Motidin

A injeção de motidina, fornecida como solução concentrada para injeção intravenosa, destina-se apenas ao uso intravenoso. A injeção de motidina é indicada em alguns pacientes hospitalizados com condições hipersecretórias patológicas ou úlceras intratáveis, ou como alternativa às formas de dosagem oral para uso a curto prazo em pacientes que não conseguem tomar medicação oral nas seguintes condições :

1. Tratamento a curto prazo da úlcera duodenal ativa. A maioria dos pacientes adultos cura dentro de 4 semanas; raramente há motivos para usar Motidin em doses completas por mais de 6 a 8 semanas. Estudos não avaliaram a segurança da Motidin na úlcera duodenal ativa não complicada por períodos superiores a 8 semanas.
2. Terapia de manutenção para pacientes com úlcera duodenal em dose reduzida após a cicatrização de uma úlcera ativa. Estudos controlados em adultos não se estenderam além de um ano.
3. Tratamento a curto prazo da úlcera gástrica benigna ativa. A maioria dos pacientes adultos cura dentro de 6 semanas. Estudos não avaliaram a segurança ou eficácia de Motidin na úlcera gástrica benigna ativa não complicada por períodos superiores a 8 semanas.
4. Tratamento a curto prazo da doença do refluxo gastroesofágico (DRGE). Motidin é indicado para tratamento a curto prazo de pacientes com sintomas de DRGE (ver FARMACOLOGIA CLÍNICA EM ADULTOS, Estudos Clínicos).
   A motidina também é indicada para o tratamento a curto prazo da esofagite devido à DRGE, incluindo doença erosiva ou ulcerativa diagnosticada por endoscopia (ver FARMACOLOGIA CLÍNICA EM ADULTOS, Estudos Clínicos).
5. Tratamento de condições hipersecretárias patológicas (por exemplo,.Síndrome de Zollinger-Ellison, múltiplos adenomas endócrinos) (Vejo FARMACOLOGIA CLÍNICA EM ADULTOS, Estudos Clínicos).

Motidin é indicado em :

1. Tratamento a curto prazo da úlcera duodenal ativa. A maioria dos pacientes adultos cura dentro de 4 semanas; raramente há motivos para usar Motidin em doses completas por mais de 6 a 8 semanas. Estudos não avaliaram a segurança da famotidina na úlcera duodenal ativa não complicada por períodos superiores a oito semanas.
2. Terapia de manutenção para pacientes com úlcera duodenal em dose reduzida após a cicatrização de uma úlcera ativa. Estudos controlados em adultos não se estenderam além de um ano.
3. Tratamento a curto prazo da úlcera gástrica benigna ativa. A maioria dos pacientes adultos cura dentro de 6 semanas. Estudos não avaliaram a segurança ou eficácia da famotidina na úlcera gástrica benigna ativa não complicada por períodos superiores a 8 semanas.
4. Tratamento a curto prazo da doença do refluxo gastroesofágico (DRGE). Motidin é indicado para tratamento a curto prazo de pacientes com sintomas de DRGE (ver FARMACOLOGIA CLÍNICA em adultos, Estudos clínicos).
   A motidina também é indicada para o tratamento a curto prazo da esofagite devido à DRGE, incluindo doença erosiva ou ulcerativa diagnosticada por endoscopia (ver FARMACOLOGIA CLÍNICA em adultos, Estudos clínicos).
5. Tratamento de condições hipersecretárias patológicas (por exemplo.Síndrome de Zollinger-Ellison, múltiplos adenomas endócrinos) (ver FARMACOLOGIA CLÍNICA em adultos, Estudos clínicos).

Em alguns pacientes hospitalizados com condições hipersecretórias patológicas ou úlceras intratáveis, ou em pacientes que não conseguem tomar medicação oral, a injeção de Motidin pode ser administrada até que a terapia oral possa ser instituída.

A dose recomendada para injeção de Motidin em pacientes adultos é de 20 mg por via intravenosa a 12 h.

As doses e o regime de administração parenteral em pacientes com DRGE não foram estabelecidos.

Dosagem para pacientes pediátricos

Vejo PRECAUÇÕES, Uso pediátrico.

Os estudos descritos em PRECAUÇÕES, Uso pediátrico sugira que a dose inicial em pacientes pediátricos de 1 a 16 anos de idade seja de 0,25 mg / kg por via intravenosa (injetada por um período não inferior a dois minutos ou como uma infusão de 15 minutos) q 12 h até 40 mg / dia.

Embora estudos clínicos não controlados publicados sugiram a eficácia do Motidin no tratamento da úlcera péptica, os dados em pacientes pediátricos são insuficientes para estabelecer a porcentagem de resposta com a dose e a duração da terapia. Portanto, a duração do tratamento (inicialmente com base nas recomendações de duração do adulto) e a dose devem ser individualizadas com base na resposta clínica e / ou determinação e endoscopia gástrica do pH. Estudos não controlados publicados em pacientes pediátricos demonstraram supressão do ácido gástrico com doses de até 0,5 mg / kg por via intravenosa a q 12 h.

Não existem dados farmacocinéticos ou farmacodinâmicos disponíveis em doentes pediátricos com menos de 1 ano de idade.

Ajustes de dosagem para pacientes com insuficiência renal moderada ou grave

Em pacientes adultos com insuficiência renal moderada (depuração da creatinina <50 mL / min) ou grave (depuração da creatinina <10 mL / min), a meia-vida de eliminação da Motidin é aumentada. Para pacientes com insuficiência renal grave, pode exceder 20 horas, atingindo aproximadamente 24 horas em pacientes anúricos. Desde que os efeitos adversos do SNC foram relatados em pacientes com insuficiência renal moderada e grave, evitar o acúmulo excessivo do medicamento em pacientes com insuficiência renal moderada ou grave, a dose da injeção de Motidin pode ser reduzida para metade da dose, ou o intervalo de dosagem pode ser prolongado para 36 a 48 horas, conforme indicado pela resposta clínica do paciente..

Com base na comparação dos parâmetros farmacocinéticos da Motidin em adultos e pacientes pediátricos, deve-se considerar o ajuste da dose em pacientes pediátricos com insuficiência renal moderada ou grave.

Condições Hipersecretoras Patológicas (por exemplo,.Síndrome de Zollinger-Ellison, Adenomas Endócrinos Múltiplos)

A dose de Motidin em pacientes com condições hipersecretárias patológicas varia de acordo com o paciente individual. A dose intravenosa recomendada para adultos é de 20 mg q 12 h. As doses devem ser ajustadas às necessidades individuais dos pacientes e devem continuar pelo tempo indicado clinicamente. Em alguns pacientes, pode ser necessária uma dose inicial mais alta. Doses orais de até 160 mg q 6 h foram administradas a alguns pacientes adultos com Síndrome de Zollinger-Ellison grave.

Preparação de soluções intravenosas

Preparar soluções intravenosas de Motidin, dilua assepticamente 2 mL de injeção de Motidin (solução contendo 10 mg / mL) com injeção de cloreto de sódio a 0,9% ou outra solução intravenosa compatível (ver Estabilidade), para um volume total de 5 mL ou 10 mL e injete por um período não inferior a 2 minutos.

Preparar soluções de infusão intravenosa de Motidin, dilua assepticamente 2 mL de injeção de Motidin com 100 mL de dextrose a 5% ou outra solução compatível (consulte Estabilidade) e infundir por um período de 15 a 30 minutos.

Uso concomitante de antiácidos

Antiácidos podem ser administrados concomitantemente, se necessário.

Estabilidade

Os medicamentos parenterais devem ser inspecionados visualmente quanto a partículas e descoloração antes da administração sempre que a solução e o recipiente permitirem.

Quando adicionado ou diluído com soluções intravenosas mais usadas, p., Água para injeção, injeção de cloreto de sódio a 0,9%, injeção de de dextrose a 5% e 10% ou injeção de campainha com lactato, injeção de motidina diluída é física e quimicamente estável (ou seja,., mantém pelo menos 90% da potência inicial) por 7 dias em temperatura ambiente - veja COMO FORNECIDO, Armazenamento.

Quando adicionada ou diluída com injeção de bicarbonato de sódio, 5%, a injeção de Motidin a uma concentração de 0,2 mg / mL (a concentração recomendada de soluções de infusão intravenosa de Motidin) é física e quimicamente estável (ou seja,., mantém pelo menos 90% da potência inicial) por 7 dias em temperatura ambiente - veja COMO FORNECIDO, Armazenamento No entanto, um precipitado pode se formar em concentrações mais altas de injeção de Motidin (> 0,2 mg / mL) na injeção de bicarbonato de sódio, 5%.

Úlcera duodenal

Terapia aguda: A dose oral recomendada para adultos para úlcera duodenal ativa é de 40 mg uma vez ao dia na hora de dormir. A maioria dos pacientes cura dentro de 4 semanas; raramente há motivos para usar Motidin em doses completas por mais de 6 a 8 semanas. Um regime de 20 mg b.i.d. também é eficaz.

Terapia de manutenção: A dose oral recomendada para adultos é de 20 mg uma vez ao dia na hora de dormir.

Úlcera gástrica benigna

Terapia aguda: A dose oral recomendada para adultos para úlcera gástrica benigna ativa é de 40 mg uma vez ao dia na hora de dormir.

Doença do Refluxo Gastroesofágico (DRGE)

A dose oral recomendada para o tratamento de pacientes adultos com sintomas de DRGE é de 20 mg b.i.d. por até 6 semanas. A dose oral recomendada para o tratamento de pacientes adultos com esofagite, incluindo erosões e ulcerações e sintomas acompanhantes devido à DRGE, é de 20 ou 40 mg b.i.d. por até 12 semanas (ver FARMACOLOGIA CLÍNICA em adultos, Estudos clínicos).

Dosagem para pacientes pediátricos <1 ano de idade Doença do Refluxo Gastroesofágico (DRGE)

Vejo PRECAUÇÕES, Pacientes pediátricos com menos de 1 ano de idade.

Os estudos descritos em PRECAUÇÕES, Pacientes pediátricos com menos de 1 ano de idade sugerem as seguintes doses iniciais em pacientes pediátricos com menos de 1 ano de idade: Doença do Refluxo Gastroesofágico (DRGE) -0,5 mg / kg / dose de suspensão oral de famotidina para o tratamento de DRGE por até 8 semanas uma vez ao dia em pacientes com menos de 3 meses de idade e 0,5 mg / kg / dose duas vezes ao dia em pacientes com 3 meses a <1 ano de idade . Os pacientes também devem estar recebendo medidas conservadoras (por exemplo,., alimentos espessados). O uso de famotidina intravenosa em pacientes pediátricos com menos de 1 ano de idade com DRGE não foi adequadamente estudado.

Dosagem para pacientes pediátricos de 1 a 16 anos de idade

Vejo PRECAUÇÕES, Pacientes pediátricos de 1 a 16 anos de idade.

Os estudos descritos em PRECAUTIONS, Pacientes pediátricos de 1 a 16 anos de idade sugerem as seguintes doses iniciais em pacientes pediátricos de 1 a 16 anos de idade :

Úlcera péptica - 0,5 mg / kg / dia p.o. na hora de dormir ou dividido b.i.d. até 40 mg / dia.

Doença do refluxo gastroesofágico com ou sem esofagite, incluindo erosões e ulcerações - 1,0 mg / kg / dia p.o. dividido b.i.d. até 40 mg b.i.d.

Embora estudos não controlados publicados sugiram a eficácia da famotidina no tratamento da doença do refluxo gastroesofágico e da úlcera péptica, os dados em pacientes pediátricos são insuficientes para estabelecer a porcentagem de resposta com a dose e a duração da terapia. Portanto, a duração do tratamento (inicialmente com base nas recomendações de duração do adulto) e a dose devem ser individualizadas com base na resposta clínica e / ou determinação do pH (gástrico ou esofágico) e endoscopia. Estudos clínicos não controlados publicados em pacientes pediátricos de 1 a 16 anos de idade empregaram doses de até 1 mg / kg / dia para úlcera péptica e 2 mg / kg / dia para DRGE com ou sem esofagite, incluindo erosões e ulcerações.

Condições Hipersecretoras Patológicas (por exemplo,.Síndrome de Zollinger-Ellison, Adenomas Endócrinos Múltiplos)

A dose de Motidin em pacientes com condições hipersecretárias patológicas varia de acordo com o paciente individual. A dose inicial oral recomendada para adultos em condições hipersecretórias patológicas é de 20 mg q 6 h. Em alguns pacientes, pode ser necessária uma dose inicial mais alta. As doses devem ser ajustadas às necessidades individuais dos pacientes e devem continuar pelo tempo indicado clinicamente. Doses de até 160 mg q 6 h foram administradas a alguns pacientes adultos com Síndrome de Zollinger-Ellison grave.

Uso concomitante de antiácidos

Antiácidos podem ser administrados concomitantemente, se necessário.

Ajuste da dose para pacientes com insuficiência renal moderada ou grave

Em pacientes adultos com insuficiência renal moderada (depuração da creatinina <50 mL / min) ou grave (depuração da creatinina <10 mL / min), a meia-vida de eliminação da Motidin é aumentada. Para pacientes com insuficiência renal grave, pode exceder 20 horas, atingindo aproximadamente 24 horas em pacientes anúricos. Desde que os efeitos adversos do SNC foram relatados em pacientes com insuficiência renal moderada e grave, evitar o acúmulo excessivo do medicamento em pacientes com insuficiência renal moderada ou grave, a dose de Motidin pode ser reduzida para metade da dose ou o intervalo de dosagem pode ser prolongado para 36-48 horas, conforme indicado pela resposta clínica do paciente.

Com base na comparação dos parâmetros farmacocinéticos da Motidin em adultos e pacientes pediátricos, deve-se considerar o ajuste da dose em pacientes pediátricos com insuficiência renal moderada ou grave.

Hypersensitivity to any component of this product. Cross sensitivity in this class of compounds has been observed. Therefore, Motidin should not be administered to patients with a history of hypersensitivity to other H₂ -receptor antagonists.

Hypersensitivity to any component of these products. Cross sensitivity in this class of compounds has been observed. Therefore, Motidin should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists.

WARNINGS

No information provided.

PRECAUTIONS

General

Symptomatic response to therapy with famo-tidine injection does not preclude the presence of gastric malignancy.

Patients with Moderate or Severe Renal Insufficiency

Since CNSadverse effects have been reported in patients with moderate and severe renal insufficiency, longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance < 50 mL/min) or severe (creatinine clearance < 10 mL/min) renal insufficiency to adjust for the longer elimination half-life of Motidin. (See CLINICAL PHARMACOLOGY IN ADULTS, DOSAGE AND ADMINISTRATION.)

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic potential for Motidin.

Motidin was negative in the microbial mutagen test (Ames test) using Salmonella typhimuriumand Escherichia coliwith or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed.

In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected.

Pregnancy

Pregnancy Category B

Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day, respectively, and in both species at IV doses of up to 200 mg/kg/day, and have revealed no significant evidence ofimpaired fertility or harm to the fetus due to Motidin. While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Studies performed in lactating rats have shown that Motidin is secreted into breast milk. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Motidin is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from Motidin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Use of Motidin in pediatric patients 1-16 years of age is supported by evidence from adequate and well-controlled studies of famoti-dine in adults, and by thefollowing studies in pediatric patients: In published studies in small numbers of pediatric patients 1-15 years of age, clearance of Motidin was similar to that seen in adults. In pediatric patients 11-15 years of age, oral dosesof 0.5 mg/kg were associated with a mean area under the curve (AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1-15 years of age, intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated intravenously with 40 mg. Limited published studies also suggest that the relationship between serum concentration and acid suppression is similar in pediatric patients 1-15 years of age as compared with adults. These studies suggest that the starting dose for pediatric patients 1-16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15 minute infusion) q 12 h up to 40 mg/day.

While published uncontrolled clinical studies suggest effectiveness of Motidin in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric pH determination and endoscopy. Published uncontrolled studies in pediatric patients have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.

No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1year of age.

Geriatric Use

Of the 4,966 subjects in clinical studies who were treated with Motidin, 488 subjects (9.8%) were 65 and older, and 88 subjects (1.7%) were greater than 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, greater sensitivity of some older patients cannot be ruled out.

No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS, Pharmacokinetics). This drug is known to be substantially excreted by the kidney, and the risk of toxic 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. Dosage adjustment in the case of moderate or severe renal impairment is necessary (see PRECAUTIONS, Patients with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency).

WARNINGS

No information provided

PRECAUTIONS

General

Symptomatic response to therapy with Motidin does not preclude the presence of gastric malignancy.

Patients With Moderate Or Severe Renal Insufficiency

Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance < 50 mL/min) or severe (creatinine clearance < 10 mL/min) renal insufficiency to adjust for the longer elimination half-life of famotidine (see CLINICAL PHARMACOLOGY in adults and DOSAGE AND ADMINISTRATION). Prolonged QT interval has been reported very rarely in patients with impaired renal function whose dose/dosing interval of famotidine may not have been adjusted appropriately.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 106-week study in rats and a 92-week study in mice given oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic potential for Motidin.

Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed.

In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected.

Pregnancy

Pregnancy Category B

Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day, respectively, and in both species at I.V. doses of up to 200 mg/kg/day, and have revealed no significant evidence of impaired fertility or harm to the fetus due to Motidin. While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from Motidin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Patients < 1 Year Of Age

Use of Motidin in pediatric patients < 1 year of age is supported by evidence from adequate and well-controlled studies of Motidin in adults, and by the following studies in pediatric patients < 1 year of age.

Two pharmacokinetic studies in pediatric patients < 1 year of age (N=48) demonstrated that clearance of famotidine in patients > 3 months to 1 year of age is similar to that seen in older pediatric patients (1-15 years of age) and adults. In contrast, pediatric patients 0-3 months of age had famotidine clearance values that were 2- to 4-fold less than those in older pediatric patients and adults. These studies also show that the mean bioavailability in pediatric patients < 1 year of age after oral dosing is similar to older pediatric patients and adults. Pharmacodynamic data in pediatric patients 0-3 months of age suggest that the duration of acid suppression is longer compared with older pediatric patients, consistent with the longer famotidine half-life in pediatric patients 0-3 months of age. (See CLINICAL PHARMACOLOGY In Pediatric Patients, Pharmacokinetics and Pharmacodynamics.)

In a double-blind, randomized, treatment-withdrawal study, 35 pediatric patients < 1 year of age who were diagnosed as having gastroesophageal reflux disease were treated for up to 4 weeks with famotidine oral suspension (0.5 mg/kg/dose or 1 mg/kg/dose). Although an intravenous famotidine formulation was available, no patients were treated with intravenous famotidine in this study. Also, caregivers were instructed to provide conservative treatment including thickened feedings. Enrolled patients were diagnosed primarily by history of vomiting (spitting up) and irritability (fussiness). The famotidine dosing regimen was once daily for patients < 3 months of age and twice daily for patients ≥ 3 months of age. After 4 weeks of treatment, patients were randomly withdrawn from the treatment and followed an additional 4 weeks for adverse events and symptomatology. Patients were evaluated for vomiting (spitting up), irritability (fussiness) and global assessments of improvement. The study patients ranged in age at entry from 1.3 to 10.5 months (mean 5.6 ± 2.9 months), 57% were female, 91% were white and 6% were black. Most patients (27/35) continued into the treatment-withdrawal phase of the study. Two patients discontinued famotidine due to adverse events. Most patients improved during the initial treatment phase of the study. Results of the treatment-withdrawal phase were difficult to interpret because of small numbers of patients. Of the 35 patients enrolled in the study, agitation was observed in 5 patients on famotidine that resolved when the medication was discontinued; agitation was not observed in patients on placebo (see ADVERSE REACTIONS, Pediatric Patients).

These studies suggest that a starting dose of 0.5 mg/kg/dose of famotidine oral suspension may be of benefit for the treatment of GERD for up to 4 weeks once daily in patients < 3 months of age and twice daily in patients 3 months to < 1 year of age; the safety and benefit of famotidine treatment beyond 4 weeks have not been established. Famotidine should be considered for the treatment of GERD only if conservative measures (e.g., thickened feedings) are used concurrently and if the potential benefit outweighs the risk.

Pediatric Patients 1-16 years Of Age

Use of Motidin in pediatric patients 1-16 years of age is supported by evidence from adequate and well-controlled studies of Motidin in adults, and by the following studies in pediatric patients: In published studies in small numbers of pediatric patients 1-15 years of age, clearance of famotidine was similar to that seen in adults. In pediatric patients 11-15 years of age, oral doses of 0.5 mg/kg were associated with a mean area under the curve (AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1-15 years of age, intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated intravenously with 40 mg. Limited published studies also suggest that the relationship between serum concentration and acid suppression is similar in pediatric patients 1-15 years of age as compared with adults. These studies suggest a starting dose for pediatric patients 1-16 years of age as follows:

Peptic Ulcer - 0.5 mg/kg/day p.o. At Bedtime Or Divided b.i.d. Up To 40 mg/day.

Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations - 1.0 mg/kg/day p.o. divided b.i.d. up to 40 mg b.i.d.

While published uncontrolled studies suggest effectiveness of famotidine in the treatment of gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric patients have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations.

Geriatric Use

Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and older, and 88 subjects (1.7%) were greater than 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY in adults, Pharmacokinetics). This drug is known to be substantially excreted by the kidney, and the risk of toxic 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. Dosage adjustment in the case of moderate or severe renal impairment is necessary (see PRECAUTIONS, Patients with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency).

As reações adversas listadas abaixo foram relatadas durante ensaios clínicos nacionais e internacionais em aproximadamente 2500 pacientes. Nos ensaios clínicos controlados em que os comprimidos de famoti-dine foram comparados ao placebo, a incidência de experiências adversas no grupo que recebeu comprimidos de Motidin, 40 mg na hora de dormir, foi semelhante à do grupo placebo.

As seguintes reações adversas foram relatadas para ocorrer em mais de 1% dos pacientes em terapia com Motidin em ensaios clínicos controlados e podem estar causalmente relacionadas ao medicamento: dor de cabeça (4,7%), tontura (1,3%), constipação (1,2%) e diarréia (1,7%).

As seguintes outras reações adversas foram relatadas com pouca frequência em ensaios clínicos ou desde que o medicamento foi comercializado. A relação com a terapia com Motidin não ficou clara em muitos casos. Dentro de cada categoria, as reações adversas são listadas em ordem decrescente de gravidade :

Corpo como um todo: febre, astenia, fadiga

Cardiovascular: arritmia, bloqueio AV, palpitação

Gastrointestinal: icterícia colestática, anormalidades das enzimas hepáticas, vômitos, náusea, desconforto abdominal, anorexia, boca seca

Hematológico: casos raros de agranulocito-sis, pancitopenia, leucopenia, trombocitopenia

Hipersensibilidade: anafilaxia, angioedema, edema orbital ou facial, urticária, erupção cutânea, injeção conjucal

Musculoesquelético: dor musculoesquelética, incluindo cãibras musculares, artralgia

Sistema Nervoso / Psiquiátrico: convulsão grave; distúrbios psíquicos, reversíveis nos casos em que foi obtido acompanhamento, incluindo alucinações, confusão, agitação, depressão, ansiedade, diminuição da libido; parestesia; insônia; sonolência

Respiratório: broncoespasmo

Pele: necrólise epidérmica tóxica (muito rara), alopecia, acne, prurido, pele seca, rubor

Sentidos especiais: zumbido, distúrbio do paladar

De outros: casos raros de impotência e casos raros de ginecomastia foram relatados; no entanto, em ensaios clínicos controlados, as inci-denas não foram maiores do que as observadas com o placebo.

As reações adversas relatadas para os comprimidos de Motidin também podem ocorrer com Motidin para suspensão oral, Motidin comprimidos desintegrantes por via oral, Motidin injeção conservante livre em recipiente plástico ou injeção de Motidin.

As reações adversas listadas abaixo foram relatadas durante ensaios clínicos nacionais e internacionais em aproximadamente 2500 pacientes. Nos ensaios clínicos controlados em que os comprimidos de Motidin foram comparados ao placebo, a incidência de experiências adversas no grupo que recebeu comprimidos de Motidin, 40 mg na hora de dormir, foi semelhante à do grupo placebo.

As seguintes reações adversas foram relatadas para ocorrer em mais de 1% dos pacientes em terapia com Motidin em ensaios clínicos controlados e podem estar causalmente relacionadas ao medicamento: dor de cabeça (4,7%), tontura (1,3%), constipação (1,2%) e diarréia (1,7%).

As seguintes outras reações adversas foram relatadas com pouca frequência em ensaios clínicos ou desde que o medicamento foi comercializado. A relação com a terapia com Motidin não tem sido clara em muitos casos. Dentro de cada categoria, as reações adversas são listadas em ordem decrescente de gravidade :

Corpo como um todo : febre, astenia, fadiga

Cardiovascular: arritmia, bloqueio AV, palpitação. O intervalo QT prolongado, em pacientes com insuficiência renal, foi relatado muito raramente.

Gastrointestinal: icterícia colestática, hepatite, anormalidades das enzimas hepáticas, vômitos, náusea, desconforto abdominal, anorexia, boca seca

Hematológico: casos raros de agranulocitose, pancitopenia, leucopenia, trombocitopenia

Hipersensibilidade: anafilaxia, angioedema, edema orbital ou facial, urticária, erupção cutânea, injeção conjuntival

Músculo-esquelético: rabdomiólise, dor músculo-esquelética, incluindo cãibras musculares, artralgia

Sistema Nervoso / Psiquiatria : convulsão grave; distúrbios psíquicos, reversíveis nos casos em que foi obtido acompanhamento, incluindo alucinações, confusão, agitação, depressão, ansiedade, diminuição da libido; parestesia; insônia; sonolência. Convulsões, em pacientes com insuficiência renal, foram relatadas muito raramente.

Respiratório: broncoespasmo, pneumonia intersticial

Pele: necrólise epidérmica tóxica / síndrome de Stevens-Johnson (muito rara), alopecia, acne, prurido, pele seca, rubor

Sentidos especiais : zumbido, distúrbio do paladar

De outros: casos raros de impotência e casos raros de ginecomastia foram relatados; no entanto, em ensaios clínicos controlados, as incidências não foram maiores do que as observadas com o placebo.

As reações adversas relatadas para os comprimidos de Motidin também podem ocorrer com Motidin para suspensão oral.

Pacientes pediátricos

Num estudo clínico em 35 doentes pediátricos com menos de 1 ano de idade com sintomas de DRGE [por exemplo,., vômito (cuspir), irritabilidade (barulho)], foi observada agitação em 5 pacientes em uso de famotidina que se resolveram quando o medicamento foi interrompido.

Até o momento, não há experiência com superdosagem deliberada. Doses orais de até 640 mg / dia foram administradas a pacientes adultos com condições hipersecretárias patológicas sem efeitos adversos graves. Em caso de sobredosagem, o tratamento deve ser sintomático e de suporte. O material não absorvido deve ser removido do trato gastrointestinal, o paciente deve ser monitorado e a terapia de suporte deve ser empregada.

O LD50 intravenoso de Motidin para camundongos e ratos variou de 254 a 563 mg / kg e a dose mínima letal única de IV em cães foi de aproximadamente 300 mg / kg. Sinais de intoxicação aguda em cães tratados com IV foram êmese, inquietação, palidez das mucosas ou vermelhidão da boca e orelhas, hipotensão, taquicardia e colapso. O LD50 oral de Motidin em ratos e camundongos machos e fêmeas foi superior a 3000 mg / kg e a dose oral aguda letal mínima em cães excedeu 2000 mg / kg. A motidina não produziu efeitos evidentes em altas doses orais em camundongos, ratos, gatos e cães, mas induziu anorexia significativa e depressão do crescimento em coelhos, começando com 200 mg / kg / dia por via oral.

As reações adversas em casos de sobredosagem são semelhantes às reações adversas encontradas na experiência clínica normal (ver REAÇÕES ADVERSAS). Doses orais de até 640 mg / dia foram administradas a pacientes adultos com condições hipersecretárias patológicas sem efeitos adversos graves. Em caso de sobredosagem, o tratamento deve ser sintomático e de suporte. O material não absorvido deve ser removido do trato gastrointestinal, o paciente deve ser monitorado e a terapia de suporte deve ser empregada.

O LD50 oral de famotidina em ratos e camundongos machos e fêmeas foi superior a 3000 mg / kg e a dose oral aguda letal mínima em cães excedeu 2000 mg / kg. A famotidina não produziu efeitos evidentes em altas doses orais em camundongos, ratos, gatos e cães, mas induziu anorexia significativa e depressão do crescimento em coelhos, começando com 200 mg / kg / dia por via oral. O LD50 intravenoso de famotidina para camundongos e ratos variou de 254-563 mg / kg e o mínimo letal único de V.I. a dose em cães foi de aproximadamente 300 mg / kg. Sinais de intoxicação aguda em V.I. os cães tratados eram emese, inquietação, palidez das mucosas ou vermelhidão da boca e orelhas, hipotensão, taquicardia e colapso.

Orally administered Motidin is incompletely absorbed and its bioavailability is 40 to 45%. Motidin undergoes minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1to 3 hours. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of Motidin in plasma is protein bound. Motidin has an elimination half-life of 2.5 to 3.5 hours. Motidin is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65 to 70% of an intravenous dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the S-oxide.

There is a close relationship between crea-tinine clearance values and the elimination half-life of Motidin. In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life ofMotidin may exceed 20 hours and adjustment ofdose or dosing intervals in moderate and severe renal insufficiency may be necessary (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).

In elderly patients, there are no clinically significant age-related changes in the pharma-cokinetics of Motidin. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see PRECAUTIONS, Geriatric Use).

OVERDOSE

The adverse reactions in overdose cases are similar to the adverse reactions encountered in normal clinical experience (see ADVERSE REACTIONS). Oral doses of up to 640 mg/day have been given to adult patients with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage, treatment should be symptomatic and supportive. Unabsorbed material should be removed from the gastrointestinal tract, the patient should be monitored, and supportive therapy should be employed.

The oral LD50 of famotidine in male and female rats and mice was greater than 3000 mg/kg and the minimum lethal acute oral dose in dogs exceeded 2000 mg/kg. Famotidine did not produce overt effects at high oral doses in mice, rats, cats and dogs, but induced significant anorexia and growth depression in rabbits starting with 200 mg/kg/day orally. The intravenous LD50 of famotidine for mice and rats ranged from 254-563 mg/kg and the minimum lethal single I.V. dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in I.V. treated dogs were emesis, restlessness, pallor of mucous membranes or redness of mouth and ears, hypotension, tachycardia and collapse.

CONTRAINDICATIONS

Hypersensitivity to any component of these products. Cross sensitivity in this class of compounds has been observed. Therefore, Motidin should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists.

CLINICAL PHARMACOLOGY

Clinical Pharmacology In Adults

GI Effects

Motidin is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic activity of Motidin is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are suppressed by Motidin, while changes in pepsin secretion are proportional to volume output.

In normal volunteers and hypersecretors, Motidin inhibited basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration, the onset of the antisecretory effect occurred within one hour; the maximum effect was dose-dependent, occurring within one to three hours. Duration of inhibition of secretion by doses of 20 and 40 mg was 10 to 12 hours.

Single evening oral doses of 20 and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours. The same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean suppression was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively, 8 to 10 hours after administration. In some subjects who received the 20-mg dose, however, the antisecretory effect was dissipated within 6-8 hours. There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by evening doses of 20 and 40 mg of Motidin to mean values of 5.0 and 6.4, respectively. When Motidin was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 or 40 mg of Motidin was raised to about 5.

Motidin had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine pancreatic function were not affected by Motidin.

Other Effects

Systemic effects of Motidin in the CNS, cardiovascular, respiratory or endocrine systems were not noted in clinical pharmacology studies. Also, no antiandrogenic effects were noted. (See ADVERSE REACTIONS.) Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with Motidin.

Pharmacokinetics

Motidin is incompletely absorbed. The bioavailability of oral doses is 40-45%. Bioavailability may be slightly increased by food, or slightly decreased by antacids; however, these effects are of no clinical consequence. Motidin undergoes minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1-3 hours. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of Motidin in plasma is protein bound. Motidin has an elimination half-life of 2.5-3.5 hours. Motidin is eliminated by renal (65-70%) and metabolic (30-35%) routes. Renal clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65-70% of an intravenous dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the S-oxide.

There is a close relationship between creatinine clearance values and the elimination half-life of Motidin. In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life of Motidin may exceed 20 hours and adjustment of dose or dosing intervals in moderate and severe renal insufficiency may be necessary (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).

In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of Motidin. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see PRECAUTIONS, Geriatric Use).

Clinical Studies

Duodenal Ulcer

In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally administered Motidin was compared to placebo. As shown in Table 1, 70% of patients treated with Motidin 40 mg h.s. were healed by week 4.

Table 1 : Outpatients with Endoscopically Confirmed Healed Duodenal Ulcers

Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with Motidin had healed versus 45% of patients treated with placebo. The incidence of ulcer healing with Motidin was significantly higher than with placebo at each time point based on proportion of endoscopically confirmed healed ulcers.

In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving Motidin than for patients receiving placebo; patients receiving Motidin also took less antacid than the patients receiving placebo.

Long-Term Maintenance Treatment of Duodenal Ulcers

Motidin, 20 mg p.o. h.s., was compared to placebo h.s. as maintenance therapy in two double-blind, multicenter studies of patients with endoscopically confirmed healed duodenal ulcers. In the U.S. study the observed ulcer incidence within 12 months in patients treated with placebo was 2.4 times greater than in the patients treated with Motidin. The 89 patients treated with Motidin had a cumulative observed ulcer incidence of 23.4% compared to an observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p < 0.01). These results were confirmed in an international study where the cumulative observed ulcer incidence within 12 months in the 307 patients treated with Motidin was 35.7%, compared to an incidence of 75.5% in the 325 patients treated with placebo (p < 0.01).

Gastric Ulcer

In both a U.S. and an international multicenter, double-blind study in patients with endoscopically confirmed active benign gastric ulcer, orally administered Motidin, 40 mg h.s., was compared to placebo h.s. Antacids were permitted during the studies, but consumption was not significantly different between the Motidin and placebo groups. As shown in Table 2, the incidence of ulcer healing (dropouts counted as unhealed) with Motidin was statistically significantly better than placebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6 and 8 in the international study, based on the number of ulcers that healed, confirmed by endoscopy.

Table 2 : Patients with Endoscopically Confirmed Healed Gastric Ulcers

Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving Motidin than for patients receiving placebo; however, in neither study was there a statistically significant difference in the proportion of patients whose pain was relieved by the end of the study (week 8).

Gastroesophageal Reflux Disease (GERD)

Orally administered Motidin was compared to placebo in a U.S. study that enrolled patients with symptoms of GERD and without endoscopic evidence of erosion or ulceration of the esophagus. Motidin 20 mg b.i.d. was statistically significantly superior to 40 mg h.s. and to placebo in providing a successful symptomatic outcome, defined as moderate or excellent improvement of symptoms (Table 3).

Table 3 : % Successful Symptomatic Outcome

By two weeks of treatment, symptomatic success was observed in a greater percentage of patients taking Motidin 20 mg b.i.d. compared to placebo (p ≤ 0.01).

Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in two additional trials. Healing was defined as complete resolution of all erosions or ulcerations visible with endoscopy. The U.S. study comparing Motidin 40 mg p.o. b.i.d. to placebo and Motidin 20 mg p.o. b.i.d. showed a significantly greater percentage of healing for Motidin 40 mg b.i.d. at weeks 6 and 12 (Table 4).

Table 4 : % Endoscopic Healing - U.S. Study

As compared to placebo, patients who received Motidin had faster relief of daytime and nighttime heartburn and a greater percentage of patients experienced complete relief of nighttime heartburn. These differences were statistically significant.

In the international study, when Motidin 40 mg p.o. b.i.d. was compared to ranitidine 150 mg p.o. b.i.d., a statistically significantly greater percentage of healing was observed with Motidin 40 mg b.i.d. at week 12 (Table 5). There was, however, no significant difference among treatments in symptom relief.

Table 5 : % Endoscopic Healing - International Study

Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)

In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or without multiple endocrine adenomas, Motidin significantly inhibited gastric acid secretion and controlled associated symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments were necessary with time in some patients. Motidin was well tolerated at these high dose levels for prolonged periods (greater than 12 months) in eight patients, and there were no cases reported of gynecomastia, increased prolactin levels, or impotence which were considered to be due to the drug.

Clinical Pharmacology In Pediatric Patients

Pharmacokinetics

Table 6 presents pharmacokinetic data from clinical trials and a published study in pediatric patients ( < 1 year of age; N=27) given famotidine I.V. 0.5 mg/kg and from published studies of small numbers of pediatric patients (1-15 years of age) given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg I.V. for pediatric patients 1-15 years of age and compared with an extrapolated 40 mg intravenous dose in adults (extrapolation based on results obtained with a 20 mg I.V. adult dose).

Table 6 : Pharmacokinetic Parameters^a of Intravenous Famotidine

Plasma clearance is reduced and elimination half-life is prolonged in pediatric patients 0-3 months of age compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages > 3 months-15 years, are comparable to those obtained for adults.

Bioavailability studies of 8 pediatric patients (11-15 years of age) showed a mean oral bioavailability of 0.5 compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved AUCs of 645 ± 249 ng-hr/mL and 580 ± 60 ng-hr/mL in pediatric patients < 1 year of age (N=5) and in pediatric patients 11-15 years of age, respectively, compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally.

Pharmacodynamics

Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2-13 years of age using the sigmoid Emax model. These data suggest that the relationship between serum concentration of famotidine and gastric acid suppression is similar to that observed in one study of adults (Table 7).

Table 7 : Pharmacodynamics of famotidine using the sigmoid Emax model

Five published studies (Table 8) examined the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients. While each study had a different design, acid suppression data over time are summarized as follows:

Table 8

The duration of effect of famotidine I.V. 0.5 mg/kg on gastric pH and acid suppression was shown in one study to be longer in pediatric patients < 1 month of age than in older pediatric patients. This longer duration of gastric acid suppression is consistent with the decreased clearance in pediatric patients < 3 months of age (see Table 6).