Cezera

Rinite alérgica perene

Cezera é indicado para o alívio dos sintomas associados à rinite alérgica perene em crianças de 6 meses a 2 anos de idade.

Urticária idiopática crônica

Cezera é indicado para o tratamento das manifestações cutâneas não complicadas da urticária idiopática crônica em adultos e crianças com 6 meses de idade ou mais.

Cezera está disponível em solução oral de 2,5 mg / 5 mL (0,5 mg / mL) e em comprimidos quebráveis de 5 mg (pontuados), permitindo a administração de 2,5 mg, se necessário. Cezera pode ser tomado sem levar em consideração o consumo de alimentos.

Rinite alérgica perene

Crianças de 6 meses a 2 anos de idade

A dose inicial recomendada de Cezera é de 1,25 mg (solução oral de 1/2 colher de chá) [2,5 ml] uma vez ao dia à noite. A dose de 1,25 mg uma vez ao dia não deve ser excedida com base na exposição comparável a adultos que recebem 5 mg.

Urticária idiopática crônica

Adultos e crianças com 12 anos de idade e mais

A dose recomendada de Cezera é de 5 mg (1 comprimido ou 2 colheres de chá [10 mL] solução oral) uma vez ao dia à noite. Alguns pacientes podem ser adequadamente controlados por 2,5 mg (1/2 comprimido ou 1 colher de chá [5 mL] de solução oral) uma vez ao dia à noite.

Crianças de 6 a 11 anos de idade

A dose recomendada de Cezera é de 2,5 mg (1/2 comprimido ou 1 colher de chá [5 mL] solução oral) uma vez ao dia à noite. A dose de 2,5 mg não deve ser excedida porque a exposição sistêmica com 5 mg é aproximadamente o dobro da dos adultos.

Crianças de 6 meses a 5 anos de idade

A dose inicial recomendada de Cezera é de 1,25 mg (solução oral de 1/2 colher de chá) [2,5 ml] uma vez ao dia à noite. A dose de 1,25 mg uma vez ao dia não deve ser excedida com base na exposição comparável a adultos que recebem 5 mg.

Ajuste da dose para comprometimento renal e hepático

Em adultos e crianças com 12 anos de idade ou mais com:

• Insuficiência renal leve (depuração da creatinina [CL_CR] = 50-80 mL / min): recomenda-se uma dose de 2,5 mg uma vez ao dia;
• Compromisso renal moderado (CL_CR = 30-50 mL / min): recomenda-se uma dose de 2,5 mg uma vez a cada dois dias;
• Insuficiência renal grave (CL_CR = 10-30 mL / min): recomenda-se uma dose de 2,5 mg duas vezes por semana (administrada uma vez a cada 3-4 dias);
• Pacientes com doença renal em estágio terminal (CL_CR <10 mL / min) e pacientes em hemodiálise não devem receber Cezera.

Não é necessário ajuste da dose em doentes com compromisso hepático. Em doentes com compromisso hepático e compromisso renal, recomenda-se o ajuste da dose.

O uso de Cezera está contra-indicado em :

Pacientes com hipersensibilidade conhecida

Pacientes com hipersensibilidade conhecida à levocetirizina ou a qualquer um dos ingredientes de Cezera ou à cetirizina. As reações observadas variam de urticária a anafilaxia.

Pacientes com doença renal em estágio terminal

Pacientes com doença renal em estágio terminal (CL_CR <10 mL / min) e pacientes em hemodiálise

Pacientes pediátricos com função renal prejudicada

Crianças de 6 meses a 11 anos de idade com insuficiência renal

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 Cezera. 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 Cezera. Concurrent use of Cezera 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 Cezera. Cezera should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as Cezera may increase the risk of urinary retention. Discontinue Cezera 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 Cezera 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, Cezera 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 Cezera in nursing mothers is not recommended.

Pediatric Use

The recommended dose of Cezera 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 Cezera 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 Cezera in adults and pediatric patients and on the safety profile of Cezera 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 Cezera 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 Cezera 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 Cezera 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 Cezera 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 Cezera 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 Cezera to 6 to 12 year old pediatric patients resulted in about 2-fold the systemic exposure (AUC) observed when 5 mg of Cezera 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 Cezera 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

Cezera 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 Cezera has been associated with somnolence, fatigue, asthenia, and urinary retention.

Clinical Trials Experience

The safety data described below reflect exposure to Cezera 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 Cezera 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 Cezera 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 Cezera 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 Cezera 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 Cezera 5 mg once daily. Long term safety data are also available from an 18-month trial in 255 Cezera-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 Cezera 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 Cezera 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 Cezera 2.5 mg or 5 mg in eight placebo-controlled clinical trials and that were more common with Cezera than placebo.

Table 1 Adverse Reactions Reported in ≥ 2%* of Subjects Aged 12 Years and Older Exposed to Cezera 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 Cezera 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 Cezera 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 Cezera 5 mg in placebo-controlled clinical trials and that were more common with Cezera than placebo.

Table 2 Adverse Reactions Reported in ≥2%* of Subjects Aged 6-12 Years Exposed to Cezera 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 Cezera 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 Cezera 1.25 mg twice daily in the placebo-controlled safety trial and that were more common with Cezera than placebo.

Table 3 Adverse Reactions Reported in ≥2%* of Subjects Aged 1-5 Years Exposed to Cezera 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 Cezera 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 Cezera 1.25 mg once daily in the placebo-controlled safety trial and that were more common with Cezera than placebo included diarrhea and constipation which were reported in 6 (13%) and 1 (4%) and 3 (7%) and 1 (4%) children in the Cezera 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 Cezera 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 Cezera 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 Cezera. 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 Cezera, 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 Cezera.

• 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)

Sobredosagem foi relatada com Cezera.

Os sintomas de sobredosagem podem incluir sonolência em adultos. Nas crianças, agitação e inquietação podem ocorrer inicialmente, seguidas de sonolência. Não existe antídoto específico conhecido para Cezera. Caso ocorra sobredosagem, recomenda-se tratamento sintomático ou de suporte. A cezera não é efetivamente removida por diálise e a diálise será ineficaz, a menos que um agente dialisável tenha sido ingerido concomitantemente.

A dose oral máxima aguda não letal de levocetirizina foi de 240 mg / kg em camundongos (aproximadamente 190 vezes a dose oral diária máxima recomendada em adultos, aproximadamente 230 vezes a dose oral diária máxima recomendada em crianças de 6 a 11 anos de idade, e aproximadamente 180 vezes a dose oral diária máxima recomendada em crianças de 6 meses a 5 anos de idade em mg / m² base). Em ratos, a dose oral não letal máxima foi de 240 mg / kg (aproximadamente 390 vezes a dose oral diária máxima recomendada em adultos, aproximadamente 460 vezes a dose oral diária máxima recomendada em crianças de 6 a 11 anos de idade, e aproximadamente 370 vezes a dose oral diária máxima recomendada em crianças de 6 meses a 5 anos de idade em mg / m² base).

Estudos em indivíduos saudáveis adultos mostraram que a levocetirizina em doses de 2,5 mg e 5 mg inibiu o soro e o reflexo da pele causados pela injeção intradérmica de histamina. Por outro lado, a dextrocetirizina não exibiu uma mudança clara na inibição da reação do soro e da chama. A levocetirizina na dose de 5 mg inibiu o soro e o surto causados pela injeção intradérmica de histamina em 14 indivíduos pediátricos (de 6 a 11 anos) e a atividade persistiu por pelo menos 24 horas. A relevância clínica dos testes cutâneos da histamina é desconhecida.

Um estudo de QT / QTc usando uma dose única de 30 mg de levocetirizina não demonstrou um efeito no intervalo QTc. Embora uma dose única de levocetirizina não tenha efeito, os efeitos da levocetirizina podem não estar em estado estacionário após dose única. O efeito da levocetirizina no intervalo QTc após a administração de doses múltiplas é desconhecido. Não se espera que a levocetirizina tenha efeitos QT / QTc devido aos resultados de estudos de QTc com cetirizina e à longa história pós-comercialização da cetirizina sem relatos de prolongamento do intervalo QT.

A levocetirizina exibiu farmacocinética linear no intervalo de doses terapêuticas em indivíduos saudáveis adultos.

Absorção

A levocetirizina é rápida e extensamente absorvida após administração oral. Nos adultos, as concentrações plasmáticas máximas são atingidas 0,9 horas após a administração do comprimido oral. A taxa de acumulação após administração oral diária é de 1,12, com estado estacionário alcançado após 2 dias. As concentrações máximas são tipicamente 270 ng / mL e 308 ng / mL após uma dose única e repetida de 5 mg uma vez ao dia, respectivamente. Os alimentos não tiveram efeito na extensão da exposição (AUC) do comprimido de levocetirizina, mas a Tmax foi adiada em cerca de 1,25 horas e a Cmax diminuiu cerca de 36% após a administração com uma refeição rica em gordura; portanto, a levocetirizina pode ser administrada com ou sem alimentos.

Uma dose de 5 mg (10 mL) de solução oral de Cezera é bioequivalente a uma dose de 5 mg de comprimidos de Cezera. Após administração oral de uma dose de 5 mg de solução oral de Cezera a indivíduos adultos saudáveis, as concentrações plasmáticas máximas médias foram atingidas aproximadamente 0,5 horas após a dose.

Distribuição

A ligação média às proteínas plasmáticas da levocetirizina in vitro variou de 91 a 92%, independentemente da concentração na faixa de 90-5000 ng / mL, o que inclui os níveis plasmáticos terapêuticos observados. Após a administração oral, o volume aparente médio de distribuição é de aproximadamente 0,4 L / kg, representativo da distribuição na água corporal total.

Metabolismo

A extensão do metabolismo da levocetirizina em humanos é inferior a 14% da dose e, portanto, espera-se que as diferenças resultantes do polimorfismo genético ou da ingestão concomitante de inibidores da enzima metabolizadora de medicamentos hepáticos sejam insignificantes. As vias metabólicas incluem oxidação aromática, N-e O-desalquilação e conjugação de taurina. As vias de desalquilação são mediadas principalmente pelo CYP 3A4, enquanto a oxidação aromática envolve múltiplas isoformas do CYP não identificadas e / ou não identificadas.

Eliminação

A meia-vida plasmática em indivíduos saudáveis adultos foi de cerca de 8 a 9 horas após a administração de comprimidos orais e solução oral, e a depuração corporal total oral média para levocetirizina foi de aproximadamente 0,63 mL / kg / min. A principal via de excreção de levocetirizina e seus metabólitos é via urina, representando uma média de 85,4% da dose. A excreção através das fezes representa apenas 12,9% da dose. A levocetirizina é excretada tanto pela filtração glomerular quanto pela secreção tubular ativa. A depuração renal da levocetirizina correlaciona-se com a da depuração da creatinina. Em doentes com compromisso renal, a depuração da levocetirizina é reduzida.