Letzit

Rhinite allergique pérenne

Letzit est indiqué pour le soulagement des symptômes associés à la rhinite allergique pérenne chez les enfants de 6 mois à 2 ans.

Urticaire chronique idiopathique

Letzit est indiqué pour le traitement des manifestations cutanées non compliquées de l'urticaire chronique idiopathique chez les adultes et les enfants de 6 mois et plus.

Letzit est disponible sous forme de solution buvable de 2,5 mg / 5 ml (0,5 mg / ml) et sous forme de comprimés cassables (numérisés) à 5 mg, permettant l'administration de 2,5 mg, si nécessaire. Letzit peut être pris sans égard à la consommation alimentaire.

Rhinite allergique pérenne

Enfants de 6 mois à 2 ans

La dose initiale recommandée de Letzit est de 1,25 mg (solution buvable à 1/2 cuillère à café) [2,5 ml] une fois par jour le soir. La dose de 1,25 mg une fois par jour ne doit pas être dépassée en fonction d'une exposition comparable à des adultes recevant 5 mg.

Urticaire chronique idiopathique

Adultes et enfants de 12 ans et plus

La dose recommandée de Letzit est de 5 mg (1 comprimé ou 2 cuillères à café [10 ml] de solution buvable) une fois par jour le soir. Certains patients peuvent être contrôlés de manière adéquate par 2,5 mg (1/2 comprimé ou 1 cuillère à café [5 ml] de solution buvable) une fois par jour le soir.

Enfants de 6 à 11 ans

La dose recommandée de Letzit est de 2,5 mg (1/2 comprimé ou 1 cuillère à café [5 ml] de solution buvable) une fois par jour le soir. La dose de 2,5 mg ne doit pas être dépassée car l'exposition systémique à 5 mg est environ le double de celle des adultes.

Enfants de 6 mois à 5 ans

La dose initiale recommandée de Letzit est de 1,25 mg (solution buvable à 1/2 cuillère à café) [2,5 ml] une fois par jour le soir. La dose de 1,25 mg une fois par jour ne doit pas être dépassée en fonction d'une exposition comparable à des adultes recevant 5 mg.

Ajustement de la dose pour une déficience rénale et hépatique

Chez les adultes et les enfants de 12 ans et plus avec:

• Insuffisance rénale légère (clairance de la créatinine [CL_CR] = 50-80 ml / min): une dose de 2,5 mg une fois par jour est recommandée ;
• Insuffisance rénale modérée (CL_CR = 30-50 ml / min): une dose de 2,5 mg une fois tous les deux jours est recommandée ;
• Insuffisance rénale sévère (CL_CR = 10-30 ml / min): une dose de 2,5 mg deux fois par semaine (administrée une fois tous les 3-4 jours) est recommandée ;
• Patients atteints d'insuffisance rénale terminale (CL_CR <10 ml / min) et les patients sous hémodialyse ne doivent pas recevoir Letzit.

Aucun ajustement posologique n'est nécessaire chez les patients présentant uniquement une insuffisance hépatique. Chez les patients présentant à la fois une insuffisance hépatique et une insuffisance rénale, un ajustement de la dose est recommandé.

L'utilisation de Letzit est contre-indiquée dans:

Patients présentant une hypersensibilité connue

Patients présentant une hypersensibilité connue à la lévocétirizine ou à l'un des ingrédients de Letzit, ou à la cétirizine. Les réactions observées vont de l'urticaire à l'anaphylaxie.

Patients atteints d'une maladie rénale terminale

Patients atteints d'insuffisance rénale terminale (CL_CR <10 ml / min) et les patients sous hémodialyse

Patients pédiatriques présentant une fonction rénale altérée

Enfants de 6 mois à 11 ans présentant une insuffisance rénale

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Somnolence

In clinical trials the occurrence of somnolence, fatigue, and asthenia has been reported in some patients under therapy with Letzit. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness, and motor coordination such as operating machinery or driving a motor vehicle after ingestion of Letzit. Concurrent use of Letzit with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.

Urinary Retention

Urinary retention has been reported post-marketing with Letzit. Letzit should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as Letzit may increase the risk of urinary retention. Discontinue Letzit if urinary retention occurs.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenicity studies have been performed with levocetirizine. However, evaluation of cetirizine carcinogenicity studies are relevant for determination of the carcinogenic potential of levocetirizine. In a 2-year carcinogenicity study, in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily oral dose in adults, approximately 10 times the maximum recommended daily oral dose in children 6 to 11 years of age and approximately 15 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m² basis). In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign hepatic tumors in males at a dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily oral dose in adults, approximately 4 times the maximum recommended daily oral dose in children 6 to 11 years of age, and approximately 6 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m² basis). No increased incidence of benign tumors was observed at a dietary dose of 4 mg/kg (approximately 2 times the maximum recommended daily oral dose in adults, equivalent to the maximum recommended daily oral dose in children 6 to 11 years of age and approximately 2 times the maximum recommended daily oral dose in children 6 months to 5 years of age on a mg/m² basis). The clinical significance of these findings during long-term use of Letzit is not known.

Levocetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in mice.

In a fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg (approximately 25 times the recommended daily oral dose in adults on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Letzit should be used during pregnancy only if clearly needed.

Teratogenic Effects

In rats and rabbits, levocetirizine was not teratogenic at oral doses approximately 320 and 390, respectively, times the maximum recommended daily oral dose in adults on a mg/m² basis.

Nursing Mothers

No peri-and post-natal animal studies have been conducted with levocetirizine. In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams that was approximately 40 times the maximum recommended daily oral dose in adults on a mg/m² basis. Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk, use of Letzit in nursing mothers is not recommended.

Pediatric Use

The recommended dose of Letzit for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in patients 6 months to 17 years of age is based on extrapolation of efficacy from adults 18 years of age and older.

The recommended dose of Letzit in patients 6 months to 2 years of age for the treatment of the symptoms of perennial allergic rhinitis and 6 months to 11 years of age with chronic idiopathic urticaria is based on cross-study comparisons of the systemic exposure of Letzit in adults and pediatric patients and on the safety profile of Letzit in both adult and pediatric patients at doses equal to or higher than the recommended dose for patients 6 months to 11 years of age.

The safety of Letzit 5 mg once daily was evaluated in 243 pediatric patients 6 to 12 years of age in two placebo-controlled clinical trials lasting 4 and 6 weeks. The safety of Letzit 1.25 mg twice daily was evaluated in one 2-week clinical trial in 114 pediatric patients 1 to 5 years of age and the safety of Letzit 1.25 mg once daily was evaluated in one 2-week clinical trial in 45 pediatric patients 6 to 11 months of age.

The effectiveness of Letzit 1.25 mg once daily (6 months to 5 years of age) and 2.5 mg once daily (6 to 11 years of age) for the treatment of the symptoms of perennial allergic rhinitis and chronic idiopathic urticaria is supported by the extrapolation of demonstrated efficacy of Letzit 5 mg once daily in patients 12 years of age and older based on the pharmacokinetic comparison between adults and children.

Cross-study comparisons indicate that administration of a 5 mg dose of Letzit to 6 to 12 year old pediatric patients resulted in about 2-fold the systemic exposure (AUC) observed when 5 mg of Letzit was administered to healthy adults. Therefore, in children 6 to 11 years of age the recommended dose of 2.5 mg once daily should not be exceeded. In a population pharmacokinetics study the administration of 1.25 mg once daily in children 6 months to 5 years of age resulted in systemic exposure comparable to 5 mg once daily in adults..

Geriatric Use

Clinical studies of Letzit for each approved indication did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Renal Impairment

Letzit is known to be substantially excreted by the kidneys and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

Hepatic Impairment

As levocetirizine is mainly excreted unchanged by the kidneys, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment.

Use of Letzit has been associated with somnolence, fatigue, asthenia, and urinary retention.

Clinical Trials Experience

The safety data described below reflect exposure to Letzit in 2708 patients with allergic rhinitis or chronic idiopathic urticaria in 14 controlled clinical trials of 1 week to 6 months duration.

The short-term (exposure up to 6 weeks) safety data for adults and adolescents are based upon eight clinical trials in which 1896 patients (825 males and 1071 females aged 12 years and older) were treated with Letzit 2.5, 5, or 10 mg once daily in the evening.

The short-term safety data from pediatric patients are based upon two clinical trials in which 243 children with allergic rhinitis (162 males and 81 females 6 to 12 years of age) were treated with Letzit 5 mg once daily for 4 to 6 weeks, one clinical trial in which 114 children (65 males and 49 females 1 to 5 years of age) with allergic rhinitis or chronic idiopathic urticaria were treated with Letzit 1.25 mg twice daily for 2 weeks, and one clinical trial in which 45 children (28 males and 17 females 6 to 11 months of age) with symptoms of allergic rhinitis or chronic urticaria were treated with Letzit 1.25 mg once daily for 2 weeks.

The long-term (exposure of 4 or 6 months) safety data in adults and adolescents are based upon two clinical trials in which 428 patients (190 males and 238 females) with allergic rhinitis were exposed to treatment with Letzit 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 Letzit-treated subjects 12-24 months of age.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

Adults And Adolescents 12 Years Of Age And Older

In studies up to 6 weeks in duration, the mean age of the adult and adolescent patients was 32 years, 44% of the patients were men and 56% were women, and the large majority (more than 90%) was Caucasian.

In these trials 43% and 42% of the subjects in the Letzit 2.5 mg and 5 mg groups, respectively, had at least one adverse event compared to 43% in the placebo group.

In placebo-controlled trials of 1-6 weeks in duration, the most common adverse reactions were somnolence, nasopharyngitis, fatigue, dry mouth, and pharyngitis, and most were mild to moderate in intensity. Somnolence with Letzit showed dose ordering between tested doses of 2.5, 5 and 10 mg and was the most common adverse reaction leading to discontinuation (0.5%).

Table 1 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 12 years and older exposed to Letzit 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with Letzit than placebo.

Table 1 Adverse Reactions Reported in ≥ 2%* of Subjects Aged 12 Years and Older Exposed to Letzit 2.5 mg or 5 mg Once Daily in Placebo-Controlled Clinical Trials 1-6 Weeks in Duration

Additional adverse reactions of medical significance observed at a higher incidence than in placebo in adults and adolescents aged 12 years and older exposed to Letzit are syncope (0.2%) and weight increased (0.5%).

Pediatric Patients 6 To 12 Years Of Age

A total of 243 pediatric patients 6 to 12 years of age received Letzit 5 mg once daily in two short-term placebo controlled double-blind trials. The mean age of the patients was 9.8 years, 79 (32%) were 6 to 8 years of age, and 50% were Caucasian. Table 2 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 6 to 12 years exposed to Letzit 5 mg in placebo-controlled clinical trials and that were more common with Letzit than placebo.

Table 2 Adverse Reactions Reported in ≥2%* of Subjects Aged 6-12 Years Exposed to Letzit 5 mg Once Daily in Placebo-Controlled Clinical Trials 4 and 6 Weeks in Duration

Pediatric Patients 1 To 5 Years Of Age

A total of 114 pediatric patients 1 to 5 years of age received Letzit 1.25 mg twice daily in a two week placebo-controlled double-blind safety trial. The mean age of the patients was 3.8 years, 32% were 1 to 2 years of age, 71% were Caucasian and 18% were Black. Table 3 lists adverse reactions that were reported in greater than or equal to 2% of subjects aged 1 to 5 years exposed to Letzit 1.25 mg twice daily in the placebo-controlled safety trial and that were more common with Letzit than placebo.

Table 3 Adverse Reactions Reported in ≥2%* of Subjects Aged 1-5 Years Exposed to Letzit 1.25 mg Twice Daily in a 2-Week Placebo-Controlled Clinical Trial

Pediatric Patients 6 To 11 Months Of Age

A total of 45 pediatric patients 6 to 11 months of age received Letzit 1.25 mg once daily in a two week placebo-controlled double-blind safety trial. The mean age of the patients was 9 months, 51% were Caucasian and 31% were Black. Adverse reactions that were reported in more than 1 subject (i.e. greater than or equal to 3% of subjects) aged 6 to 11 months exposed to Letzit 1.25 mg once daily in the placebo-controlled safety trial and that were more common with Letzit than placebo included diarrhea and constipation which were reported in 6 (13%) and 1 (4%) and 3 (7%) and 1 (4%) children in the Letzit and placebo-treated groups, respectively.

Long-Term Clinical Trials Experience

In two controlled clinical trials, 428 patients (190 males and 238 females) aged 12 years and older were treated with Letzit 5 mg once daily for 4 or 6 months. The patient characteristics and the safety profile were similar to that seen in the short-term studies. Ten (2.3%) patients treated with Letzit discontinued because of somnolence, fatigue or asthenia compared to 2 (<1%) in the placebo group.

There are no long term clinical trials in children below 12 years of age with allergic rhinitis or chronic idiopathic urticaria.

Laboratory Test Abnormalities

Elevations of blood bilirubin and transaminases were reported in <1% of patients in the clinical trials. The elevations were transient and did not lead to discontinuation in any patient.

Post-Marketing Experience

In addition to the adverse reactions reported during clinical trials and listed above, the following adverse reactions have also been identified during post-approval use of Letzit. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Cardiac disorders: palpitations, tachycardia
• Ear and labyrinth disorders: vertigo
• Eye disorders: blurred vision, visual disturbances
• Gastrointestinal disorders: nausea, vomiting
• General disorders and administration site conditions: edema
• Hepatobiliary disorders: hepatitis
• Immune system disorders: anaphylaxis and hypersensitivity
• Metabolism and nutrition disorders: increased appetite
• Musculoskeletal, connective tissues, and bone disorders: arthralgia, myalgia
• Nervous system disorders: dizziness, dysgeusia, febrile seizure, movement disorders (including dystonia and oculogyric crisis), paraesthesia, seizure (reported in subjects with and without a known seizure disorder), tremor
• Psychiatric disorders: aggression and agitation, depression, hallucinations, insomnia, nightmare, suicidal ideation
• Renal and urinary disorders: dysuria, urinary retention
• Respiratory, thoracic, and mediastinal disorders: dyspnea
• Skin and subcutaneous tissue disorders: angioedema, fixed drug eruption, pruritus, rash and urticaria

Besides these reactions reported under treatment with Letzit, other potentially severe adverse events have been reported from the post-marketing experience with cetirizine. Since levocetirizine is the principal pharmacologically active component of cetirizine, one should take into account the fact that the following adverse events could also potentially occur under treatment with Letzit.

• Cardiac disorders: severe hypotension
• Gastrointestinal disorders: cholestasis
• Nervous system disorders: extrapyramidal symptoms, myoclonus, orofacial dyskinesia, tic
• Pregnancy, puerperium and perinatal conditions: stillbirth
• Renal and urinary disorders: glomerulonephritis
• Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis (AGEP)

Un surdosage a été signalé avec Letzit.

Les symptômes d'un surdosage peuvent inclure une somnolence chez l'adulte. Chez les enfants, l'agitation et l'agitation peuvent initialement se produire, suivies de somnolence. Il n'y a pas d'antidote spécifique connu à Letzit. En cas de surdosage, un traitement symptomatique ou de soutien est recommandé. Letzit n'est pas efficacement éliminé par dialyse, et la dialyse sera inefficace à moins qu'un agent dialysable n'ait été ingéré de manière concomitante.

La dose orale maximale aiguë non létale de lévocétirizine était de 240 mg / kg chez la souris (environ 190 fois la dose orale quotidienne maximale recommandée chez l'adulte, environ 230 fois la dose orale quotidienne maximale recommandée chez les enfants de 6 à 11 ans, et environ 180 fois la dose orale quotidienne maximale recommandée chez les enfants de 6 mois à 5 ans en mg / m² base). Chez le rat, la dose orale maximale non létale était de 240 mg / kg (environ 390 fois la dose orale quotidienne maximale recommandée chez l'adulte, environ 460 fois la dose orale quotidienne maximale recommandée chez les enfants de 6 à 11 ans, et environ 370 fois la dose orale quotidienne maximale recommandée chez les enfants de 6 mois à 5 ans en mg / m² base).

Des études chez des sujets sains adultes ont montré que la lévocétirizine à des doses de 2,5 mg et 5 mg inhibait la flore et la desquamation cutanées causées par l'injection intradermique d'histamine. En revanche, la dextrocetirizine n'a montré aucun changement clair dans l'inhibition de la réaction de la papule et de la fusée. La lévocétirizine à une dose de 5 mg a inhibé la lactosérum et l'éruption causées par l'injection intradermique d'histamine chez 14 sujets pédiatriques (âgés de 6 à 11 ans) et l'activité a persisté pendant au moins 24 heures. La pertinence clinique des tests cutanés de l'histamine sur la peau est inconnue.

Une étude QT / QTc utilisant une dose unique de 30 mg de lévocétirizine n'a pas démontré d'effet sur l'intervalle QTc. Bien qu'une dose unique de lévocétirizine n'ait eu aucun effet, les effets de la lévocétirizine peuvent ne pas être à l'état d'équilibre après une dose unique. L'effet de la lévocétirizine sur l'intervalle QTc après l'administration de doses multiples est inconnu. La lévocétirizine ne devrait pas avoir d'effets QT / QTc en raison des résultats des études QTc avec la cétirizine et de la longue histoire post-commercialisation de la cétirizine sans rapports d'allongement de l'intervalle QT.

La lévocétirizine a présenté une pharmacocinétique linéaire sur la plage de doses thérapeutiques chez les sujets sains adultes.

Absorption

La lévocétirizine est rapidement et largement absorbée après administration orale. Chez l'adulte, les concentrations plasmatiques maximales sont atteintes 0,9 heure après l'administration du comprimé oral. Le taux d'accumulation après administration orale quotidienne est de 1,12 avec un état d'équilibre atteint après 2 jours. Les concentrations maximales sont généralement de 270 ng / ml et 308 ng / ml après une dose unique et répétée de 5 mg une fois par jour, respectivement. Les aliments n'ont eu aucun effet sur l'étendue de l'exposition (ASC) du comprimé de lévocétirizine, mais le Tmax a été retardé d'environ 1,25 heure et la Cmax a diminué d'environ 36% après l'administration avec un repas riche en graisses; par conséquent, la lévocétirizine peut être administrée avec ou sans nourriture.

Une dose de 5 mg (10 ml) de solution buvable de Letzit est bioéquivalente à une dose de 5 mg de comprimés de Letzit. Après administration orale d'une dose de 5 mg de solution buvable de Letzit à des sujets adultes en bonne santé, les concentrations plasmatiques maximales moyennes ont été atteintes environ 0,5 heure après l'administration.

Distribution

La liaison moyenne aux protéines plasmatiques de la lévocétirizine in vitro variait de 91 à 92%, indépendamment de la concentration dans la plage de 90 à 5000 ng / ml, qui comprend les taux plasmatiques thérapeutiques observés. Après administration orale, le volume de distribution apparent moyen est d'environ 0,4 L / kg, représentatif de la distribution dans l'eau corporelle totale.

Métabolisme

L'étendue du métabolisme de la lévocétirizine chez l'homme est inférieure à 14% de la dose et, par conséquent, les différences résultant du polymorphisme génétique ou de l'apport concomitant d'inhibiteurs de l'enzyme de métabolisation hépatique devraient être négligeables. Les voies métaboliques comprennent l'oxydation aromatique, la N-et O-désalkylation et la conjugaison de la taurine. Les voies de désalkylation sont principalement médiées par le CYP 3A4 tandis que l'oxydation aromatique implique des isoformes CYP multiples et / ou non identifiées.

Élimination

La demi-vie plasmatique chez les sujets sains adultes était d'environ 8 à 9 heures après l'administration des comprimés oraux et de la solution buvable, et la clairance corporelle totale orale moyenne de la lévocétirizine était d'environ 0,63 ml / kg / min. La principale voie d'excrétion de la lévocétirizine et de ses métabolites est l'urine, représentant une moyenne de 85,4% de la dose. L'excrétion par les matières fécales ne représente que 12,9% de la dose. La lévocétirizine est excrétée à la fois par filtration glomérulaire et sécrétion tubulaire active. La clairance rénale de la lévocétirizine est en corrélation avec celle de la clairance de la créatinine. Chez les patients atteints d'insuffisance rénale, la clairance de la lévocétirizine est réduite.