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Revisión médica por Kovalenko Svetlana Olegovna Última actualización de farmacia el 15.03.2022
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Úlcera duodenal
Losectil (+ bicarbonato de sodio) (omeprazol / bicarbonato de sodio) está indicado para el tratamiento a corto plazo de la úlcera duodenal activa. La mayoría de los pacientes sanan en cuatro semanas. Algunos pacientes pueden requerir cuatro semanas adicionales de terapia.
Úlcera gástrica
Losectil (+ bicarbonato de sodio) está indicado para el tratamiento a corto plazo (4-8 semanas) de la úlcera gástrica benigna activa.
Tratamiento de la enfermedad por reflujo gastroesofágico (ERGE)
ERGE sintomático
Losectil (+ bicarbonato de sodio) está indicado para el tratamiento de la acidez estomacal y otros síntomas asociados con la ERGE durante hasta 4 semanas.
Esofagitis erosiva
Losectil (+ Bicarbonato de sodio) está indicado para el tratamiento a corto plazo (4-8 semanas) de esofagitis erosiva que ha sido diagnosticada por endoscopia.
No se ha establecido la eficacia de Losectil (+ bicarbonato de sodio) utilizado durante más de 8 semanas en estos pacientes. Si un paciente no responde a 8 semanas de tratamiento, puede ser útil renunciar a 4 semanas adicionales de tratamiento. Si hay recurrencia de esofagitis erosiva o síntomas de ERGE (p. Ej., acidez estomacal), se pueden considerar cursos adicionales de 4 a 8 semanas de Losectil (+ Bicarbonato de sodio).
Mantenimiento de la curación de la esofagitis erosiva
Losectil (+ bicarbonato de sodio) está indicado para mantener la curación de la esofagitis erosiva. Los estudios controlados no se extienden más allá de los 12 meses.
Reducción del riesgo de sangrado gastrointestinal superior en pacientes con enfermedades críticas (solo 40 mg de suspensión oral)
Losectil (+ Bicarbonato de sodio) Polvo para suspensión oral 40 mg / 1680 mg está indicado para la reducción del riesgo de hemorragia gastrointestinal superior en pacientes con enfermedades críticas.
Losectil (+ Bicarbonato de sodio) (omeprazol / bicarbonato de sodio) está disponible como cápsula y como polvo para suspensión oral en dosis de 20 mg y 40 mg de omeprazol para uso adulto. Las instrucciones de uso para cada indicación se resumen en la Tabla 1. Todas las dosis recomendadas a lo largo del etiquetado se basan en omeprazol.
Dado que los paquetes de suspensión oral de 20 mg y 40 mg contienen la misma cantidad de bicarbonato de sodio (1680 mg) dos paquetes de 20 mg no son equivalentes a un paquete de Losectil(+ Bicarbonato de sodio) 40 mg; por lo tanto, dos paquetes de 20 mg de Losectil(+ Bicarbonato de sodio) no debe sustituirse por un paquete de Losectil(+ Bicarbonato de sodio) 40 mg.
Dado que las cápsulas de 20 mg y 40 mg contienen la misma cantidad de bicarbonato de sodio (1100 mg) dos cápsulas de 20 mg no son equivalentes a una cápsula de Losectil(+ Bicarbonato de sodio) 40 mg; por lo tanto, dos cápsulas de 20 mg de Losectil(+ Bicarbonato de sodio) no debe sustituirse por una cápsula de Losectil(+ Bicarbonato de sodio) 40 mg.
Losectil (+ bicarbonato de sodio) debe tomarse con el estómago vacío al menos una hora antes de una comida.
Para los pacientes que reciben alimentación continua con tubo nasogástrico (NG) / orogástrico (OG), la alimentación enteral debe suspenderse aproximadamente 3 horas antes y 1 hora después de la administración de polvo de losectil (+ bicarbonato de sodio) para suspensión oral.
Tabla 1: Dosis recomendadas de losectilo (+ bicarbonato de sodio) por indicación para adultos mayores de 18 años
Indicación | Dosis recomendada | Frecuencia |
Tratamiento a corto plazo de la úlcera duodenal activa | 20 mg | Una vez al día durante 4 semanas * + |
Úlcera gástrica benigna | 40 mg | Una vez al día durante 4-8 semanas **, + |
Enfermedad por reflujo gastroesofágico (ERGE) | ||
ERGE sintomático (sin erosiones esofágicas) | 20 mg | Una vez al día por hasta 4 semanas + |
Esofagitis erosiva | 20 mg | Una vez al día durante 4-8 semanas + |
Mantenimiento de la curación de la esofagitis erosiva | 20 mg | Una vez al día ** |
Reducción del riesgo de sangrado gastrointestinal superior en pacientes con enfermedades críticas (solo 40 mg de suspensión oral) | 40 mg | 40 mg inicialmente seguido de 40 mg 6-8 horas después y 40 mg diarios a partir de entonces durante 14 días ** |
* La mayoría de los pacientes sanan en 4 semanas. Algunos pacientes pueden requerir 4 semanas adicionales de terapia. ** Los estudios controlados no se extienden más allá de los 12 meses. + Para información adicional, |
Poblaciones especiales
Insuficiencia hepática
Considere la reducción de la dosis, particularmente para el mantenimiento de la curación de la esofagitis erosiva.
Administración de cápsulas
Las cápsulas de losectil (+ bicarbonato de sodio) deben tragarse intactas con agua. NO USE OTROS LÍQUIDOS. NO ABRA EL CÁPSULO Y LOS CONTENIDO ESPRINCULARES EN ALIMENTOS
Preparación y administración de suspensión
Instrucciones de uso: Vacíe el contenido del paquete en una taza pequeña que contenga 1-2 cucharadas de agua. NO USE OTROS LÍQUIDOS O ALIMENTOS. Revuelva bien y beba de inmediato. Vuelva a llenar la taza con agua y beba.
Si se va a administrar Losectil (+ Bicarbonato de sodio) a través de un tubo nasogástrico (NG) u orogástrico (OG), la suspensión debe constituirse con aproximadamente 20 ml de agua. NO USE OTROS LÍQUIDOS O ALIMENTOS. Revuelva bien y administre de inmediato. Se debe usar una jeringa del tamaño adecuado para inculcar la suspensión en el tubo. La suspensión debe lavarse a través del tubo con 20 ml de agua.
Losectil (+ bicarbonato de sodio) está contraindicado en pacientes con hipersensibilidad conocida a cualquier componente de la formulación. Las reacciones de hipersensibilidad pueden incluir anafilaxia, shock anafiláctico, angioedema, broncoespasmo, nefritis intersticial aguda y urticaria.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Concomitant Gastric Malignancy
Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy.
Atrophic gastritis
Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole.
Acute Interstitial Nephritis
Acute interstitial nephritis has been observed in patients taking PPIs including Losectil(+Sodium Bicarbonate). Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue Losectil(+Sodium Bicarbonate) if acute interstitial nephritis develops..
Cyanocobalamin (vitamin B-12) Deficiency
Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo-or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
Buffer Content
Each Losectil(+Sodium Bicarbonate) Capsule contains 1100 mg (13 mEq) of sodium bicarbonate. The total content of sodium in each capsule is 304 mg.
Each packet of Losectil(+Sodium Bicarbonate) Powder for Oral Suspension contains 1680 mg (20 mEq) of sodium bicarbonate (equivalent to 460 mg of Na+).
The sodium content of Losectil(+Sodium Bicarbonate) products should be taken into consideration when administering to patients on a sodium restricted diet.
Because Losectil(+Sodium Bicarbonate) products contain sodium bicarbonate, they should be used with caution in patients with Bartter's syndrome, hypokalemia, hypocalcemia, and problems with acid-base balance. Long-term administration of bicarbonate with calcium or milk can cause milk-alkali syndrome.
Chronic use of sodium bicarbonate may lead to systemic alkalosis and increased sodium intake can produce edema and weight increase.
Clostridium Difficile Associated Diarrhea
Published observational studies suggest that PPI therapy like Losectil(+Sodium Bicarbonate) may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.
Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Interaction With Clopidogrel
Avoid concomitant use of Losectil(+Sodium Bicarbonate) with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that interfere with CYP2C19 activity. Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using Losectil(+Sodium Bicarbonate), consider alternative anti-platelet therapy.
Bone Fracture
Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines.
Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
Concomitant Use Of Losectil(+Sodium Bicarbonate) With St John's Wort Or Rifampin
Drugs which induce CYP2C19 OR CYP34A (such as St John's Wort or rifampin) can substantially decrease omeprazole concentrations. Avoid concomitant use of Losectil(+Sodium Bicarbonate) with St John's Wort or rifampin.
Interactions With Investigations For Neuroendocrine Tumors
Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop omeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary..
Concomitant Use Of Losectil(+Sodium Bicarbonate) With Methotrexate
Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients..
Patient Counseling Information
See FDA-Approved Medication Guide.
Instruct patients that Losectil(+Sodium Bicarbonate) should be taken on an empty stomach at least one hour prior to a meal.
Instruct patients in Directions for Use as follows:
Capsules: Swallow intact capsule with water. DO NOT USE OTHER LIQUIDS. DO NOT OPEN CAPSULE AND SPRINKLE CONTENTS INTO FOOD.
Powder for Oral Suspension: Empty packet contents into a small cup containing 1-2 tablespoons of water. DO NOT USE OTHER LIQUIDS OR FOODS. Stir well and drink immediately. Refill cup with water and drink.
Losectil(+Sodium Bicarbonate) is available either as 40 mg or 20 mg capsules with 1100 mg sodium bicarbonate. Losectil(+Sodium Bicarbonate) is also available either as 40 mg or 20 mg single-dose packets of powder for oral suspension with 1680 mg sodium bicarbonate.
Patients should be instructed not to substitute Losectil(+Sodium Bicarbonate) Capsules or Suspension for other Losectil(+Sodium Bicarbonate) dosage forms because different dosage forms contain different amounts of sodium bicarbonate and magnesium hydroxide.
Patients should be advised that since both the 20 mg and 40 mg oral suspension packets contain the same amount of sodium bicarbonate (1680 mg), two packets of 20 mg are not equivalent to one packet of Losectil(+Sodium Bicarbonate) 40 mg; therefore, two 20 mg packets of Losectil(+Sodium Bicarbonate) should not be substituted for one packet of Losectil(+Sodium Bicarbonate) 40 mg. Conversely ½ of a 40mg packet should not be substituted for one 20mg packet.
Patients should be advised that since both the 20 mg and 40 mg capsules contain the same amount of sodium bicarbonate (1100 mg), two capsules of 20 mg are not equivalent to one capsule of Losectil(+Sodium Bicarbonate) 40 mg; therefore, two 20 mg capsules of Losectil(+Sodium Bicarbonate) should not be substituted for one capsule of Losectil(+Sodium Bicarbonate) 40 mg. Patients should be advised that this drug is not approved for use in patients less than 18 years of age.
Patients on a sodium-restricted diet or patients at risk of developing congestive heart failure (CHF) should be informed of the sodium content of Losectil(+Sodium Bicarbonate) Capsules (304 mg per capsule) and Losectil(+Sodium Bicarbonate) Powder (460 mg per packet). Patients should be informed that chronic use of sodium bicarbonate may cause problems and increased sodium intake can cause swelling and weight gain. If this occurs, they should contact their healthcare provider.
Patients should be informed that the most frequent adverse reactions associated with Losectil(+Sodium Bicarbonate) include headache, abdominal pain, nausea, diarrhea, vomiting and flatulence.
Pregnant women should be advised that a harmful effect of Losectil(+Sodium Bicarbonate) on the fetus can not be ruled out and that the drug should be used with caution during pregnancy.
Patients should be advised to use this drug with caution if they are regularly taking calcium supplements.
Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea.
Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures and tetany as these may be signs of hypomagnesemia.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (approximately 0.4 to 34.2 times the human dose of 40 mg/day on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (approximately 3.36 times the human dose of 40 mg/day on a body surface area basis) for one year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated versus 10% controls). By the second year the difference between treated and control rats was much smaller (46% versus 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.9 times the human dose of 40 mg/day on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males and females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.
Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames Test, an in vitro mouse lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay.
In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.
Omeprazole at oral doses up to 138 mg/kg/day (about 33.6 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on the fertility and general reproductive performance in rats.
Use In Specific Populations
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies on the use of Losectil(+Sodium Bicarbonate) in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about68 times and 42 times, respectively, an oral human dose of 40 mg (based on a body surface area basis for a 60 kg person). However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 33.6 times an oral human dose of 40 mg (see Animal Data). Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, Losectil(+Sodium Bicarbonate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Human Data Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls.
A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population.
A population-based retrospective cohort study covering all live births in Denmark from 1996-2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester.
A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively.
A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups.
Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia.
Animal Data
Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 33.6times an oral human dose of 40 mg on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.36 to 33.6 times an oral human dose of 40 mg on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 3.36 to 33.6 times an oral human dose of 40 mg on a body surface area basis).
Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium.
A pre-and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development were performed with the S-enantiomer, esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg of esomeprazole on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 16.8 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses of esomeprazole magnesium equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis).
Effects on maternal bone were observed in pregnant and lactating rats in a pre-and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses of esomeprazole magnesium equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis).
A pre-and post natal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above.
Nursing Mothers
Pediatric Use
Safety and effectiveness of Losectil(+Sodium Bicarbonate) have not been established in pediatric patients less than 18 years of age.
Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg on a body surface area basis. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth.
Geriatric Use
Omeprazole was administered to over 2000 elderly individuals ( ≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Pharmacokinetic studies with buffered omeprazole have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects). The plasma half-life averaged one hour, about twice that in nonelderly, healthy subjects taking Losectil(+Sodium Bicarbonate). However, no dosage adjustment is necessary in the elderly.
Hepatic Impairment
Consider dose reduction, particularly for maintenance of healing of erosive esophagitis.
Renal Impairment
No dose reduction is necessary.
Asian Population
Recommend dose reduction, particularly for maintenance of healing of erosive esophagitis.
Clinical Trials Experience
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 trials of another drug and may not reflect the rates observed in clinical practice.
In the U.S. clinical trial population of 465 patients, the adverse reactions summarized in Table 2 were reported to occur in 1% or more of patients on therapy with omeprazole. Numbers in parentheses indicate percentages of the adverse reactions considered by investigators as possibly, probably or definitely related to the drug.
Table 2: Adverse Reactions Occurring In 1% or More of Patients on Omeprazole Therapy
Omeprazole (n = 465) | Placebo (n = 64) | Ranitidine (n = 195) | |
Headache | 6.9 (2.4) | 6.3 | 7.7 (2.6) |
Diarrhea | 3.0 (1.9) | 3.1 (1.6) | 2.1 (0.5) |
Abdominal Pain | 2.4 (0.4) | 3.1 | 2.1 |
Nausea | 2.2 (0.9) | 3.1 | 4.1 (0.5) |
URI | 1.9 | 1.6 | 2.6 |
Dizziness | 1.5 (0.6) | 0.0 | 2.6 (1.0) |
Vomiting | 1.5 (0.4) | 4.7 | 1.5 (0.5) |
Rash | 1.5 (1.1) | 0.0 | 0.0 |
Constipation | 1.1 (0.9) | 0.0 | 0.0 |
Cough | 1.1 | 0.0 | 1.5 |
Asthenia | 1.1 (0.2) | 1.6 (1.6) | 1.5 (1.0) |
Back Pain | 1.1 | 0.0 | 0.5 |
Table 3 summarizes the adverse reactions that occurred in 1% or more of omeprazole-treated patients from international double-blind, and open-label clinical trials in which 2,631 patients and subjects received omeprazole.
Table 3: Incidence of Adverse Reactions ≥ 1% Causal Relationship not Assessed
Omeprazole (n = 2631) | Placebo (n = 120) | |
Body as a Whole, site unspecified | ||
Abdominal pain | 5.2 | 3.3 |
Asthenia | 1.3 | 0.8 |
Digestive System | ||
Constipation | 1.5 | 0.8 |
Diarrhea | 3.7 | 2.5 |
Flatulence | 2.7 | 5.8 |
Nausea | 4.0 | 6.7 |
Vomiting | 3.2 | 10.0 |
Acid regurgitation | 1.9 | 3.3 |
Nervous System/Psychiatric | ||
Headache | 2.9 | 2.5 |
A controlled clinical trial was conducted in 359 critically ill patients, comparing Losectil(+Sodium Bicarbonate) 40 mg/1680 mg suspension once daily to I.V. cimetidine 1200 mg/day for up to 14 days. The incidence and total number of AEs experienced by ≥ 3% of patients in either group are presented in Table 4 by body system and preferred term.
Table 4: Number (%) of Critically Ill Patients with Frequently Occurring ( ≥ 3%) Adverse Events by Body System and Preferred Term
MedDRA Body System Preferred Term | Losectil(+Sodium Bicarbonate)® (N=178) | Cimetidine (N=181) |
All AEs n (%) | All AEs n (%) | |
BLOOD AND LYMPHATIC SYSTEM DISORDERS | ||
Anemia NOS | 14 (7.9) | 14 (7.7) |
Anemia NOS Aggravated | 4 (2.2) | 7(3.9) |
Thrombocytopenia | 18 (10.1) | 11 (6.1) |
CARDIAC DISORDERS | ||
Atrial Fibrillation | 11 (6.2) | 7(3.9) |
Bradycardia NOS | 7(3.9) | 5 (2.8) |
Supraventricular Tachycardia | 6 (3.4) | 2(1.1) |
Tachycardia NOS | 6 (3.4) | 6 (3.3) |
Ventricular Tachycardia | 8 (4.5) | 6 (3.3) |
GASTROINTESTINAL DISORDERS * | ||
Constipation | 8 (4.5) | 8 (4.4) |
Diarrhea NOS | 7(3.9) | 15 (8.3) |
Gastric Hypomotility | 3 (1.7) | 6 (3.3) |
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS | ||
Hyperpyrexia | 8 (4.5) | 3 (1.7) |
Edema NOS | 5 (2.8) | 11 (6.1) |
Pyrexia | 36 (20.2) | 29 (16.0) |
INFECTIONS AND INFESTATIONS | ||
Candidal Infection NOS | 3 (1.7) | 7 (3.9) |
Oral Candidiasis | 7 (3.9) | 1 (0.6) |
Sepsis NOS | 9 (5.1) | 9 (5.0) |
Urinary Tract Infection NOS | 4 (2.2) | 6 (3.3) |
INVESTIGATIONS | ||
Liver Function Tests NOS Abnormal | 3 (1.7) | 6 (3.3) |
METABOLISM AND NUTRITION DISORDERS | ||
Fluid Overload | 9 (5.1) | 14 (7.7) |
Hyperglycaemia NOS | 19 (10.7) | 21 (11.6) |
Hyperkalaemia | 4 (2.2) | 6 (3.3) |
Hypernatraemia | 3 (1.7) | 9 (5.0) |
Hypocalcaemia | 11 (6.2) | 10 (5.5) |
Hypoglycaemia NOS | 6 (3.4) | 8 (4.4) |
Hypokalaemia | 22 (12.4) | 24 (13.3) |
Hypomagnesaemia | 18 (10.1) | 18 (9.9) |
Hyponatraemia | 7(3.9) | 5 (2.8) |
Hypophosphataemia | 11 (6.2) | 7(3.9) |
PSYCHIATRIC DISORDERS | ||
Agitation | 6 (3.4) | 16 (8.8) |
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS | ||
Acute Respiratory Distress Syndrome | 6 (3.4) | 7 (3.9) |
Nosocomial Pneumonia | 20 (11.2) | 17 (9.4) |
Pneumothorax NOS | 1 (0.6) | 8 (4.4) |
Respiratory Failure | 3 (1.7) | 6 (3.3) |
SKIN AND SUBCUTANEOUS TISSUE DISORDERS | ||
Decubitus Ulcer | 6 (3.4) | 5 (2.8) |
Rash NOS | 10 (5.6) | 11 (6.1) |
VASCULAR DISORDERS | ||
Hypertension NOS | 14 (7.9) | 6 (3.3) |
Hypotension NOS | 17 (9.6) | 12 (6.6) |
* Clinically significant upper gastrointestinal bleeding was considered a serious adverse event but it is not included in this table. NOS = Not otherwise specified. |
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of omeprazole. Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.
Body as a Whole: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria (see also Skin below), fever, pain, fatigue, malaise.
Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitation, elevated blood pressure, and peripheral edema.
Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis and abdominal swelling. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.
Hepatic: Mild and, rarely, marked elevations of liver function tests [ALT (SGPT), AST (SGOT), γ-glutamyl transpeptidase, alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has occurred, including hepatocellular, cholestatic, or mixed hepatitis, liver necrosis (some fatal), hepatic failure (some fatal), and hepatic encephalopathy.
Infections and Infestations: Clostridium difficile associated diarrhea.
Metabolism and Nutritional Disorders: Hyponatremia, hypoglycemia, hypomagnesemia, and weight gain.
Musculoskeletal: Muscle cramps, myalgia, muscle weakness, joint pain, bone fracture, and leg pain.
Nervous System/Psychiatric: Psychic disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream abnormalities; vertigo; paresthesia; and hemifacial dysesthesia.
Respiratory: Epistaxis, pharyngeal pain.
Skin: Severe generalized skin reactions including toxic epidermal necrolysis (TEN; some fatal), Stevens-Johnson syndrome, and erythema multiforme (some severe); purpura and/or petechiae (some with rechallenge); skin inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis.
Special Senses: Tinnitus, taste perversion.
Ocular: Blurred vision, ocular irritation, dry eye syndrome, optic atrophy, anterior ischemic optic neuropathy, optic neuritis and double vision.
Urogenital: Interstitial nephritis (some with positive rechallenge), urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, and gynecomastia.
Hematologic: Rare instances of pancytopenia, agranulocytosis (some fatal), thrombocytopenia, neutropenia, leukopenia, anemia, leucocytosis, and hemolytic anemia have been reported.
The incidence of clinical adverse experiences in patients greater than 65 years of age was similar to that in patients 65 years of age or less.
Additional adverse reactions that could be caused by sodium bicarbonate include metabolic alkalosis, seizures, and tetany.
Se han recibido informes de sobredosis con omeprazol en humanos. Las dosis oscilaron hasta 2400 mg (120 veces la dosis clínica recomendada habitual). Las manifestaciones fueron variables, pero incluyeron confusión, somnolencia, visión borrosa, taquicardia, náuseas, vómitos, diaforesis, enrojecimiento, dolor de cabeza, boca seca y otras reacciones adversas similares a las observadas en la experiencia clínica normal. Los síntomas fueron transitorios y no se ha informado un resultado clínico grave cuando se tomó omeprazol solo. No se conoce ningún antídoto específico para la sobredosis de omeprazol. El omeprazol está ampliamente unido a proteínas y, por lo tanto, no es fácilmente dializable. En caso de sobredosis, el tratamiento debe ser sintomático y de apoyo.
Al igual que con el manejo de cualquier sobredosis, se debe considerar la posibilidad de ingestión múltiple de medicamentos. Para obtener información actual sobre el tratamiento de cualquier sobredosis de drogas, se debe contactar a un Centro Regional de Control de Envenenamiento certificado. Los números de teléfono se enumeran en la Referencia del escritorio de médicos (PDR) o en la guía telefónica local.
Las dosis orales únicas de omeprazol a 1350, 1339 y 1200 mg / kg fueron letales para ratones, ratas y perros, respectivamente. Los animales que recibieron estas dosis mostraron sedación, ptosis, temblores, convulsiones y disminución de la actividad, temperatura corporal y frecuencia respiratoria y mayor profundidad de la respiración.
Además, una sobredosis de bicarbonato de sodio puede causar hipocalcemia, hipocalemia, hipernatremia e convulsiones.
Actividad antisecretora
Los resultados de un estudio PK / PD del efecto antisecretor de la administración repetida una vez al día de 40 mg y 20 mg de Suspensión oral de losectil (+ bicarbonato de sodio) en sujetos sanos se muestran en la Tabla 5 a continuación.
Tabla 5: Efecto de la suspensión oral de losectil (+ bicarbonato de sodio) sobre el pH intragástrico, día 7
Parámetro | Omeprazo Bicarl | le / onato de sodio |
40 mg / 1680 mg (n = 24) | 20 mg / 1680 mg (n = 28) | |
% Disminución de la línea de base para la acidez gástrica integrada (mmol-hr / L) | 84% | 82% |
Coeficiente de variación | 20% | 24% |
% Tiempo pH gástrico> 4 * (Horas) * | 77% (18,6 h) | 51% (12,2 h) |
Coeficiente de variación | 27% | 43% |
pH medio | 5.2 | 4.2 |
Coeficiente de variación | 17% | 37% |
Nota: Los valores representan a los medianos. Todos los parámetros se midieron durante un período de 24 horas. * p <0.05 20 mg vs. 40 mg |
Resultados de un estudio separado de PK / PD del efecto antisecretor en la administración repetida una vez al día de 40 mg / 1100 mg y 20 mg / 1100 mg de Losectil(+ Bicarbonato de sodio) Las cápsulas en sujetos sanos muestran efectos similares en general en los tres parámetros de PD anteriores que los de Losectil(+ Bicarbonato de sodio) 40 mg / 1680 mg y 20 mg / 1680 mg de suspensión oral, respectivamente.
El efecto antisecretor dura más de lo esperado de la vida media plasmática muy corta (1 hora), aparentemente debido a la unión irreversible a la enzima parietal H + / K + ATPasa.
Efectos celulares similares a la enterocromafina (ECL)
En estudios de carcinogenicidad de 24 meses en ratas, se observó un aumento significativo relacionado con la dosis en tumores carcinoides gástricos e hiperplasia de células ECL en animales machos y hembras. También se han observado tumores carcinoides en ratas sometidas a fundectomía o tratamiento a largo plazo con otros inhibidores de la bomba de protones o altas dosis de antagonistas de los receptores H2. Se han obtenido muestras de biopsia gástrica humana de más de 3000 pacientes tratados con omeprazol en ensayos clínicos a largo plazo. La incidencia de hiperplasia celular de ECL en estos estudios aumentó con el tiempo; sin embargo, no se ha encontrado ningún caso de carcinoides, displasia o neoplasia de células de ECL en estos pacientes. Estos estudios tienen una duración y un tamaño insuficientes para descartar la posible influencia de la administración a largo plazo de omeprazol en el desarrollo de cualquier condición premaligna o maligna.
Efectos de la gastrina sérica
En estudios con más de 200 pacientes, los niveles séricos de gastrina aumentaron durante las primeras 1 a 2 semanas de administración una vez al día de dosis terapéuticas de omeprazol en paralelo con la inhibición de la secreción ácida. No se produjo un aumento adicional en la gastrina sérica con el tratamiento continuo. En comparación con los antagonistas de los receptores H2 de histamina, los aumentos medios producidos por dosis de 20 mg de omeprazol fueron mayores (1.3 a 3.6 veces vs. Aumento de 1.1 a 1.8 veces). Los valores de gastrina volvieron a los niveles de pretratamiento, generalmente dentro de 1 a 2 semanas después de la interrupción de la terapia.
El aumento de la gastrina causa hiperplasia celular similar a la enterocromafina y un aumento de los niveles séricos de cromogranina A (CgA). El aumento de los niveles de CgA puede causar resultados falsos positivos en las investigaciones de diagnóstico de tumores neuroendocrinos.
Otros efectos
No se han encontrado efectos sistémicos de omeprazol en el SNC, los sistemas cardiovascular y respiratorio hasta la fecha. El omeprazol, administrado en dosis orales de 30 o 40 mg durante 2 a 4 semanas, no tuvo efecto sobre la función tiroidea, el metabolismo de los carbohidratos o los niveles circulantes de hormona paratiroidea, cortisol, estradiol, testosterona, prolactina, colecistocinina o secretina. No se demostró ningún efecto sobre el vaciado gástrico de los componentes sólidos y líquidos de una comida de prueba después de una dosis única de 90 mg de omeprazol. En sujetos sanos, un solo I.V. La dosis de omeprazol (0,35 mg / kg) no tuvo efecto sobre la secreción del factor intrínseco. No se ha observado ningún efecto sistemático dependiente de la dosis en la producción de pepsina basal o estimulada en humanos. Sin embargo, cuando el pH intragástrico se mantiene a 4.0 o más, la producción basal de pepsina es baja y la actividad de pepsina disminuye.
Al igual que otros agentes que elevan el pH intragástrico, el omeprazol administrado durante 14 días en sujetos sanos produjo un aumento significativo en las concentraciones intragástricas de bacterias viables. El patrón de la especie bacteriana no cambió con respecto al que se encuentra comúnmente en la saliva. Todos los cambios se resolvieron dentro de los tres días posteriores a la interrupción del tratamiento.
El curso del esófago de Barrett en 106 pacientes se evaluó en un estudio controlado doble ciego de EE. UU. De omeprazol 40 mg b.i.d. durante 12 meses seguido de 20 mg b.i.d. durante 12 meses o ranitidina 300 mg b.i.d. por 24 meses. No se observó un impacto clínicamente significativo en la mucosa de Barrett por la terapia antisecretora. Aunque el epitelio neosquamous se desarrolló durante la terapia antisecretora, no se logró la eliminación completa de la mucosa de Barrett. No se observaron diferencias significativas entre los grupos de tratamiento en el desarrollo de displasia en la mucosa de Barrett y ningún paciente desarrolló carcinoma esofágico durante el tratamiento. No se observaron diferencias significativas entre los grupos de tratamiento en el desarrollo de hiperplasia de células ECL, gastritis atrófica del cuerpo, metaplasia intestinal del cuerpo o pólipos de colon de más de 3 mm de diámetro.
Absorption
In separate in vivo bioavailability studies, when Losectil(+Sodium Bicarbonate) Oral Suspension and Capsules are administered on an empty stomach 1 hour prior to a meal, the absorption of omeprazole is rapid, with mean peak plasma levels (% CV) of omeprazole being 1954 ng/mL (33%) and 1526 ng/mL (49%), respectively, and time to peak of approximately 30 minutes (range 10-90 min) after a single-dose or repeated-dose administration. Absolute bioavailability of Losectil(+Sodium Bicarbonate) Powder for Oral Suspension (compared to I.V. administration) is about 30-40% at doses of 20 – 40 mg, due in large part to presystemic metabolism. When Losectil(+Sodium Bicarbonate) Oral Suspension 40 mg/1680 mg was administered in a two-dose loading regimen, the omeprazole AUC (0-inf) (ng•hr/mL) was 1665 after Dose 1 and 3356 after Dose 2, while Tmax was approximately 30 minutes for both Dose 1 and Dose 2.
Following single or repeated once daily dosing, peak plasma concentrations of omeprazole from Losectil(+Sodium Bicarbonate) are approximately proportional from 20 to 40 mg doses, but a greater than linear mean AUC (three-fold increase) is observed when doubling the dose to 40 mg. The bioavailability of omeprazole from Losectil(+Sodium Bicarbonate) increases upon repeated administration.
When Losectil(+Sodium Bicarbonate) is administered 1 hour after a meal, the omeprazole AUC is reduced by approximately 24% relative to administration 1 hour prior to a meal.
Distribution
Omeprazole is bound to plasma proteins. Protein binding is approximately 95%.
Metabolism
Following single-dose oral administration of omeprazole, the majority of the dose (about 77%) is eliminated in urine as at least six metabolites. Two metabolites have been identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma – the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity.
Excretion
Following single-dose oral administration of omeprazole, little if any, unchanged drug is excreted in urine. The mean plasma omeprazole half-life in healthy subjects is approximately 1 hour (range 0.4 to 3.2 hours) and the total body clearance is 500-600 mL/min.
Concomitant Use with Clopidogrel
In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when coadministered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period.
In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction.
Concomitant Use with Mycophenolate Mofetil
Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA.