Giazo

COLAZAL está indicado no tratamento de colite ulcerativa leve a moderadamente ativa em pacientes com 5 anos de idade ou mais. A segurança e eficácia do COLAZAL além de 8 semanas em crianças (de 5 a 17 anos) e 12 semanas em adultos não foram estabelecidas.

Dose adulta

Para o tratamento da colite ulcerativa ativa em pacientes adultos, a dose usual é de três cápsulas de 750 mg COLAZAL a serem tomadas 3 vezes ao dia (6,75 g por dia) por até 8 semanas. Alguns pacientes nos ensaios clínicos em adultos necessitaram de tratamento por até 12 semanas.

Dose pediátrica

Para o tratamento da colite ulcerativa ativa em pacientes pediátricos, com idades entre 5 e 17 anos, a dose habitual é SE :

• três cápsulas de 750 mg de COLAZAL 3 vezes ao dia (6,75 g por dia) por até 8 semanas; OU:
• uma cápsula de 750 mg de COLAZAL 3 vezes ao dia (2,25 g por dia) por até 8 semanas.

O uso de COLAZAL na população pediátrica por mais de 8 semanas não foi avaliado em ensaios clínicos.

Alternativas de administração

As cápsulas COLAZAL também podem ser administradas abrindo cuidadosamente a cápsula e aspergindo o conteúdo da cápsula em molho de maçã. Toda a mistura de droga / molho de maçã deve ser engolida imediatamente; o conteúdo pode ser mastigado, se necessário, uma vez que o conteúdo de COLAZAL NÃO é revestido de miçangas / grânulos. Os pacientes devem ser instruídos a não armazenar nenhuma mistura de medicamento / molho de maçã para uso futuro.

Se as cápsulas forem abertas para aspersão, a variação de cor do pó dentro das cápsulas varia de laranja a amarelo e é esperada devido à variação de cor do ingrediente farmacêutico ativo.

Dentes e / ou coloração da língua podem ocorrer em alguns pacientes que usam COLAZAL na forma de polvilha com alimentos.

Pacientes com hipersensibilidade a salicilatos ou a qualquer um dos componentes de cápsulas COLAZAL ou metabolitos de balsalazida. As reações de hipersensibilidade podem incluir, entre outras: anafilaxia, broncoespasmo e reação da pele.

AVISO

Incluído como parte do PRECAUÇÕES seção.

PRECAUÇÕES

Exacerbações da colite ulcerativa

Nos ensaios clínicos em adultos, 3 em cada 259 pacientes relataram exacerbação dos sintomas da colite ulcerativa. Nos ensaios clínicos pediátricos, 4 em 68 pacientes relataram exacerbação dos sintomas da colite ulcerativa.

Observe atentamente os pacientes quanto ao agravamento desses sintomas durante o tratamento.

Estenose pilórica

Pacientes com estenose pilórica podem ter retenção gástrica prolongada de cápsulas COLAZAL.

Renal

Toxicidade renal foi observada em animais e pacientes que receberam outros produtos de mesalamina. Portanto, deve-se ter cautela ao administrar COLAZAL a pacientes com disfunção renal conhecida ou histórico de doença renal.

Toxicologia Não Clínica

Carcinogênese, Mutagênese, Comprometimento de Fertilidade

Num estudo de carcinogenicidade em ratos de 24 meses (Sprague Dawley), a balsalazida oral (dietética) dissódica em doses de até 2 g / kg / dia não foi tumorigênica. Para uma pessoa de 50 kg de altura média, esta dose representa 2,4 vezes a dose humana recomendada em uma área de superfície corporal. A balsalazida dissódica não foi genotóxica a seguir in vitro ou testes in vivo: teste de Ames, teste de aberração cromossômica de linfócitos humanos e teste de mutação para frente de células de linfoma de camundongo (L5178Y / TK +/-) ou teste de micronúcleo de camundongo. No entanto, foi genotóxico no in vitro Teste de mutação para frente de células pulmonares de hamster chinês (CH V79 / HGPRT).

O 4-aminobenzoil-s-alanina, um metabólito da balsalazida dissódica, não foi genotóxico no teste de Ames e na célula de linfoma de camundongo (L5178Y / TK + / -) teste de mutação para a frente, mas foi positivo no teste de aberração cromossômica de linfócitos humanos. O N-acetil-4-aminobenzoil-ß-alanina, um metabólito conjugado da balsalazida dissódica, não foi genotóxico no teste de Ames, na célula de linfoma de camundongo (L5178Y / TK + / -) no teste de mutação para a frente ou no teste de aberração cromossômica de linfócitos humanos. Verificou-se que a balsalazida dissódica em doses orais de até 2 g / kg / dia, 2,4 vezes a dose humana recomendada com base na área da superfície corporal, não afeta a fertilidade e o desempenho reprodutivo em ratos.

Use em populações específicas

Gravidez

Categoria de gravidez B

Estudos de reprodução foram realizados em ratos e coelhos em doses orais de até 2 g / kg / dia, 2,4 e 4,7 vezes a dose humana recomendada com base na área da superfície corporal para ratos e coelhos, respectivamente, e não revelou evidência de fertilidade prejudicada ou dano ao feto devido à bálsalazida dissódica. No entanto, não existem estudos adequados e bem controlados em mulheres grávidas. Como os estudos de reprodução animal nem sempre são preditivos da resposta humana, este medicamento deve ser usado durante a gravidez somente se for claramente necessário.

Mães de enfermagem

Não se sabe se a balsalazida dissódica é excretada no leite humano. Como muitos medicamentos são excretados no leite humano, deve-se ter cautela quando COLAZAL é administrado a uma mulher que amamenta.

Uso pediátrico

O uso de COLAZAL em pacientes pediátricos e adolescentes de 5 a 17 anos de idade para o tratamento de colite ulcerativa leve a moderadamente ativa é suportado por :

• extrapolação dos resultados de estudos clínicos que apoiaram a aprovação do COLAZAL para adultos.
• um ensaio clínico de 68 pacientes com idades entre 5 e 17 anos comparando duas doses de COLAZAL (6,75 g / dia e 2,25 g / dia) e
• um estudo farmacocinético realizado em um subconjunto da população do estudo pediátrico..

Com base nos dados limitados disponíveis, a dosagem pode ser iniciada em 6,75 ou 2,25 g / dia.

A segurança e eficácia de COLAZAL em pacientes pediátricos com menos de 5 anos de idade não foram estabelecidas.

Clinical Studies Experience

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

Adult Ulcerative Colitis

During clinical development, 259 adult patients with active ulcerative colitis were exposed to 6.75 g/day COLAZAL in 4 controlled trials.

In the 4 controlled clinical trials patients receiving a COLAZAL dose of 6.75 g/day most frequently reported the following adverse reactions: headache (8%), abdominal pain (6%), diarrhea (5%), nausea (5%), vomiting (4%), respiratory infection (4%), and arthralgia (4%). Withdrawal from therapy due to adverse reactions was comparable among patients on COLAZAL and placebo.

Adverse reactions reported by 1% or more of patients who participated in the 4 well-controlled, Phase 3 trials are presented by treatment group (Table 1).

The number of placebo patients (35), however, is too small for valid comparisons. Some adverse reactions, such as abdominal pain, fatigue, and nausea were reported more frequently in women than in men. Abdominal pain, rectal bleeding, and anemia can be part of the clinical presentation of ulcerative colitis.

Table 1: Adverse Reactions Occurring in ≥ 1% of Adult COLAZAL Patients in Controlled Trials*

Pediatric Ulcerative Colitis

In a clinical trial in 68 pediatric patients aged 5 to 17 years with mildly to moderately active ulcerative colitis who received 6.75 g/day or 2.25 g/day COLAZAL for 8 weeks, the most frequently reported adverse reactions were headache (15%), abdominal pain upper (13%), abdominal pain (12%), vomiting (10%), diarrhea (9%), colitis ulcerative (6%), nasopharyngitis (6%), and pyrexia (6%).

One patient who received COLAZAL 6.75 g/day and 3 patients who received COLAZAL 2.25 g/ day discontinued treatment because of adverse reactions. In addition, 2 patients in each dose group discontinued because of a lack of efficacy.

Adverse reactions reported by 3% or more of pediatric patients within either treatment group in the Phase 3 trial are presented in Table 2.

Table 2: Treatment-Emergent Adverse Reactions Reported by ≥ 3% of Patients in Either Treatment Group in a Controlled Study of 68 Pediatric Patients

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of balsalazide in clinical practice:

myocarditis, pericarditis, vasculitis, pruritus, pleural effusion, pneumonia (with and without eosinophilia), alveolitis, renal failure, interstitial nephritis, pancreatitis, and alopecia.

Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to balsalazide.

Hepatic

Postmarketing adverse reactions of hepatotoxicity have been reported for products which contain (or are metabolized to) mesalamine, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal; however, no fatalities associated with these adverse reactions were reported in COLAZAL clinical trials. One case of Kawasaki-like syndrome which included hepatic function changes was also reported, however, this adverse reaction was not reported in COLAZAL clinical trials.

Nenhum caso de sobredosagem ocorreu com o COLAZAL. É relatado que um menino de 3 anos ingeriu 2 g de outro produto de mesalamina. Ele foi tratado com ipecac e carvão ativado sem reações adversas.

Se ocorrer uma overdose com COLAZAL, o tratamento deve ser favorável, com atenção especial à correção de anormalidades eletrolíticas.

COLAZAL capsules contain a powder of balsalazide disodium that is insoluble in acid and designed to be delivered to the colon as the intact prodrug. Upon reaching the colon, bacterial azoreductases cleave the compound to release 5-ASA, the therapeutically active portion of the molecule, and 4-aminobenzoyl-ß-alanine. The 5-ASA is further metabolized to yield N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), a second key metabolite.

Absorption

The plasma pharmacokinetics of balsalazide and its key metabolites from a crossover study in healthy volunteers are summarized in Table 3. In this study, a single oral dose of COLAZAL 2.25 g was administered to healthy volunteers as intact capsules (3 x 750 mg) under fasting conditions, as intact capsules (3 x 750 mg) after a high-fat meal, and unencapsulated (3 x 750 mg) as sprinkles on applesauce.

Table 3: Plasma Pharmacokinetics for Balsalazide and Key Metabolites (5—ASA and N-Ac-5- ASA) with Administration of COLAZAL Following a Fast, a High-Fat Meal, and Drug Contents Sprinkled on Applesauce (Mean ± SD)

A relatively low systemic exposure was observed under all three administered conditions (fasting, fed with high-fat meal, sprinkled on applesauce), which reflects the variable, but minimal absorption of balsalazide disodium and its metabolites. The data indicate that both Cmax and AUClast were lower, while tmax was markedly prolonged, under fed (high-fat meal) compared to fasted conditions. Moreover, the data suggest that dosing balsalazide disodium as a sprinkle or as a capsule provides highly variable, but relatively similar mean pharmacokinetic parameter values. No inference can be made as to how the systemic exposure differences of balsalazide and its metabolites in this study might predict the clinical efficacy under different dosing conditions (i.e., fasted, fed with high-fat meal, or sprinkled on applesauce) since clinical efficacy after balsalazide disodium administration is presumed to be primarily due to the local effects of 5-ASA on the colonic mucosa.

In a separate study of adult patients with ulcerative colitis, who received balsalazide, 1.5 g twice daily, for over 1 year, systemic drug exposure, based on mean AUC values, was up to 60 times greater (0.008 μg•hr/mL to 0.480 μg•hr/mL) when compared to that obtained in healthy subjects who received the same dose.

Distribution

The binding of balsalazide to human plasma proteins was ≥ 99%.

Metabolism

The products of the azoreduction of this compound, 5-ASA and 4-aminobenzoyl-ß-alanine, and their N-acetylated metabolites have been identified in plasma, urine and feces.

Elimination

Following single-dose administration of 2.25 g COLAZAL (three 750 mg capsules) under fasting conditions in healthy subjects, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.20%, 0.22% and 10.2%, respectively.

In a multiple-dose study in healthy subjects receiving a COLAZAL dose of two 750 mg capsules twice daily (3 g/day) for 10 days, mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.1%, 0%, and 11.3%, respectively. During this study, subjects received their morning dose 0.5 hours after being fed a standard meal, and subjects received their evening dose 2 hours after being fed a standard meal.

In a study with 10 healthy volunteers, 65% of a single 2.25-gram dose of COLAZAL was recovered as 5-ASA, 4-aminobenzoyl-ß-alanine, and the N-acetylated metabolites in feces, while < 1% of the dose was recovered as parent compound.

In a study that examined the disposition of balsalazide in patients who were taking 3-6 g of COLAZAL daily for more than 1 year and who were in remission from ulcerative colitis, less than 1% of an oral dose was recovered as intact balsalazide in the urine. Less than 4% of the dose was recovered as 5-ASA, while virtually no 4-aminobenzoyl-ß-alanine was detected in urine. The mean urinary recovery of N-Ac-5-ASA and N-acetyl-4-aminobenzoyl-s-alanine comprised < 16% and < 12% of the balsalazide dose, respectively. No fecal recovery studies were performed in this population.

Pediatric Population

In studies of pediatric patients with mild-to-moderate active ulcerative colitis receiving three 750 mg COLAZAL capsules 3 times daily (6.75 g/day) for 8 weeks, steady state was reached within 2 weeks, as observed in adult patients. Likewise, the pharmacokinetics of balsalazide, 5-ASA, and N-Ac-5-ASA were characterized by very large inter-patient variability, which is also similar to that seen in adult patients.

The pro-drug moiety, balsalazide, appeared to exhibit dose-independent (i.e., dose-linear) kinetics in children, and the systemic exposure parameters (Cmax and AUC0-8) increased in an almost dose-proportional fashion after the 6.75 g/day versus the 2.25 g/day doses. However, the absolute magnitude of these exposure parameters was greater relative to adults. The Cmax and AUC0-8 observed in pediatric patients were 26% and 102% greater than those observed in adult patients at the 6.75 g/ day dosage level. In contrast, the systemic exposure parameters for the active metabolites, 5-ASA and N-Ac-5-ASA, in pediatric patients increased in a less than dose-proportional manner after the 6.75 g/ day dose versus the 2.25 g/day dose. Additionally, the magnitude of these exposure parameters was decreased for both metabolites relative to adults. For the metabolite of key safety concern from a systemic exposure perspective, 5-ASA, the Cmax and AUC0-8 observed in pediatric patients were 67% and 64% lower than those observed in adult patients at the 6.75 g/day dosage level. Likewise, for N-Ac-5-ASA, the Cmax and AUC0-8 observed in pediatric patients were 68% and 55% lower than those observed in adult patients at the 6.75 g/day dosage level.

All pharmacokinetic studies with COLAZAL are characterized by large variability in the plasmaconcentration versus time profiles for balsalazide and its metabolites, thus half-life estimates of these analytes are indeterminate.