety of rupatadine in PER (new ARIA group classification) has been investigated in adults and adolescents (aged ≥12 years) in 2 clinical trials in comparison with placebo and cetirizine. • Rupatadine 10 mg is effective and safe in the treatment of PER. • Rupatadine, but not cetirizine, was significantly superior to placebo in improving the symptoms of PER over 12 weeks of treatment, including nasal congestion. Nasal Challenge Studies • Rupatadine 10 mg was effective in alleviating nasal symptoms and showed a rapid onset of action in patients undergoing aeroallergen exposure in a controlled allergen-exposure chamber. • Rupatadine 10 mg reduces nasal obstruction as measured by acoustic rhinometry in patients under nasal allergen challenge. • Rupatadine 20 mg, but not levocetirizine 10 mg, significantly reduced PAF-induced overall nasal symptoms in allergic rhinitis patients. Quality of Life (QoL) Rupatadine significantly improves patients’ overall QoL after short- (4 weeks), medium- (3 months) and long-term (12 months) treatment. Meta-analysis in Allergic Rhinitis Data from randomized double-blind controlled trials were pooled in the form of meta-analysis. The results reinforce the potent efficacy and safety of rupatadine in the control and management of allergic rhinoconjunctivitis.

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4. Rupatadine efficacy profile in urticaria

The efficacy of rupatadine in urticaria, and in diseases related to urticaria, has been assessed in a total of seven double-blind, placebo-controlled clinical trials (Table 9). Four studies, including one pooled (responder) analysis and one in comparison with levocetirizine, of 4-6 weeks’ duration, were carried out in patients with moderate to severe chronic idiopathic urticaria (CIU), with a pruritus score of ≥2 for at least 3 out of the last 7 days. As noted earlier, the symptomatology of CIU would now be classified as chronic urticaria under the subheading of ‘chronic spontaneous urticaria’ (CSU) according to the recently updated EAACI/GA2LEN/EDF/WAO guideline recommendations30 (Table 1, item 8.2.2. of Part I of this manual). Another study included patients with cold urticaria, a physical urticaria now classified within the group of “inducible urticarias”, that is a subtype of chronic urticarias according to the recent recommendations30 (Table 1, item 8.2.2. of Part I of this manual).

Table 9. Clinical trials carried out with rupatadine in urticaria and related conditions (CIU: chronic idiopathic urticaria, m: multicenter, r: randomized, db: double blind, sb: single blind, pc: placebo-controlled, co: crossover, po: proof-of-concept, LEV: levocetirizine)

Number of Study design and Treatment Duration Reference patients level of evidence PLA od 69 4 weeks m,r,db,pc,pg Dubertret L. RUP 5 mg od 68 level 2 Eur J Dermatol 2007; RUP 10 mg od 73 17: 223-228.90 RUP 20 mg od 67 Dose-finding CIU PLA od 111 6 weeks m,r,db,pc,pg Gimenez-Arnau A. RUP 10 mg od 110 level 2 Allergy. 2007; 62(5); RUP 20 mg od 108 539-546.91 CIU

PLA od 180 4 weeks m,r,db,pc,pg Gimenez-Arnau A. RUP 10 mg od 183 level 2 JEADV 2009; RUP 20 mg od 175 23:1088-91.92 Pooled (responder) analysis CIU PLA od 21 (total) 1 week r,db,pc,co,po Metz M. RUP 20 mg od level 2 Ann Allergy Asthma Cold Urticaria Immunol. 2010; 104(1):86-92.99

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Number of Study design and Treatment Duration Reference patients level of evidence RUP 10 mg od 35 4 weeks r,sb,pg Maiti R. LEV 5 mg od 35 level 2 J Drugs Dermatol CIU 2011;10(12): 1444- 50.93

PLA od 30 (total) 4 days db,pc,co Karppinen A. RUP 10 mg od level 2 J Eur Acad Dermatol Mosquito bite Venereol 2012; 26(7):919-922.106

RUP 20 mg od 19 12 months prospective Martinez-Escala ME. Acquired Cold observational Acta Derm Venereol. Contact Urticaria level 3 2015;95:1-5.100

The efficacy of rupatadine has also been assessed in an immediate mosquito-bite allergy study (with symptoms similar to those of urticaria lesions). In patients with chronic spontaneous urticaria (CSU), efficacy was evaluated using Mean Pruritus Score (MPS) as the primary outcome measure, and mean number of wheals (MNW), Mean of Total Symptoms Score (MTSS), Dermatology Life Quality Index (DLQI), visual analog scale (VAS), and overall investigator evaluation as secondary outcome measures.

4.1 Chronic spontaneous urticaria (CSU)

4.1.1 Dose-finding study

A preliminary dose-finding study in patients with moderate to severe chronic idiopathic urticaria (CIU, now classified as CSU30) was conducted. This was a multicenter, randomized, double-blind, parallel group, placebo-controlled trial to examine the efficacy and safety of different rupatadine doses90. In this study, 283 patients, aged 12-65 years with moderate or severe pruritus, were randomized to treatment, and data from 277 patients were analyzed (69: placebo; 68: rupatadine 5 mg; 73: rupatadine 10 mg; 67: rupatadine 20 mg, once daily for 28 days) (Table 9). The primary outcome was daily change from baseline in mean pruritus score (MPS). Secondary outcomes were the reduction of the mean number of wheals, mean total daily symptom score (i.e, the sum of wheal and pruritus scores) and the interference of CSU symptoms with sleep and daily activities. Reductions in MPS from baseline were 71.9% in the 20 mg group (p<0.05 vs. placebo); 62.1% in the 10 mg group (p<0.05 vs. placebo); 51.3% in the 5 mg group (p=non-significant vs placebo) and 46.6% in the placebo group (Figure 29).

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Change from baseline in the Mean Pruritus Severity Score (primary endpoint) 0 * p < 0.05 vs placebo Placebo

-10 † p < 0.05 Rup 20 mg vs Rup 5 mg Rup 5 mg Rup 10 mg -20 ‡ p < 0.05 Rup 20 mg vs Rup 10 mg Rup 20 mg -30 39.5 -40 46.0 46.9 46.6 48.8 -50 51.3 49.7 50.4 -60 54.8* 59.2* 62.1* Reduction from baseline (%) † 61.1* -70 63.3 * †‡ 68.6 * 70.8 *†‡ 71.9 *† -80 Week 1 Week 2 Week 3 Week 4 Time

Figure 29. Effect of treatment (rupatadine and placebo) on pruritus severity over the course of the study (adapted from Dubertret et al.90).

The study clearly showed that rupatadine 10 and 20 mg provides fast onset (day 7) and long-lasting relief from pruritus, possibly the most bothersome symptom of chronic urticaria. Both doses were well tolerated, with no significant differences in tolerability between rupatadine 10 mg and placebo. Importantly, these results suggest that there is a linear relationship between the treatment dose and the main efficacy variable, with constant dose increases producing constant decreases in pruritus scores.

4.1.2 Rupatadine 10 mg and 20 mg versus placebo

This was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study involving five scheduled visits91. Eligible patients with a pruritus score of >2 for at least 3 of the last 7 days were randomized to receive either rupatadine 10 mg, rupatadine 20 mg or placebo once daily for 6 weeks. A total of 400 patients were screened, 334 (83.5%) of whom were randomized to receive one of three study treatments. Overall, 283 patients completed the trial. The intention-to-treat (ITT) population comprised 329 patients (111 placebo, 110 rupatadine 10 mg and 108 rupatadine 20 mg). Statistical assessment of the demographic and clinical characteristics of this cohort showed that, at baseline, the three treatment groups were not significantly different in any way. Rupatadine 10 and 20 mg significantly reduced the mean pruritus score (MPS) compared with baseline, by 57.5% and 63.3% respectively, versus 44.5% for placebo during the 4-week period. At 6 weeks, the percentage of pruritus reduction was 59.5% for rupatadine 10 mg, 66.1% for rupatadine 20 mg and 42.8% for placebo (Figure 30).

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Mean Pruritus Score change (primary endpoint)

*p < 0.05 vs placebo **p < 0.005 vs placebo Placebo **p < 0.0001 vs placebo Rup 10 mg Rup 20 mg -37.8% -31.5% -44.5% -48.2%** -48.8%

-54.3%** -57.5%** -59.5%*

-53.4%** -58.2%** -63.3%** -66.1%**

Time MPS change in week 1 MPS change in week 2 MPS change in week 4 MPS change in week 6

Figure 30. Effect of treatment on percentage reduction from baseline in mean pruritus score (MPS) over the course of the study.

Rupatadine also resulted in significant improvements in secondary efficacy outcomes compared with placebo. The reduction in the mean number of wheals (MNW) was significantly greater with rupatadine 10 mg and 20 mg compared with placebo (p<0.05) during a 4-week period, with a favorable trend at week 6 (Figure 31).

Reduction (%) from baseline in Mean Number of Wheals

* p < 0.05 vs placebo 100 * 80 57.0% 59.2% * 56.1% 54.3% 60 39.7% 43.5% 40

Reduction (%) 20

0 Week 4 Week 6

Placebo Rupatadine 10 mg Rupatadine 20 mg

Figure 31. Effect of treatment on percentage reduction from baseline in mean number of wheals (MNW).

At doses of 10 and 20 mg, rupatadine showed statistically significant improvements with respect to placebo in the reduction of mean total symptom score (MTSS) from baseline over the 4- and 6-week periods (Figure 32).

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Reduction (%) from baseline in Mean Total Symptom Score

* p < 0.05, * * p < 0.005, * * * p < 0.0001 vs placebo 100 * * * 80 60.3% * 62.9%* * * * 58.4% 56.3% 60 42.0% 46.2% 40

Reduction (%) 20

0 Week 4 Week 6

Placebo Rupatadine 10 mg Rupatadine 20 mg

Figure 32. Effect of treatment on percentage reduction from baseline in mean total symptom score (MTSS).

The 10 mg and 20 mg doses of rupatadine were well tolerated during the 6-week study period. The most frequently reported AEs were headache (8.0%, 4.5% and 8.3% of patients in the placebo, rupatadine 10 mg and rupatadine 20 mg groups, respectively) and somnolence (5.3%, 2.7% and 8.3%, respectively). Only rupatadine 20 mg significantly decreased the Dermatology Life Quality Index (DLQI) from baseline, by 26.6% (p<0.005) and 29.2% (p<0.005) over the 4- and 6-week study periods, respectively, compared with reductions of 18.4% and 20.5% in placebo-treated patients (Figure 33). Rupatadine 20 mg improved all the subdomain scores to a greater extent than placebo over time, with differences being significant (p<0.05) for all scores, except for the Work and School and Treatment subdomain scores after 4 weeks, and for the Personal Relationships subdomain score after 6 weeks.

Change in Dermatology Life Quality Index (%)

Over 4 weeks Over 6 weeks 0

-5

-10

-15

-20 -18.4 -20.5 -25

Change DLQI (%) -26.6* -30 -29.2* -35

-40 Placebo Rupatadine 20 mg *p < 0.005 vs placebo

Figure 33. Change in Dermatology Life Quality Index (DLQI) (%) over 4 and 6 weeks of treatment.

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Treatment with rupatadine 20 mg significantly decreased the baseline Visual Analog Scale (VAS) score for general discomfort by 57.9% and 68.6% over the 4- and 6-week treatment periods, respectively, compared with reductions of 36.9% and 46.5% for placebo. The VAS scores were also reduced with rupatadine 10 mg from baseline by 50.6% and 60.5% over 4 and 6 weeks, although these were not significant compared with placebo. In conclusion: • Rupatadine 10 and 20 mg significantly reduced the primary end point (MPS) from baseline in patients with chronic urticaria and both doses were well tolerated. • Rupatadine 10 and 20 mg were also significantly better than placebo in reducing the secondary end points (MNW and MTSS) from week 1 onwards over 6 weeks. • Rupatadine 10 and 20 mg effectively relieved chronic urticaria symptoms after the first dose, demonstrating a rapid onset of action with significant improvement after 7 days of treatment, and lasting until the end of the study (6 weeks). • Rupatadine 20 mg significantly improved QoL (DLQI) in these patients.

4.1.3 Responder analysis: pooled data from efficacy studies

This analysis included pooled data from the above two randomized, double-blind, placebo-controlled, multicenter studies in patients with chronic urticaria treated with rupatadine at different doses (dose- finding study90 and phase III efficacy study91). A total of 538 patients were included (180 placebo; 183 rupatadine 10 mg and 175 rupatadine 20 mg)92. Responder rates were defined as the percentage of patients who, after 4 weeks of treatment, exhibited a reduction of symptoms by at least 50% or 75% compared to baseline. The following variables were analyzed: Mean Pruritus Score (MPS), Mean Number of Wheals (MNW) and Mean Urticaria Activity Score (UAS). After 4 weeks of treatment, 68.3% and 76% of patients treated with rupatadine 10 and 20 mg, respectively, experienced a reduction in MPS of at least 50% from baseline compared to 48.9% of patients in the placebo group, and the differences were statistically significant versus placebo (Figure 34). Using the 75% responder criterion, similar results were obtained: 42.1% of patients treated with rupatadine 10 mg and 58.9% of patients treated with rupatadine 20 mg exhibited at least 75% reduction of symptoms, measured by the MPS, compared with 20.6% of patients in the placebo group. Responder rates in the rupatadine treatment groups were statistically significant versus placebo group and the responder rate for rupatadine 20 mg was significantly higher than with rupatadine 10 mg (Figure 34).

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Mean Pruritus Score, % responders by criteria

*** * 100 ** *** 80 76% *** 68.3% 58.9% 60 48.9% 42.1% 40 20.6% 20

0 ≥ 50% Reduction from baseline ≥ 75% Reduction from baseline

Placebo Rupatadine 10 mg Rupatadine 20 mg * p < 0.01, ** p < 0.001, *** p < 0.0001

Figure 34. Percentage of patients with a ≥50% and ≥75% reduction of symptoms, using the Mean Pruritus Score (MPS) as the variable analyzed.

Similar data were obtained when MNW and UAS were the variables analyzed. This responder analysis confirms that rupatadine 10 and 20 mg are significantly better than placebo. Also, rupatadine 20 mg resulted in a higher responder rate and was better than rupatadine 10 mg in patients with a ≥75% reduction of symptoms. These results support the use of higher than standard doses of rupatadine in chronic urticaria patients.

4.1.4 Rupatadine 10 mg versus levocetirizine 5 mg

A randomized, single-blind, single-center, parallel-group outdoor-based clinical study was conducted in 70 patients with chronic idiopathic urticaria (CIU), to compare treatment with rupatadine and levocetirizine93. After initial clinical assessment and baseline tests, rupatadine 10 mg was prescribed to 35 patients and levocetirizine 5 mg to another 35 patients once daily for 4 weeks. At follow-up, the patients were re-evaluated and then compared using different statistical tools. Main outcome measures were differential eosinophil count, absolute eosinophil count, serum IgE, Total Symptom Score (TSS), Aerius Quality of Life Questionnaire (AEQLQ) score, and global efficacy score. There was a 28.2% decrease in TSS in the rupatadine group compared with 15.4% in the levocetirizine group (p<0.05) (Figure 35).

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Total Symptom Score decrease

Levocetirizine Rupatadine 0

-5

-10 -15.4% -15

-20

-25 -28.2% -30 Decrease in TSS (%) Decrease in -35 p < 0.05 vs. levocetirizine -40

Figure 35. Percent decrease in Total Symptom Score (TSS) after rupatadine and levocetirizine treatment. Rupatadine has a better efficacy profile than levocetirizine in patients with urticaria (TSS).

In the rupatadine group, there was a 27.9% decrease in differential eosinophil count compared with 11.9% in the levocetirzine group (p=0.027). The changes in absolute eosinophil count were –35.6% and –14.4%, respectively (p=0.036). For serum IgE, there was a reduction of 15.3% in the rupatadine group and 7.03% in the levocetirizine group (p=0.024). The global efficacy score was significantly higher in the rupatadine group (2.81 ± 1.1) compared with the levocetirizine group (1.96 ± 1.2) (p=0.009). Regarding the change in AEQLQ score, there was a 27.3% reduction in the rupatadine group and 12.4% in the levocetirizine group (p=0.006). Individual parameters were analyzed in both groups, rupatadine decreased pruritus severity, number of wheals, size of wheals and separate urticaria episodes significantly. The effect of levocetirizine was only significant in decreasing pruritus severity and the size of wheals. The results of this study show that rupatadine can be a better choice than levocetirizine in the treatment of chronic urticaria.

4.2 Cold urticaria

Acquired cold urticaria (ACU) is characterized by the immediate appearance of itchy wheals and angioedema in response to cold exposure or cooling of the skin94,95. ACU also has important occupational and employment implications96 and is evenly distributed by sex (55% women) and age (mean [SD] age 41 ± 16 years), at least in the German population, according to the only scientific epidemiologic study available97. Platelet-activating factor (PAF) is a mediator implicated in many inflammatory conditions (see section 7.5.3.), including ACU98. Intradermal injection of PAF leads to a dose-dependent, biphasic, wheal-and-flare response and this effect has been inhibited by rupatadine, 45,51 a dual anti-H1 and anti-PAF compound . In addition, current guidelines specifically recognize that PAF is an important mediator in the pathophysiology of urticaria30. For all these reasons, it was considered important to assess the efficacy of rupatadine in preventing reactions to cold urticaria in patients with ACU.

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This was a randomized, double-blind, placebo-controlled crossover study in which 21 patients with ACU received rupatadine 20 mg/day or placebo for 1 week99. The main outcome was the critical stimulation time threshold (CSTT) determined by ice cube challenge. Secondary outcomes included CSTT and the critical temperature threshold (CTT) assessed by a cold provocation device (TempTest® 3.0), as well as scores for wheal reactions, pruritus, burning sensations, and subjective complaints after cold challenge. After rupatadine treatment, 11 (52%) of 21 patients exhibited a complete response (i.e. no urticaria lesions after ice cube provocation). A significant improvement in CSTT compared with placebo was observed after ice cube and TempTest® 3.0 challenge (p=0.03 and p=0.004, respectively) (Figure 36). A significant reduction of CTT (p<0.001) was also observed (Figure 37) as well as reduced scores for cold provocation-induced wheal reactions (p=0.01), pruritus (p=0.005), burning sensation (p=0.03), and subjective complaints (p=0.03) after rupatadine treatment. Mild fatigue (n=4), somnolence (n=1), and moderate headache (n=1) were reported during active treatment.

Critical stimulation time thresholds (CSTT)

CSTT by TempTest (minutes)

7 p = 0.0043

6 * 5 * 4 *

3 40% Improvement

2

1 * 0 *

Baseline Placebo Rupatadine

Figure 36. Rupatadine significantly improves critical stimulation time thresholds (CSTTs) versus placebo (40% increase) (TempTest® 3.0) in patients with acquired cold urticaria. The lower and upper whisker lines represent the 10th and 90th percentile scores. Data points that are outside this percentile range are represented with asterisks.

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Critical Temperature Thresholds (CTTs)

TempTest (in ºC)

28 p = 0.0006 26 * 24 * 22 * 20 18 * 16 14

Improvement 12 -11º C 10 8 6 4 * 2 * 0 Baseline Placebo Rupatadine

Figure 37. Rupatadine significantly improves critical temperature thresholds (CTTs) (11ºC reduction) in patients with acquired cold urticaria. The lower and upper whisker lines represent the 10th and 90th percentile scores. Data points that are outside this percentile range are represented with asterisks.

In conclusion, rupatadine, 20 mg/day, improved exposure time thresholds, critical temperature thresholds, and symptom control compared with placebo treatment. Taken together, treatment with rupatadine 20 mg/day, should be effective and well tolerated in the management of patients with ACU in their daily lives. The results of this study can not be extrapolated to other nonsedating antihistamines and suggest that the dual action of rupatadine on H1 and PAF receptors could be particularly beneficial in this physical urticaria condition. Another randomized, double-blind, 3-way crossover, placebo-controlled study in patients with confirmed cold urticaria was designed to assess the effects of rupatadine updosing. A total of 23 patients were randomized to receive placebo, rupatadine 20 mg/day, or rupatadine 40 mg/day for 1 week. The primary outcome was change in critical temperature thresholds and critical stimulation time thresholds after treatment. Secondary endpoints included assessment of safety and tolerability of rupatadine. Both 20 and 40 mg rupatadine were highly effective in reducing critical temperature thresholds (p<0.001) and critical stimulation time thresholds (p<0.001). In conclusion, rupatadine 20 and 40 mg significantly reduced the development of chronic cold urticaria symptoms without an increase in adverse effects100.

4.3 Long-term treatment follow-up in urticaria

Cold contact urticaria is the second most common subtype of physical urticaria. Cold stimulation standardized tests are mandatory to confirm the diagnosis and the typical course of the disease. A positive cold provocation test, on the basis of monitoring threshold temperatures, has been used in the assessment of the effect of rupatadine in patients with ACU. A Temp Test® device was used to establish the highest temperature and the shortest stimulation time that will induce a wheal-and-flare

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reaction (critical temperature threshold: CTT and cold stimulation time threshold: CsTT, respectively)101. A decrease in the CTT parameter or an increase in the CsTT reflects a favorable effect of treatment. Nineteen adult patients (10 women and 9 men; mean age 45 years) were included in the study and the diagnosis was confirmed with the ice-cube test and TempTest®3.0. Patients were treated continuously for 1 year with 20 mg/day rupatadine. Threshold measurements were made before and after treatment. Improvements in temperature (CTT) and critical time thresholds (CsTT) were found in the study sample, demonstrating the efficacy of continuous treatment with rupatadine. At baseline, mean ± SD CsTT was 2 min and 35 s ± 1 min and 9 s (range 1–5 min) at 4°C; after 1 year, this was increased significantly to 4 min and 28 s ± 1 min and 6 s (range 1–5 min). Therefore, a 1-year period of treatment with rupatadine, 20 mg/day, was associated with a significant increase in CsTT, with a mean of 39.8% (t=7.77, p<0.0005). Similarly, the mean ± SD CTT at baseline was 13.7 ± 6.0°C (range 26°C–4°C), and this improved significantly after treatment to 5.7 ± 5.5°C (range 24–3°C) (t=6.60, p<0.0005), indicating a mean temperature reduction of approximately 60%. After 1 year of continuous treatment with rupatadine all patients showed a reduction in CTT. No side-effects were detected in any of the patients in the study sample during the 1-year treatment period with rupatadine. This is the first study to demonstrate that monitoring patients with ACU in normal clinical practice, using the Peltier-effect electronic device TempTest®, is useful in assessing the clinical course of ACU and the patient’s response to treatment. Patients with ACU who were treated with rupatadine 20 mg/day for 1 year experienced a significant improvement.

4.4 Other urticaria skin lesions: mosquito-bite allergy

Mosquitoes frequently cause harmful bite reactions such as immediate wheals and delayed bite papules in children and adults. People exposed for the first time to the bites of certain mosquito species are first non-reactive, but after repeated bites, they become sensitized and bite reactivity often persists for years102. Mosquito-bite whealing is known to be mediated by antisaliva IgE antibodies and histamine103. In agreement with this, oral second-generation antihistamines have been shown to decrease whealing and accompanying pruritus in placebo-controlled trials104,105,106. A double-blind, placebo-controlled, crossover study was performed with rupatadine 10 mg and matching placebo in 30 mosquito-bite-allergic adults107. Either rupatadine 10 mg or placebo was taken at 8 am for 4 days, followed by a 5-day washout period, and then alternative treatment was given for 4 days. All 30 participants were evaluated for safety, of which 26 individuals were available for efficacy evaluation. On day 3 of both treatment periods the subjects received two mosquito bites on the forearm. The size of 15-minute bite wheals and accompanying pruritus (visual analog scale: VAS) were measured. The mean wheal size was reduced by 48% with rupatadine compared with placebo, from 106 mm2 in the placebo group to 55 mm2 in the rupatadine group (Figure 38). Accompanying pruritus was reduced by 21% (VAS: 60 mm in the placebo group and 47.5 mm in the rupatadine group) (Figure 39).

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Mean Wheal size decrease

150

p = 0.0003 ) 2 100 –48%

50 Wheal area (mm

0 Placebo Rupatadine

Figure 38. Wheal size in 26 mosquito-bite sensitized subjects treated with rupatadine 10 mg and placebo. Mean wheal size was significantly reduced by rupatadine 15 minutes after the mosquito bite.

Pruritus decrease

100

80 p = 0.019

60 –21%

40 Pruritus (%)

20

0 Placebo Rupatadine

Figure 39. Reduction in accompanying pruritus (15 minutes after mosquito bite) by rupatadine 10 mg in comparison to placebo. Pruritus was significantly reduced by rupatadine 15 minutes after the mosquito bite.

In conclusion, this double-blind, placebo-controlled, crossover study in mosquito bite-sensitive adults shows that prophylactic rupatadine 10 mg is an effective treatment for mosquito-bite whealing and skin pruritus.

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4.5 Quality of life

In previous sections (see 4.1.2. and 4.1.3) the favorable effect of rupatadine on Quality of Life (QoL) has been demonstrated in patients with chronic urticaria (phase III91 and phase IV studies93) (Figure 33). Differences between treatments were seen in terms of the total score for the QoL questionnaire DLQI between placebo and rupatadine 10 mg at 14 and 28 days; between placebo and rupatadine 20 mg at 14, 28 and 42 days; and between rupatadine 10 mg and rupatadine 20 mg at 42 days91. Evaluation of the treatment effect on the individual domains of the DLQI showed that all scores had improved significantly compared with placebo after 2 weeks of treatment with rupatadine at doses of 10 and 20 mg (p<0.05 for all scores). For rupatadine 10 mg, all domains improved except “leisure” and “personal relationships”91.

SUMMARY • Rupatadine tablets 10 and 20 mg are effective and well tolerated in the treatment of urticaria (adults and adolescents over 12 years old). • Rupatadine has a rapid onset and sustained action in urticaria. • Rupatadine produces a significant and marked reduction in the pruritus score and the number of wheals. • Rupatadine 10 and 20 mg significantly improved QoL in patients with chronic urticaria. • Rupatadine significantly reduces the size of wheals and the pruritus caused by mosquito- bite allergy. • Rupatadine is a better choice in CU in comparison to levocetirizine due to its better efficacy and safety profile. • Rupatadine is well tolerated in long-term treatment.

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5. Rupatadine safety profile

Safety has been one of the main priorities when developing rupatadine, since some second-generation antihistamines have been associated with cardiac problems. Consequently, rupatadine has undergone an extensive battery of safety tests in the laboratory, both in vitro and in vivo. Besides these tests on laboratory animals, rupatadine has been tested widely in humans during its clinical development. All in all, rupatadine has largely met the strictest requirements and has been demonstrated to afford many advantages over other second-generation antihistamines. Rupatadine is metabolized via microsomal pathways mainly involving CYP3A4 and, therefore, may interact with drugs metabolized via the same system. In this section, we will summarize the main studies of rupatadine pharmacokinetic interactions with other drugs, as this can be considered to be an aspect which is related to rupatadine safety. Also, this section specifically summarizes the safety and tolerability of rupatadine on two key target organ systems (CNS and cardiac) as well its safety after long-term use (1 year). We will also focus attention on the effect on QTc interval prolongation (torsades des pointes), an important life-threatening side effect that has been described for some non-sedating antihistamines (astemizole and terfenadine). Finally, we present a review and summary of rupatadine adverse drug reactions from clinical trials, at the therapeutic dose of 10 mg in adults and adolescents (≥12 years), and a comparison with adverse drug reactions in children.

5.1 Pharmacokinetic interactions

• Effect of known CYP3A4 inhibitors on rupatadine As indicated above, Rupatadine is transformed in the liver by the action of CYP3A4. Thus, rupatadine’s metabolism slows down when it is concomitantly administered with other agents inhibiting the CYPA34 route, such as erythromycin and ketoconazole. Drug interactions were studied after the concomitant administration of rupatadine 20 mg and known CYP3A4 inhibitors, such as ketoconazole (200 mg/day) or erythromycin (500 mg three times a day) for 7 days58,59. Ketoconazole inhibited both the presystemic and systemic metabolism of rupatadine, producing a 10-fold enhancement of exposure to the unaltered drug and reducing exposure to metabolites. On the other hand, the pharmacokinetic profile of ketoconazole was not affected by concomitant rupatadine use. Erythromycin exhibited lower inhibition of the presystemic metabolism of rupatadine compared to ketoconazole, and led to a 2- to 3-fold increase in systemic exposure to unaltered rupatadine, with no significant increases in the mean elimination half-life of rupatadine or the systemic exposure to analyzed metabolites.

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Despite increases in plasma concentrations of the original drug in both studies, no clinically relevant changes were seen in ECG parameters (including QTc intervals), laboratory tests, vital signs and adverse events. Co-administration with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, nefazodone) should be avoided and co- medication with moderate CYP3A4 inhibitors (erythromycin, fluconazole, diltiazem) should be used with caution.

• Effect of rupatadine on alcohol and CNS depressants The effect of rupatadine when it is co-administered with alcohol or with drugs with narrow therapeutic windows such as CNS depressants, has been evaluated In a randomized, crossover, placebo-controlled study in 18 healthy young volunteers, a single therapeutic dose of rupatadine 10 mg did not increase the depressant effects of alcohol on psychomotor and cognitive performance. At a dose of 20 mg or higher, rupatadine increased the impairement caused by alcohol. Rupatadine plasma concentrations were not significantly affected by the concomitant administration of alcohol108. In a randomized, crossover, placebo-controlled study in 16 healthy young volunteers, oral rupatadine 10 mg, once daily for 7 days, did not enhance the CNS depressant effects of lorazepam (benzodia­ zepine, 2 mg orally, single dose) either in objective psychomotor tests or in subjective evaluations109.

• Effect of food on rupatadine The influence of food on the oral bioavailability of rupatadine (20 mg single oral dose) was evaluated in healthy volunteers110. Food intake increased rupatadine AUC by approximately 23%. Exposure to

metabolites (desloratadine and 3-hydroxydesloratadine) was virtually the same. Tmax (the time to

achieve peak plasma concentrations) was delayed 1 hour and Cmax was not affected by food intake. Rupatadine was well tolerated under fed and fasting conditions and no major changes in severity and/or prevalence of adverse events were reported, concluding that any interaction with food has low or no clinical relevance. Thus, rupatadine can be taken with or without food.

• Effect of grapefruit juice on rupatadine The effects of the concomitant administration of grapefruit juice on the pharmacokinetic parameters and tolerability of rupatadine and its metabolites were assessed in a study in healthy volunteers. Grapefruit juice inhibited rupatadine presystemic metabolism, producing a 3-fold enhancement of exposure to the unaltered drug and no significant increase in systemic exposure to the two metabolites58. Based on these results, grapefruit should not be taken simultaneously with rupatadine. The administration of rupatadine with grapefruit juice increases the AUC value and triples the maximum plasma concentration, so their joint administration is not recommended.

• Co-administration with azithromycin: effect on rupatadine A study with healthy volunteers assessed the safety profile of rupatadine administered concomitantly with azithromycin, a drug that has not been reported to inhibit CYP3A4. Subjects received rupatadine 10 mg/day for 6 days with or without azithromycin 500 mg on day 2 and 250 mg from day 3 to day 6. No clinically relevant changes were seen in the mean pharmacokinetic parameters of rupatadine

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and active metabolites when rupatadine was administered with azythromycin. The combination of rupatadine and azithromycin was well tolerated, and concomitant administration is safe at therapeutic doses (rupatadine 10 mg)61.

• Co-administration with fluoxetine: effect on rupatadine Bearing in mind that fluoxetine has been described as a potent inhibitor of some CYP family isoenzymes, such as CYP2D6 and CYP3A4, a study in healthy volunteers was conducted to assess the effects of concomitant use of fluoxetine and rupatadine on the pharmacokinetic and tolerability parameters of rupatadine58. No clinically relevant changes were seen in the mean pharmacokinetic parameters of rupatadine and its metabolites when administered concomitantly with fluoxetine. The combination of rupatadine and fluoxetine was well tolerated such that fluoxetine can be administered safely with rupatadine 10 mg.

5.2 Central nervous system (CNS) effects

The CNS effects of rupatadine have been assessed in several safety trials. A study in healthy volunteers was conducted to assess the CNS effects of rupatadine at doses of 10, 20, 40 and 80 mg compared to a positive standard substance (hydroxyzine 25 mg), used in a randomized, double-blind, placebo-controlled, crossover study46. Neither the 10 mg nor the 20 mg doses of rupatadine produced impairment in objective psychomotor function tests or in subjective reports versus placebo. Significant impairment was only observed with the highest assessed doses of 80 mg as well as with hydroxyzine 25 mg. Rupatadine 10 mg did not enhance the CNS depressive effect of alcohol (0.8 g/kg) after a single dose in the objective and subjective measures of psychomotor function, including quantitative electroencephalography. However, a pharmacodynamic interaction was observed with the concomitant administration of alcohol and hydroxyzine 25 mg108. In another double-blind, randomized, controlled study in healthy volunteers to assess the effects of rupatadine on driving performance111, all volunteers received a single oral dose of rupatadine 10 mg, hydroxyzine 50 mg or placebo. Driving performance was assessed and no differences were seen between rupatadine and placebo in the primary outcome variable (SDLP: Standard Deviation of Lateral Position), while hydroxyzine did produce impairment of driving performance under real driving conditions (Figure 40). Subjective sleepiness, assessed by the Standford Sleepiness Scale, was not affected by rupatadine and placebo but it was significantly increased by hydroxyzine (p<0.001 versus placebo and versus rupatadine).

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Standard deviation lateral position (SDLP) Mean (±SEM)

28

26

24

22 SDLP (cm) SDLP 20

18 Hydroxyzine vs placebo p<0.001 Hydroxyzine vs rupatadine p<0.001 16 Rupatadine vs placebo N.S 14 Rupatadine Placebo Hydroxyzine

Figure 40. Mean (±SEM) standard deviation of lateral position (SDLP) scores for each treatment (rupatadine 10 mg, placebo, hydroxyzine 50 mg; n=20).

A randomized, double-blind, placebo-controlled, crossover study was conducted to assess potential changes in mental capacity with concomitant administration of rupatadine and a benzodiazepine. Results showed that rupatadine 10 mg does not impair mental ability and does not enhance mental deterioration caused by lorazepam109. In summary, rupatadine, at the therapeutic dose of 10 mg, does not produce CNS depressant effects and does not increase the effects of barbiturates or alcohol. It acts on the CNS in a similar way to other second-generation antihistamines that are generally considered as non-sedating antihistamines, and does not produce the characteristic depressant effects of first-generation antihistamines like diphenhydramine and hydroxyzine.

5.3 Cardiac safety

QTc interval prolongation on ECG has been associated with drug-induced torsades des pointes (TdP), life-threatening ventricular tachycardia that can be identified by the presence of a sinusoidal twisting of QRS complexes around the isoelectric line in the 12-lead ECG. In recent years, some degree of concern has been expressed regarding the cardiotoxicity of non-sedating antihistamines, and cases of TdP have been described, first with astemizole and then with terfenadine. In previous animal studies, rupatadine at over 100 times the recommended dose (10 mg) did not result in QTc or QRS interval prolongation in different animal species, such as rats, guinea pigs and dogs59. In a study assessing the effect on the cloned human ether-a-go-go-related gene (HERG) channel,

rupatadine inhibited the channel at a concentration 1685 times superior to the Cmax observed after administration of rupatadine 10 mg. Distribution studies show that rupatadine does not have cardiac tropism, and concentrations in cardiac tissue are low and become undetectable within 24 hours of administration. A total of 6450 ECGs from healthy volunteers (young and elderly, male and female, n=4000) and adult patients with allergy (n=2450) have been analyzed. Doses of rupatadine ranged from 2.5 to 80 mg, either as a single dose or once daily for 2-4 weeks, given with or without food, alone or

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concomitantly with alcohol, erythromycin or ketoconazole. In all these conditions, rupatadine produced no clinically relevant changes in QT/QTc intervals47,59. Following recommendations from the ICH E14 guideline, adopted in October 2005112, a “detailed QT/ QTc study” was conducted to establish whether rupatadine has a threshold pharmacological effect on cardiac repolarization, manifested by QT/QTc interval prolongation, both at therapeutic and supratherapeutic doses113. The study involved 160 healthy volunteers divided into 4 treatment groups: moxifloxacin 400 mg (positive control), rupatadine 10 mg (therapeutic dose), rupatadine 100 mg (supratherapeutic dose) and placebo. The validity of the trial was shown by the fact that moxifloxacin, a quinolone antibacterial agent used as the positive control, showed the expected increase in QTc duration of between 5 and 10 milliseconds. The ECG data obtained with rupatadine at doses of 10 and 100 mg showed no signs of ECG effects, manifested as an increase above 10 milliseconds, both after a single dose and after 5 days of treatment (Figure 41).

90% CI for maximum QTc mean change versus placebo

20

15 Possible Risk of arrhythmias

10

5

0

-5 Unlikely

-10 QTc change from baseline (msec) QTc Day 1 Day 5 -15 Moxifloxacin 400 mg Rupatadine 10 mg Rupatadine 100 mg

Figure 41. Maximum QTcI mean change difference versus placebo for rupatadine 10 and 100 mg, and moxifloxacin 400 mg (time-average analysis). QTcI: QTc corrected for heart rate. Risk of arrhythmias: rupatadine 10 or 100 mg has no effect on baseline QTcl values.

This study revealed that rupatadine, at a dose 10 times above the therapeutic dose, showed no signal effects on the ECG, after single and repeated administration. This study confirmed previous experience with rupatadine and demonstrated that it showed no proarrhythmic potential and raised no cardiac safety concerns.

5.4 Long-term safety

Since rupatadine has been marketed in Spain, a multicenter, open-label, phase IV study in patients recruited from 33 centers in Spain has been conducted to assess long-term safety in patients with persistent allergic rhinitis (PER)77. The aim of the study was to assess the long-term safety of rupatadine according to the clinical safety recommendations of the European Medicines Agency

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(EMA)114 and the International Conference on Harmonisation (ICH) of technical requirements for registration of pharmaceuticals for human use guideline115 . The study enrolled 324 male and female patients (aged 12-70 years) with a medical history of PER and treated with rupatadine 10 mg for at least 6 months. Of these eligible patients starting treatment, 120 were treated for more than 6 months. They were followed up and treated until the end of 12 months, according to EMA and ICH guidelines. Overall, a total of 74.1% of patients reported at least one adverse event (AE) during the 1-6 month treatment period and 65.8% of patients during the 1-12 month treatment period, whereas 20.4% and 10.8% of patients reported at least one treatment-related AE during the 1-6 months and 1-12 months treatment periods, respectively. Assessment of AEs, reported by >5% of patients during both treatment periods, showed that the three most common adverse events were headache, somnolence and catarrh. Moreover, the frequency of these AEs was similar over both treatment periods. While somnolence (7.7%) and headache (6.5%) were also reported as treatment-related AEs during the 1-6-month treatment period, only somnolence (5.8%) was reported as a treatment-related AE during the 1-12-month treatment period. Although patients also reported AEs associated with several other system organ classes, none of the specific AEs, apart from sore throat, within any of these system organ classes were found to be reported by >5% patients (Table 10).

Table 10. Long-term (1 year) safety data for rupatadine 10 mg once daily in patients with mild-to-moderate persistent allergic rhinitis

Duration 6 months (n=324) 12 months (n=120) Patients with ≥1 AE 74% 66% Patients with drug-related AE 20.4% 10.8% Somnolence 7.7% 5.8% Headache 6.5% Not reported

Detailed ECG assessments demonstrated no clinically relevant abnormal ECG findings, nor any QTc increases >60 msec or QTc values >470 msec for any patient at any time during treatment, suggesting a lack of cardiotoxicity at the therapeutic dose of rupatadine 10 mg. Rupatadine is one of the first second-generation antihistamines to have such extensive long-term safety data following European and ICH recommendations and guidelines.

5.5 Adverse drug reactions in clinical trials

Independent reviews of published phase III clinical trials with rupatadine in patients with allergic rhinitis indicate that it is well tolerated. Data are derived from a total of 3588 patients (adults and adolescents) or healthy volunteers treated with different doses of the drug58,59,63. At a dose of 10 mg once daily (the therapeutic dose) rupatadine was not significantly different from placebo regarding adverse drug reactions. Data from adults and adolescents (aged ≥12 years) who received rupatadine 10 mg (n=2141) or placebo (n=1447) during clinical trials are presented in Table 11. Most adverse effects were of mild-to-moderate severity with somnolence being the most

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commonly-reported adverse effect (9.5% vs 2.9% for placebo) followed by headache (6.5% vs 5.5%) and fatigue (3.0% vs 2.1%).

Table 11. Common adverse effects (incidence >1%) of rupatadine 10 mg in clinical trials (adolescents aged ≥12 years and adults)

Adverse event Rupatadine (n=2141) Placebo (n=1447) Somnolence 9.5% 2.9% Headache 6.5% 5.5% Fatigue 3.0% 2.1% Asthenia 1.5% 0.3% Dry mouth 1.2% 0.3%

The incidence of adverse reactions in children aged 2–11 years treated with rupatadine pediatric oral solution 1 mg/mL is lower than that reported in adults and adolescents. Overall, 306 children aged 2–11 years have been exposed to rupatadine pediatric oral solution in clinical trials (147 children were treated with rupatadine 2.5 mg once daily, and 159 were treated with 5 mg once daily, for 1–8 weeks) (Table 12). The percentages of children with adverse drug reactions in the placebo, rupatadine 2.5 mg and rupatadine 5 mg groups were 3.6%, 2.0% and 6.3%, respectively. No major differences were noted between the two rupatadine groups and placebo. The most common adverse event was headache, documented in 1.36% of patients in the lower-dose rupatadine group, in 2.52% of children in the higher-dose rupatadine group, and in 1.61% of placebo recipients (Table 12). The incidence of treatment-related somnolence (sleepiness), an important consideration from the view­ point of reduced academic performance in schoolchildren, was also very low: 1.26% in the rupatadine 5 mg group64,116. This finding is consistent with the low incidence of sedation generally reported for second-generation antihistamines in the pediatric population117.

Table 12. Common (≥1/100 to <1/10) adverse drug reactions in children aged 2-11 years

System Organ Class Term Rupatadine 2.5 mg Rupatadine 5 mg Placebo (n=147) (n=159) (n=249) Nervous system disorders Number of patients (% patients) Common Headache 2 (1.36%) 4 (2.52%) 4 (1.61%) Somnolence 0 2 (1.26%) 0

In conclusion, the low incidence of adverse drug reactions for rupatadine 10 mg tablets show that this drug is safe and well tolerated at the therapeutic dose with no statistically significant differences compared with placebo. The safety and tolerance of rupatadine as a pediatric oral solution (1 mg/ mL), is particularly good in children aged 2-11 years.

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5.6 Post-marketing safety

Post-marketing experience, since rupatadine tablets were first launched on 3 March 2003, is summarized in periodic safety update reports (PSURs). Based on the Daily Defined Dose (DDD) of 10 mg, the accumulated patient exposure to rupatadine up to 30 June 2014 was 2571652 patient-years. ADRs with rupatadine were mild to moderate in severity and they are in line with rupatadine’s Summary of Product Characteristics. The most common were somnolence, fatigue, headache, and nausea. Some other specific issues which are closely monitored in post-marketing. To date, extensive post- marketing surveillance has not indicated any change in the positive benefit-risk ratio of rupatadine. In conclusion, the overall safety assessment based on the post-marketing use of rupatadine shows a favourable benefit-risk ratio and confirms the safety profile of rupatadine as described in its Summary of Product Characteristics.

SUMMARY • Rupatadine can be taken with or without food. • Rupatadine does not present drug interactions with azithromycin, fluoxetine or lorazepam, and therefore any of these drugs can be administered concomitantly with rupatadine. The concomitant use of rupatadine and erythromycin, ketoconazole or grapefruit juice is not recommended. • Rupatadine has been shown to be safe with no significant negative effects on cognition or psychomotor performance in adults. • Rupatadine showed no adverse cardiovascular effects in preclinical or extensive clinical testing in adults. • Adverse effects for rupatadine were mild to moderate in severity but not significantly different from placebo. • Long-term safety data indicate: • The incidence of adverse effects decreases over time • No clinically relevant changes in ECG parameters in laboratory values • Rupatadine pediatric oral solution 1 mg/mL is safe and well tolerated, similar to placebo. • No serious AEs or ECG abnormalities were reported in children with allergic rhinitis and urticaria. • Post-marketing use of rupatadine shows a favorable benefit-risk ratio.

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86. Valero A, Izquierdo I, Giralt J, Bartra J et al. Rupatadine improves nasal symptoms, quality of life (ESPRINT-15), and severity in a cohort of Spanish allergic rhinitis patients. J Investig Allergol Clin Immunol 2011; 21(3):229-235. 87. Juniper EF, Guyatt GH, Willan A et al. Determining a Minimal Important Change in a disease-specific quality of life questionnaire. J Clin Epidemiol 1991; 47: 81-87. 88. Roger A, Arnáiz E, Valero A, De la Torre F et al. Rupatadine 10 mg improves quality of life in long-term treatment of persistent allergic rhinitis [abstract no. 761 plus poster]. 25th EAACI Congress 10-14 June 2006, Vienna. 89. Compalati E, Canonica GW. Efficacy and safety of rupatadine for allergic rhino-conjunctivitis: A systematic review of randomized, double-blind, placebo-controlled studies with metaanalysis. Curr Med Res Opin 2013; 29(11): 1539-1551. 90. Dubertret L, Zalupca L, Cristodoulo T, Benea V et al. Once-daily rupatadine improves the symptoms of chronic idiopathic urticaria: a randomised, double-blind, placebo-controlled study. Eur J Dermatol 2007; 17:223-228. 91. Gimenez-Arnau A, Pujol RM, Ianosi S, Kaszuba A, Malbran A, Poop G, et al. Rupatadine in the treatment of chronic idiopathic urticaria: a double-blind, randomized, placebo-controlled multicenter study. Allergy 2007; 62:539-546. 92. Gimenez-Arnau A, Izquierdo I, Maurer M. The use of a responder analysis to identify clinically meaningful differences in chronic urticaria patients following placebo-controlled treatment with rupatadine 10 and 20 mg. J Eur Acad Dermatol Venereol 2009; 23(9):1088-1091. 93. Maiti R, Jaida J, Raghavendra BN, Goud P, Ahmend I, Palani A. Rupatadine and levocetirizine in chronic idiophatic urticaria: a comparative study of efficacy and safety. J Drugs Dermatol 2011; 10(12):1444- 1450. 94. Siebenhaar F, Weller K, Mlynek A et al. Acquired cold urticaria: clinical picture and update on diagnosis and treatment. Clin Exp Dermatol 2007; 32:241–224. 95. Huissoon A, Krishna MT. Cold-induced urticaria. N Engl J Med 2008; 358:e9. 96. Fitzgerald DA, Heagerty AH, English JS. Cold urticaria as an occupational dermatosis. Contact Dermatitis 1995; 32:238. 97. Möller A, Henning M, Zuberbier T, Czarnetzki-Henz BM. Epidemiologie und Klinik der Kälteurticaria. Hautarzt 1996; 47:510–514. 98. Grandel KE, Farr RS, Wanderer AA, Eisenstadt TC et al. Association of platelet-activating factor with primary acquired cold urticaria. N Engl J Med 1985; 313:405–409. 99. Metz M, Scholz E, Ferrán M; Izquierdo I et al. Rupatadine and its effects on symptom control, stimulation time, and temperature thresholds in patients with acquired cold urticaria. Ann Allergy Asthma Immunol 2010; 104(1):86-92. 100. Abajian M, Curto-Barredo L, Krause K et al. Rupatadine 20 mg and 40 mg are Effective in Reducing theSymptoms of Chronic Cold Urticaria. Acta Derm Venereol 2016; 96: 56–59. 101. Martinez-Escala ME, Curto-Barredo L, Carnero LL et al. Temperature thresholds in assessment of the clinical course of Acquired Cold Contact Urticaria: a prospective observational one-year study. Acta Derm Venereol 2015; 95:278-282. 102. Reunala T, Brummer-Korvenkontio H, Palosuo T. Are we really allergic to mosquito bites? Ann Med 1994; 26:301–306. 103. Horsmanheimo L, Harvima IT, Harvima RJ, Brummer-Korvenkontio H et al. Histamine and leukotriene C4 release in cutaneous mosquito bite reactions. J Allergy Clin Immunol 1996; 98:408–411. 104. Reunala T, Brummer-Korvenkontio H, Karppinen A, Coulie P et al.Treatment of bites with cetirizine. Clin Exp Allergy 1993; 23:72–75. 105. Karppinen A, Kautiainen H, Petman L, Burri P, Reunala T. Comparison of cetirizine, ebastine and loratadine in the treatment of immediate mosquito-bite allergy. Allergy 2002; 57:534–537. 106. Karppinen A, Brummer-Korvenkontio H, Petman L, Kautiainen H et al. Levocetirizine for treatment of immediate and delayed mosquito bite reactions. Acta Derm Venereol 2006; 86:329–331. 107. Karppinen A, Brummer-Korvenkontio H, Reunala T, Izquierdo I. Rupatadine 10 mg in the treatment of immediate mosquito-bite allergy. J Eur Acad Dermatol Venereol 2012; 26(7):919-922.

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108. Barbanoj M J, García-Gea C, Antonijoan R et al. Evaluation of the cognitive, psychomotor and pharmacokinetic profiles of rupatadine, hydroxyzine and cetirizine, in combination with alcohol, in healthy volunteers. Hum Psychopharmacol 2006; 21:13-26. 109. García-Gea C, Ballester MR, Martínez J, Antonijoan RM et al. Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study. Br J Clin Pharmacol 2010; 63(6):663-674. 110. Solans A, Carbó M, Peña J, Nadal T et al. Influence of food on oral bioavailability of rupatadine tablets in healthy volunteers: a single-dose, randomized, open-label, two-way crossover study. Clin Ther 2007; 29:900-908. 111. Vuurman E, Theunissen E, van Oers A, van Leeuwen C, Jolles J. Lack of effects between rupatadine 10 mg and placebo on actual driving performance of healthy volunteers. Hum Psychopharmacol Clin Exp 2007; 22:289-297. 112. ICH Guidance. Clinical Evaluation of QT/Qtc Interval Prolongation and Proarrhythmic Potential for Non- Antiarrhythmic Drugs. E14. http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines. html (last accessed Oct 2014). 113. Donado E, Izquierdo I, Pérez I, García O, Antonijoan RM, Gich, I et al. No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results from a ‘thorough QT/QTc study’ performed according to ICH guidelines. Br J Clin Pharmacol 2010; 69:401-410. 114. European Agency for the Evaluation of Medicinal Products (EMEA). Committee for Medicinal Products for Human Use: guideline on the clinical development of medicinal products for the treatment of allergic rhinoconjunctivitis. London: Committee for Medicinal Products from EMEA, 2005. 115. International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Topic E1A note for guidance: population exposure: the extent of population exposure to assess clinical safety. Geneva: ICH, 1995. 116. Summary of Product Characteristics. Rupatadine 1 mg/mL oral solution. May2014. 117. de Benedictis FM, de Benedictis D, Canonica GW. New oral antihistamines in children: facts and unmeet needs. Allergy 2008; 63(10):1395-1404.

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7. Summary of Product Characteristics

1. NAME OF THE MEDICINAL PRODUCT Rupafin 10 mg Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains: 10 mg of rupatadine (as fumarate) Excipient with known effect: lactose 58 mg as lactose monohydrate For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Tablet. Round, light salmon coloured tablets.

4. CLINICAL PARTICULARS 4.1 Therapeutic indications Symptomatic treatment of allergic rhinitis and urticaria in adults and adolescents (over 12 years of age). 4.1 Posology and method of administration Adults and adolescents (over 12 years of age) The recommended dose is 10 mg (one tablet) once a day, with or without food. Elderly Rupatadine should be used with caution in elderly people (see section 4.4). Paediatric patients Rupatadine 10 mg Tablets is not recommended for use in children below age 12. In children aged 2 to 11 years, the administration of rupatadine 1 mg/ml oral solution is recommended. Patients with renal or hepatic insufficiency As there is no clinical experience in patients with impaired kidney or liver functions, the use of rupatadine 10 mg Tablets is at present not recommended in these patients. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 4.4 Special warnings and precautions for use The administration of rupatadine with grapefruit juice is not recommended (see section 4.5). The combination of rupatadine with potent CYP3A4 inhibitors should be avoided and with moderate CYP3A4 inhibitors should be administered with caution (see section 4.5).

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Dose adjustment of sensitive CYP3A4 substrates (e.g. simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic index (e.g. ciclosporin, , sirolimus, everolimus, cisapride) could be required as rupatadine may increase plasma concentrations of these drugs (see section 4.5). Cardiac safety of rupatadine was assessed in a Thorough QT/QTc study. Rupatadine up to 10 times therapeutic dose did not produce any effect on the ECG and hence raises no cardiac safety concerns. However, rupatadine should be used with caution in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, patients with ongoing proarrhythmic conditions, such as clinically significant bradycardia, acute myocardial ischemia. Rupatadine 10 mg Tablets should be used with caution in elderly patients (65 years and older). Although no overall differences in effectiveness or safety were observed in clinical trials, higher sensitivity of some older individuals cannot be excluded due to the low number of elderly patients enrolled (see section 5.2). Regarding use in children less than 12 years old and in patients with renal or hepatic impairment, see section 4.2. Due to the presence of lactose monohydrate in rupatadine 10 mg tablets, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed in adults and adolescents (over 12 years of age) with rupatadine 10 mg tablets. Effects of other drugs on rupatadine Co-administration with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, nefazodone) should be avoided and co- medication with moderate CYP3A4 inhibitors (erythromycin, fluconazole, diltiazem) should be used with caution. The concomitant administration of rupatadine 20 mg and ketoconazole or erythromycin increases the systemic exposure to rupatadine 10 times and 2-3 times respectively. These modifications were not associated with an effect on the QT interval or with an increase of the adverse reactions in comparison with the drugs when administered separately. Interaction with grapefruit: The concomitant administration of grapefruit juice increased 3.5 times the systemic exposure of rupatadine. Grapefruit juice should not be taken simultaneously. Effects of rupatadine on other drugs Caution should be taken when rupatadine is co-administered with other metabolised drugs with narrow therapeutic windows since knowledge of the effect of rupatadine on other drugs is limited. Interaction with alcohol: After administration of alcohol, a dose of 10 mg of rupatadine produced marginal effects in some psychomotor performance tests although they were not significantly different from those induced by intake of alcohol only. A dose of 20 mg increased the impairment caused by the intake of alcohol. Interaction with CNS depressants: As with other antihistamines, interactions with CNS depressants cannot be excluded Interaction with statins: Asymptomatic CPK increases have been uncommonly reported in rupatadine clinical trials. The risk of interactions with statins, some of which are also metabolised by the cytochrome P450 CYP3A4 isoenzyme, is unknown. For these reasons, rupatadine should be used with caution when it is coadministered with statins.

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4.6 Fertility, pregnancy and lactation Pregnancy There are limited amount of data from the use of rupatadine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of rupatadine during pregnancy. Breastfeeding Rupatadine is excreted in animal milk. It is unknown whether rupatadine is excreted into breast milk. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from rupatadine therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Fertility There are no clinical data on fertility. Studies in animals have shown a significant reduction of fertility at exposure levels higher than those observed in humans at the maximum therapeutic dose (see section 5.3). 4.7 Effects on the ability to drive and use machines Rupatadine 10 mg had no influence on the ability to drive and use machines. Nevertheless, care should be taken before driving or using machinery until the patient’s individual reaction on rupatadine has been established. 4.8 Undesirable effects Rupatadine 10 mg tablets has been administered to over 2025 adult and adolescents patients in clinical studies, 120 of whom received rupatadine for at least 1 year. The most common adverse reactions in controlled clinical studies were somnolence (9.5%), headache (6.9%) and fatigue (3.2%). The majority of the adverse reactions observed in clinical trials were mild to moderate in severity and they usually did not require cessation of therapy. The frequencies of adverse reactions are assigned as follows: • Common (≥ 1/100 to < 1/10) • Uncommon (≥ 1/1000 to < 1/100) • Rare (≥1/10000 to <1/1000) The frequencies of adverse reactions reported in patients treated with rupatadine 10 mg tablets during clinical trials and spontaneous reporting were as follows: • Infections and infestations – Uncommon : Pharyngitis, Rhinitis • Immune system disorders – Rare: Hypersensitivity reactions (including anaphylactic reactions, angioedema and urticaria)* • Metabolism and nutrition disorders – Uncommon : Increased appetite • Nervous system disorders: – Common : Somnolence, Headache, Dizziness – Uncommon : Disturbance in attention • Cardiac disorders – Rare: tachycardia and palpitations*

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• Respiratory, thoracic, and mediastinal disorders – Uncommon : Epistaxis, Nasal dryness, Cough, Dry throat, Oropharyngeal pain • Gastrointestinal disorders – Common : Dry mouth – Uncommon : Nausea, Abdominal pain upper, Diarrhoea, Dyspepsia, Vomiting, Abdominal pain, Constipation • Skin and subcutaneous tissue disorders – Uncommon : Rash • Musculoskeletal, connective tissues, and bone disorders – Uncommon : Back pain, Arthralgia, • General Disorders and administration site condition – Common : Fatigue, Asthenia – Uncommon: Thirst, Malaise, Pyrexia, Irritability • Investigations – Uncommon : Blood creatine phosphokinase increased, Alanine aminotransferase increased, Aspartate aminotransferase increased, Liver function test abnormal, Weight increased * tachycardia and palpitations and hypersensitivity reactions (including anaphylactic reactions, angioedema and urticarial) have been reported in post-marketing experience with rupatadine 10 mg tablets. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose No case of overdose has been reported. In a clinical safety study rupatadine at daily dose of 100 mg during 6 days was well tolerated. The most common adverse reaction was somnolence. If accidental ingestion of very high doses occurs symptomatic treatment together with the required supportive measures should be given.

5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antihistamines for systemic use, ATC code: R06A X28. Rupatadine is a second-generation antihistamine, long-acting histamine antagonist, with selective

peripheral H1 receptor antagonist activity. Some of the metabolites (desloratadine and its hydroxylated metabolites) retain an antihistaminic activity and may partially contribute to the overall efficacy of the drug. In vitro studies with rupatadine at high concentration have shown an inhibition of the degranulation of mast cells induced by immunological and non-immunological stimuli as well as the release of

cytokines, particularly of the TNFa in human mast cells and monocytes. The clinical relevance of the observed experimental data remains to be confirmed. Clinical trials in volunteers (n= 375) and patients (n=2650) with allergic rhinitis and chronic idiopathic urticaria did not show significant effect on the electrocardiogram when rupatadine was administered at doses ranging from 2 mg to 100 mg.

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Chronic idiopathic urticaria was studied as a clinical model for urticarial conditions, since the underlying pathophysiology is similar, regardless of etiology, and because chronic patients can be more easily recruited prospectively. Since histamine release is a causal factor in all urticarial diseases, rupatadine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria, as advised in clinical guidelines. In a placebo-controlled trials in patients with Chronic Idiopathic Urticaria, rupatadine was effective reducing the mean pruritus score from baseline over the 4 week treatment period (change vs baseline: rupatadine 57.5%, placebo 44.9%) and decreasing the mean number of wheals (54.3% vs 39.7%). 5.2 Pharmacokinetic properties Absorption and bioavailability

Rupatadine is rapidly absorbed after oral administration, with a tmax of approximately 0.75 hours after intake. The mean Cmax was 2.6 ng/ml after a single oral dose of 10 mg and 4.6 ng/ml after a single oral dose of 20 mg. Pharmacokinetics of rupatadine was linear for a dose between 10 and 20 mg after single and repeated doses. After a dose of 10 mg once a day for 7 days, the mean Cmax was 3.8 ng/ml. The plasma concentration followed a bi-exponential drop-off with a mean elimination half- life of 5.9 hours. The binding-rate of rupatadine to plasma proteins was 98.5-99%. As rupatadine has never been administered to humans by intravenous route, no data is available on its absolute bioavailability. Effect of the intake of food Intake of food increased the systemic exposure (AUC) to rupatadine by about 23%. The exposure to one of its active metabolites and to the main inactive metabolite was practically the same (reduction of about 5% and 3% respectively). The time taken to reach the maximum plasma concentration (tmax) of rupatadine was delayed by 1 hour. The maximum plasma concentration (Cmax) was not affected by food intake. These differences had no clinical significance. Metabolism and elimination In a study of excretion in humans (40 mg of 14C-rupatadine), 34.6% of the radioactivity administered was recovered in urine and 60.9% in faeces collected over 7 days. Rupatadine undergoes considerable pre-systemic metabolism when administered by oral route. The amounts of unaltered active substance found in urine and faeces were insignificant. This means that rupatadine is almost completely metabolised. Roughly, the active metabolites desloratadine and other hydroxylated derivatives accounted for 27% and 48%, respectively, of the total systemic exposure of the active substances. In vitro metabolism studies in human liver microsomes indicate that rupatadine is mainly metabolised by the cytochrome P450 (CYP 3A4). Specific patient groups In a study on healthy volunteers to compare the results in young adults and elderly patients, the values for AUC and Cmax for rupatadine were higher in the elderly than in young adults. This is probably due to a decrease of the first-pass hepatic metabolism in the elderly. These differences were not observed in the metabolites analysed. The mean elimination half-life of rupatadine in elderly and young volunteers was 8.7 hours and 5.9 hours respectively. As these results for rupatadine and for its metabolites were not clinically significant, it was concluded that it is not necessary to make any adjustment when using a dose of 10 mg in the elderly. 5.3 Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

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More than 100 times the clinically recommended dose (10 mg) of rupatadine did neither extend the QTc or QRS interval nor produce arrhythmia in various species of animals such as rats, guinea pigs and dogs. Rupatadine and one of its main active metabolites in humans, 3-hydroxydesloratadine, did not affect the cardiac action potential in isolated dog Purkinje fibres at concentrations at least

2000 times greater than the Cmax reached after the administration of a dose of 10 mg in humans. In a study that evaluated the effect on cloned human HERG channel, rupatadine inhibited that channel

at a concentration 1685 times greater than the Cmax obtained after the administration of 10 mg of rupatadine. Desloratadine, the metabolite with the greatest activity, had no effect at a 10 micromolar concentration. Studies of tissue distribution in rats with radiolabelled rupatadine showed that rupatadine does not accumulate in heart tissue. In the rat, a significant reduction of male and female fertility occurred at the high dose of 120 mg/

kg/day, providing Cmax 268 times those measured in humans at the therapeutic dose (10 mg/day). Foetal toxicity (growth delay, incomplete ossification, minor skeletal findings) was reported in rats at maternotoxic dose-levels only (25 and 120 mg/kg/day). In rabbits, no evidence of developmental toxicity was noted at doses up to 100 mg/kg. The developmental No Adverse Effect Levels were

determined at 5 mg/kg/day in rats and 100 mg/kg/day in rabbits, yielding Cmax 45 and 116 times higher, respectively, than those measured in humans at the therapeutic dose (10 mg/day).

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Pregelatinised maize starch Microcrystalline cellulose Red iron oxide (E-172) Yellow iron oxide (E-172) Lactose monohydrate Magnesium stearate 6.2 Incompatibilities Not applicable 6.3 Shelf life 3 years 6.4 Special precautions for storage Keep the blister in the outer carton in order to protect from light. 6.5 Nature and content of the container PVC/PVDC/aluminium blister. Packs of 3, 7, 10, 15, 20, 30, 50 and 100 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER J. Uriach y Compañía., S.A. Av. Camí Reial, 51-57 08184 Palau-solità i Plegamans (Spain) Telephone: +34 93 864 96 92 Fax: +34 93 864 66 06 e-mail address:[email protected]

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8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION Date of first authorisation: Date of last renewal: This information may vary in different countries. Please consult the local approved Summary of Product Characteristics (SPC).

10. DATE OF REVISION OF THE TEXT April 2015

This prescribing information may vary in different countries. Please consult the local approved Summary of Product Characteristics (SPC).

Date of preparation: July 2017

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