Date of approval.
Date of revision.
Esomeprazole Magnesium Enteric Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician.
Drug Name
Generic name: Esomeprazole Magnesium Enteric-coated Capsules
English name: Esomeprazole Magnesium Enteric-coated Capsules
Hanyu Pinyin: Aisi’aomeilazuomei Changrongjiaonang
Ingredients
The main ingredient of this product is Esomeprazole Magnesium.
Chemical name: Bis-S-5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazole magnesium dihydrate
Chemical structure formula.
Molecular formula: C34H36MgN6O6S2-2H2O
Molecular weight: 749.15
Properties
The contents of this product are white or off-white pills.
Indications
Gastroesophageal reflux disease (GERD)
-Treatment of reflux esophagitis
-Long-term treatment to prevent recurrence in patients with cured esophagitis
-Symptom control of GERD
Eradication of H. pylori in combination with appropriate antimicrobial therapy. and
-Healing of duodenal ulcers associated with H. pylori infection
-Prevent recurrence of H. pylori-associated peptic ulcers
Patients requiring continuous NSAID therapy
-Gastric ulcer treatment associated with NSAID treatment with (non-steroidal anti-inflammatory drugs)
Specification]
According to C17H19N3O3S (1) 20mg (2) 40mg
Dosage]
Gastroesophageal reflux disease (GERD)
-Treatment of reflux esophagitis
40mg, once daily for four weeks.
For patients with untreated esophagitis or persistent symptoms, it is recommended to take the drug for another four weeks.
Long-term maintenance therapy to prevent recurrence in patients with cured esophagitis
20mg once daily.
-Symptom control of GERD
Patients without esophagitis 20mg once daily. If symptoms are not controlled at 4 weeks, the patient should be further examined. Once symptoms have resolved, subsequent symptom control can be achieved with on-demand therapy, i.e., 20 mg orally once daily if needed. Subsequent symptom control is not recommended for patients at risk for gastric and duodenal ulcers associated with NSAID therapy.
Eradicate H. pylori in combination with appropriate antimicrobial therapy, and
-healing of H. pylori-associated duodenal ulcers
Prevention of recurrence of H. pylori-associated peptic ulcers
Esomeprazole Magnesium Enteric Capsules 20mg + Amoxicillin 1g + Clarithromycin 500mg twice daily for 7 days.
Patients requiring continuous NSAID therapy
-Treatment of gastric ulcers associated with treatment with NSAID: the usual dose is 20mg once daily for 4-8 weeks.
This product is an enteric coated capsule for oral administration. This product should be swallowed whole and should be taken at least one hour before a meal.
For patients who have difficulty swallowing the capsule, add one tablespoon of applesauce to an empty bowl, open the capsule and carefully pour the pellets inside the capsule over the applesauce. The pellets should be mixed with the applesauce and swallowed immediately: do not store for future use. The applesauce used should not be too hot and soft enough to avoid the need to chew and swallow. Pellets should not be chewed or crushed. If the pellet/applesauce mixture is not used in its entirety, any remaining mixture should be discarded immediately.
For patients with a nasogastric tube, the product may be opened and intact pellets poured into a 60 mL catheter-tipped syringe and mixed with 50 mL of water. When administering this product through a nasogastric tube, only the catheter-tipped syringe should be used. Replace the plunger and shake the syringe vigorously for 15 seconds. Lift the syringe and check for residual particles at the tip. Connect the syringe to the nasogastric tube and deliver the syringe contents to the stomach through the nasogastric tube. After taking the pellet, the nasogastric tube should be flushed with additional water. Do not use the pellets if they dissolve or disintegrate.
The mixture must be used immediately after it is prepared.
[Adverse reactions].
1. Clinical trial experience
Adverse reactions occurring at a frequency of ≥1%.
The safety of cure therapy for celiac esophagitis was evaluated in four randomized controlled clinical trials, including 1,240 patients in the esomeprazole magnesium 20 mg group, 2,434 patients in the esomeprazole magnesium 40 mg group, and 3,008 patients in the omeprazole 20 mg group, all administered once daily. In all three treatment groups, the most frequent adverse reactions (≥1%) were
Neurological: headache
Gastrointestinal: diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth.
Adverse reactions that may or are likely to be associated with esomeprazole magnesium that originated from other reports with an occurrence frequency< of 1% are listed separately by system organ as follows.
Whole body system: abdominal enlargement, allergic reaction, malaise, back pain, chest pain, subxiphoid pain, facial edema, peripheral edema, hot flashes, fatigue, fever, flu-like symptoms, generalized edema, leg edema, malaise, pain, chills.
Cardiovascular: flushing, hypertension, tachycardia.
Endocrine: goiter
Gastrointestinal: abnormal bowel function, increased constipation, dyspepsia, dysphagia, heterogeneous gastrointestinal hyperplasia, epigastric pain, belching, esophageal disease, frequent stools, gastroenteritis, gastrointestinal bleeding, gastrointestinal symptoms (nonspecific), hiccups, black stools, oral disease, pharyngeal disease, rectal disease, increased serum gastrin, tongue disease, tongue edema, ulcerative stomatitis, vomiting.
Hearing: ear pain, tinnitus.
Hematology: anemia, hemoglobinopenic anemia, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia.
Hepatic: bilirubinemia, abnormal liver function, elevated portal aminotransferase (AST), alanine aminotransferase (ALT).
Metabolic/nutritional: glycosuria, hyperuricemia, hyponatremia, elevated alkaline phosphatase, thirst, vitamin B12 deficiency, weight gain, weight loss.
Musculoskeletal system: arthralgia, exacerbation of arthritis, arthropathy, spasticity, fibromyalgia syndrome, hernia, rheumatic polymyalgia.
Neurological/psychiatric system: anorexia, affective apathy, hyperphagia, confusion, increased depression, dizziness, hypertonia, nervousness, hyperalgesia, sexual impotence, insomnia, migraine, increased migraine, sensory abnormalities, sleep disturbances, drowsiness, tremor, vertigo, visual field deficits.
Reproductive system: dysmenorrhea, menstrual disorders, vaginitis.
Respiratory system: asthma aggravation, cough, dyspnea, laryngeal edema, pharyngitis, rhinitis, sinusitis.
Skin and its accessories: acne, angioedema, dermatitis, pruritus, anal pruritus, rash, erythematous rash, maculopapular rash, skin inflammation, increased sweating, urticaria.
Special sensory organs: otitis media, olfactory inversions, loss of taste, taste inversions.
Genitourinary system: urinary abnormalities, albuminuria, cystitis, dysuria, fungal infections, hematuria, dysuria, candidiasis, genital candidiasis, polyuria.
Visual system: conjunctivitis, visual abnormalities.
In clinical trials, ≤ 1% of changes in potentially clinically significant laboratory tests (whether or not associated with esomeprazole magnesium) were as follows: creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, blood potassium concentration, blood sodium concentration, thyroxine, thyroid stimulating hormone elevation, hemoglobin, white blood cell count, platelets, blood potassium concentration, blood sodium concentration and thyroxine were decreased.
Endoscopic findings include: duodenitis, esophagitis, esophageal stricture, esophageal ulcer, esophageal varices, gastric ulcer, gastritis, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration.
During the 6-month maintenance treatment period, the incidence of treatment-related adverse reactions in the treatment group was similar to that in the placebo group. There was no difference between the types of treatment-related adverse reactions that occurred in the maintenance treatment group up to 12 months and the short-term treatment group.
In two placebo-controlled studies in 710 patients treated for symptomatic GERD, the most common adverse reactions among those likely or probably associated with the product were diarrhea (4.3%), headache (3.8%), and abdominal pain (3.8%).
2. Treatment in combination with amoxicillin and clarithromycin
In clinical trials treated with the combination of esomeprazole magnesium + amoxicillin and clarithromycin, the adverse reactions to the combination were all those seen in studies of monotherapy with esomeprazole magnesium, amoxicillin or clarithromycin, and no other adverse reactions related to the combination of these drugs were identified.
For patients receiving triple therapy for 10 consecutive days, the most frequently reported drug-related adverse reactions were diarrhea (9.2%), taste inversions (6.6%), and abdominal pain (3.7%). The frequency of adverse reactions was not higher in the triple therapy treatment group than in the esomeprazole magnesium monotherapy group.
In clinical trials treated with the combination of esomeprazole magnesium + amoxicillin and clarithromycin, there was no increase in other laboratory test abnormalities associated with the combination of these drugs.
For more information on amoxicillin or clarithromycin adverse reactions and laboratory changes, please refer to their drug inserts.
3. Post-marketing experience
The following adverse reactions have been identified during the post-marketing approval use of esomeprazole magnesium. Because these adverse reactions were spontaneously reported by an indeterminate group of people, it was not always possible to accurately estimate the frequency of adverse reactions or to establish a causal relationship between adverse reactions and drug exposure. The following are listed by body system.
Hematologic and lymphatic system: granulocyte deficiency, allogeneic cytopenia.
Ocular: blurred vision.
Gastrointestinal system: pancreatitis, stomatitis, microscopic colitis, gastric fundic gland polyps.
Hepatobiliary system: hepatic failure, jaundiced hepatitis or non-jaundiced hepatitis.
Immune system: tachyphylaxis/shock.
Infectious and invasive diseases: gastrointestinal candidiasis, Clostridium difficile-associated diarrhea.
Metabolic disorders and malnutrition: hypomagnesemia with or without hypocalcemia or hypokalemia.
Musculoskeletal and connective tissues: muscle weakness, myalgia, fractures.
Neurological: hepatic encephalopathy, abnormal taste sensation.
Psychiatric disorders: aggressive behavior, agitation, depression, hallucinations.
Diseases of the kidney and urinary system: interstitial nephritis.
Reproductive system and breast disorders: mammary gland development in men.
Respiratory system, thorax and mediastinum: bronchospasm.
Skin and subcutaneous tissue: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermolysis bullosa (some can be fatal), cutaneous lupus erythematosus.
[Contraindication].
Known hypersensitivity to estramiprazole, other benzimidazoles, or any other component of this product is contraindicated.
Hypersensitivity reactions have been reported with esomeprazole magnesium, such as: tachyphylaxis, anaphylaxis, angioedema, bronchospasm, acute interstitial nephritis and urticaria.
Esomeprazole should not be used in combination with nelfinavir (see [Drug Interactions]).
For information on contraindications to antibacterial agents (clarithromycin and amoxicillin) used in combination with esomeprazole magnesium, please refer to the contraindications section of their instructions.
[Precautions].
Warnings and Precautions
1. Complication of gastric malignancy
When any alarming symptoms (such as significant unintentional weight loss, recurrent vomiting, dysphagia, vomiting of blood or black stool), suspected gastric ulcer or existing gastric ulcer occur, malignancy should be ruled out first, because treatment with this product may alleviate symptoms and delay the diagnosis.
2. Acute interstitial nephritis
Acute interstitial nephritis has been observed in patients taking PPIs including esomeprazole magnesium. Acute interstitial nephritis may occur at any time during PPI therapy and is usually attributed to an idiopathic allergic reaction. Discontinue this product if acute interstitial nephritis develops (see [Contraindications]).
3. Atrophic gastritis
Atrophic gastritis has occasionally been found on pathologic biopsy of the gastric body in patients receiving long-term treatment with omeprazole (esomeprazole as its enantiomer).
4. Clostridium difficile (Clostridium difficile)-associated diarrhea
Published observational studies suggest that proton pump inhibitor (PPI) therapy (e.g., esomeprazole magnesium) may increase the risk of Clostridium difficile-associated diarrhea (CDAD), particularly in hospitalized patients. This diagnosis should be considered if diarrhea does not improve (see [Adverse Reactions]).
Patients should be treated with the lowest dose and shortest course of PPI appropriate to the therapeutic situation.
Clostridium difficile-associated diarrhea (CDAD) has been reported with almost all antimicrobial agents in use. For more information, particularly on the use of this product in combination with antimicrobial drugs (e.g., clarithromycin and amoxicillin), please refer to the Warnings and Precautions section of the relevant antimicrobial drug insert.
5. Interaction with Clopidogrel
The combination of this product and clopidogrel should be avoided. Clopidogrel is a precursor drug. The platelet agglutination inhibition produced by clopidogrel can be attributed solely to its active metabolite. The combined use of drugs that inhibit CYP2C19 activity (e.g., esomeprazole) can affect the metabolism of clopidogrel into its active metabolite. The combined use of clopidogrel and 40 mg esomeprazole decreases the pharmacological activity of clopidogrel. Therefore, other antiplatelet therapy should be considered when using this product (see [Drug Interactions]).
6. Bone fractures
Several published observational studies suggest that treatment with proton pump inhibitors (PPIs) may place people at increased risk for fractures of the hip, wrist, or spine due to osteoporosis. The risk of fracture is also increased in patients receiving high doses (defined as multiple daily doses) and long-term (1 year or longer) PPI therapy. Patients should be treated with the lowest dose and shortest course of PPI based on their condition. Patients who are at risk for osteoporosis-related fractures should be treated according to existing guidelines.
7. When this product is used in the treatment of H. pylori eradication, possible drug interactions between all components of the triple therapy should be considered.
8. Hypomagnesemia
In patients who received at least 3 months and the vast majority of patients who received PPI treatment for one year, very few cases of asymptomatic and symptomatic hypomagnesemia have been reported. The above serious adverse reactions include hand and foot twitching, cardiac arrhythmia and seizures. For the majority of patients, correction of hypomagnesemia requires magnesium supplementation and discontinuation of the PPI.
In anticipation of prolonged PPI therapy or in combination with drugs such as digoxin or drugs that can cause hypomagnesemia (e.g., diuretics), medical professionals may consider monitoring magnesium concentrations before starting PPI therapy and periodically.
9. Combined use of Guangyelenia or Rifampin
Drugs that induce CYP2C19 or CYP3A4 (e.g., ganoderma or rifampin) can greatly reduce the blood levels of esomeprazole. Avoid combining this product with Guanfenglianxiao or rifampin.
10 Interaction of this product with drugs used for neuroendocrine tumor screening
Increased serum chromogranin A levels secondary to decreased drug induction in gastric neuroendocrine tumors. Providers should consider suspending esomeprazole for at least 14 days prior to evaluating serum chromogranin A levels and reviewing this indicator if initial serum chromogranin A levels remain high. Because normal reference values may vary between laboratories, a series of tests (e.g., monitoring), if performed, should be performed in the same commercial laboratory.
11. Combined use of methotrexate
The literature suggests that the combination of PPIs and methotrexate (primarily at high doses; see Methotrexate Prescribing Information) may increase serum concentrations of methotrexate and/or its metabolites, prolong the duration of high serum concentrations, and may lead to methotrexate toxicity. Temporary discontinuation of PPIs may be considered in some patients on high doses of methotrexate (see [Drug Interactions])
12. Patients receiving treatment should contact their physician if their signs and symptoms change significantly. Possible drug interactions due to fluctuations in esomeprazole blood levels should be considered when treating with as-needed medication (see [Drug Interactions]).
13. This product contains sucrose. Patients with rare genetic disorders such as glucose intolerance, impaired glucose-galactose absorption, or sucrase-isomaltase deficiency should not take this product.
14. Treatment with proton pump inhibitors can lead to a slight increase in the risk of GI infections such as Salmonella and Campylobacter (see [Pharmacology and Toxicology]).
15. The combination of esomeprazole and atazanavir is not recommended (see [Drug Interactions]). If it is judged necessary to give atazanavir in combination with a proton pump inhibitor, close clinical monitoring should be considered, e.g., the dose of esomeprazole should not exceed 20 mg when the dose of atazanavir is increased to 400 mg and the dose of ritonavir (often combined with atazanavir) is increased to 100 mg.
16. Patients on long-term treatment with this drug (especially those treated for more than 1 year) should be monitored regularly.
17. As with all drugs that inhibit gastric acid, esomeprazole can be associated with decreased absorption of vitamin B12 (cyanocobalamin) due to decreased or deficient gastric acid. Therefore, this risk needs to be considered in patients with reduced body stores or with risk factors for reduced vitamin B12 absorption during long-term therapy.
18. Cutaneous and systemic lupus erythematosus: Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs including esomeprazole. Most cases of lupus erythematosus due to PPIs are CLE and, less frequently, SLE. Avoid prolonged use of PPIs beyond the instructions, and if signs or symptoms of CLE or SLE develop, discontinue the drug and consult a specialist. Most patients improve within 4 to 12 weeks after PPI discontinuation.
19. Gastric fundic polyps
Long-term use of PPIs leads to an increased risk of fundic polyps, especially with long-term use for more than one year. Most PPI users who develop fundic polyps are asymptomatic and only incidentally found to have fundic polyps during endoscopy. The shortest duration of PPI therapy should be used depending on the status of disease treatment.
Renal impairment
No dose adjustment is required in patients with renal impairment. In patients with severe renal insufficiency, treatment should be administered with caution due to limited experience with the drug (see [Pharmacokinetics]).
Hepatic Impairment
No dose adjustment is required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the dose of this drug should not exceed 20 mg (see [Pharmacokinetics]).
Effects on the ability to drive and use machines
No effects have been observed in this regard.
Pregnant women and nursing mothers
No clinical data have been reported on the use of esomeprazole in pregnant women. Data from epidemiological studies have shown that no teratogenic or fetal toxic effects have been observed in a large number of pregnant women using the racemic mixture omeprazole. Animal studies have not shown direct or indirect detrimental effects of esomeprazole on embryonic or fetal development. Animal studies with the racemic mixture did not show direct or indirect deleterious effects on pregnancy, delivery or postnatal development. However, caution should be exercised when administering esomeprazole to women during pregnancy.
It is not known whether esomeprazole is excreted through human milk. Esomeprazole has not been studied in lactating women and therefore Esomeprazole Magnesium Enteric Capsules should not be used during lactation.
Pediatric Use]
Esomeprazole should not be used in children as there are no relevant clinical studies.
Geriatric Use]
No dose adjustment is required for elderly patients.
Drug Interactions
1. Interfere with retroviral drug therapy
Combination of proton pump inhibitors with atazanavir and nelfinavir is not recommended. Combination with proton pump inhibitors is expected to result in a significant decrease in atazanavir blood levels and possible loss of efficacy and development of drug resistance. Combination with proton pump inhibitors is expected to result in increased concentrations of saquinavir (often combined with atazanavir), leading to increased toxicity and, therefore, the need for dose reduction.
Interactions have been reported with omeprazole (with esomeprazole as its enantiomer) with some retroviral drugs; however, the clinical significance and mechanism of action of these interactions are not fully understood. The absorption of retroviral drugs can be altered by an increase in gastric pH during omeprazole treatment. Other possible mechanisms of interaction are acting through CYP2C19.
Reduction of atazanavir and nelfinavir concentrations
For some retroviral drugs, such as atazanavir and nelfinavir, blood concentrations have been reported to show a decrease when combined with omeprazole. After multiple administration of nelfinavir (1250 mg twice daily) and omeprazole (40 mg once daily), the AUC of nelfinavir and its pharmacologically active metabolite M8 decreased by 36% and 92%, the Cmax by 37% and 89%, and the Cmin by 39% and 75%, respectively. After multiple administration of atazanavir (400 mg once daily) and omeprazole (40 mg once daily, administered 2 hours prior to atazanavir administration), the AUC of atazanavir decreased by 94%, Cmax by 96%, and Cmin by 95%. Therefore, the combination of omeprazole with such drugs (e.g., atazanavir and nelfinavir) is not recommended. Because omeprazole and esomeprazole have similar pharmacodynamic and pharmacokinetic profiles, administration of esomeprazole and atazanavir in combination is not recommended and administration of esomeprazole and nelfinavir in combination is contraindicated.
Increased concentrations of saquinavir
Elevated blood levels have been reported with other retroviral drugs, such as saquinavir. After multiple doses of saquinavir/ritonavir (1000/100 mg) given twice daily for 15 days and omeprazole 40 mg once daily for 11 to 15 days of continuous combination therapy, saquinavir AUC increased by 82%, Cmax by 75%, and Cmin by 106%. Therefore, clinical and laboratory monitoring of saquinavir toxicity is recommended during combination therapy with this product. For safety reasons, the dose of saquinavir should be reduced according to individual patient differences.
It has also been reported that some retroviral drugs have been used in combination with omeprazole without changes in blood levels.
2. Drugs whose bioavailability is affected by gastric pH
Esomeprazole inhibits gastric acid secretion; therefore, for drugs whose bioavailability is significantly affected by gastric pH (e.g., ketoconazole, itraconazole, atazanavir, iron salts, and digoxin), esomeprazole may affect their absorption.
3. Effects on hepatic metabolism/cytochrome P450 pathway
Esomeprazole is extensively metabolized in the liver via CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is unlikely to inhibit CYP 1A2, 2A6, 2C9, 2D6, 2E1, and 3A4, and interactions between this product and drugs metabolized by these CYP enzymes are not expected to be clinically relevant. Drug interaction studies have shown no clinically significant interactions between esomeprazole and drugs such as phenytoin, warfarin, quinidine, clarithromycin, or amoxicillin.
However, post-marketing reports have shown changes in prothrombin assay results for patients receiving the combination of warfarin and esomeprazole. Increased prothrombinogen international normalized ratio (INR) and prothrombin time can lead to abnormal bleeding and even death in patients. Therefore, patients receiving the combination of proton pump inhibitors and warfarin need to be monitored for increases in their INR and prothrombin time.
Esomeprazole inhibits CYP2C19, which is the main metabolizing enzyme of this product. Therefore, when esomeprazole is combined with drugs metabolized by CYP2C19 (e.g., diazepam, citalopram, promethazine, clomipramine, phenytoin, etc.), plasma concentrations of these drugs can be elevated and dose reductions may be required. This should be considered especially when this product is used for on-demand treatment. The combination of 30 mg of this product can decrease the clearance of diazepam metabolized by CYP2C19 by 45%. The combination of 40 mg of this product increased plasma phenytoin trough concentrations by 13% in patients with epilepsy. Therefore, monitoring of phenytoin blood levels during phenytoin therapy is recommended when this product is combined or discontinued. Omeprazole 40 mg once daily increased voriconazole (voriconazole: a substrate of CYP2C19) Cmax and AUCt by 15% and 41%, respectively.
Esomeprazole is metabolized by CYP2C19 and CYP3A4. Esomeprazole in combination with the CYP3A4 inhibitor clarithromycin (500 mg twice daily) doubles the body’s exposure (AUC) to esomeprazole. The combination of esomeprazole with CYP2C19 and CYP3A4 co-inhibitors increased esomeprazole exposure more than twofold. voriconazole, an inhibitor of CYP2C19 and CYP3A4, increased esomeprazole AUCt280%. The dose of estramiprazole does not need to be routinely adjusted in either case. However, dose adjustment should be considered for patients with severe liver damage and those requiring long-term therapy.
Clopidogrel
Clopidogrel is partially metabolized by the CYP2C19 enzyme to its active metabolite. The combination of esomeprazole 40 mg may reduce the plasma concentration of the active metabolite of clopidogrel, which in turn may reduce platelet inhibition. Therefore, the combination of this product with clopidogrel should be avoided. Other antiplatelet therapy should be considered when using this product.
Omeprazole is an inhibitor of CYP2C19. A crossover study of omeprazole and cilostazol in 20 healthy subjects showed that administration of omeprazole 40 mg once daily for one week increased the Cmax and AUC of cilostazol by 18% and 26%, respectively, and the Cmax and AUC of its active metabolite 3,4-dihydro-cilostazol (4 to 7 times more active than cilostazol) by 29% and 69%. It is expected that the concentrations of cilostazol and its above-mentioned active metabolites can be increased after cilostazol is coadministered with esomeprazole. Therefore, a reduction in the dose of cilostazol from 100 mg twice a day to 50 mg twice a day should be considered.
CYP2C19 or CYP3A4 inducers or both of these enzyme inducers (e.g., rifampin) cause a decrease in estramiprazole blood concentrations. Interactions between omeprazole (of which esomeprazole is the enantiomer) and the CYP3A4-inducing agent, onychomycin, have been reported. In a crossover study that included 12 healthy male subjects, Guanye Lianxiang (300 mg three times daily for 14 days) resulted in a significant reduction in systemic exposure to omeprazole in CYP2C19 slow metabolizers (Cmax and AUC values decreased by 37.5% and 37.9%, respectively) and fast metabolizers (Cmax and AUC values decreased by 49.6% and 43.9%, respectively). Therefore, it should be avoided in combination with Guangyelian or rifampin.
No clinically relevant pharmacokinetic interactions were shown in short-term studies evaluating the combination of estramiprazole and naproxen or rofecoxib.
4. Interaction of this product with drugs examined for neuroendocrine tumors
Drug-induced decrease in gastric acid can lead to increased intestinal chromophobe cell proliferation and chromogranin A levels, thus interfering with the examination of neuroendocrine tumors.
5. Tacrolimus
Combination of this drug with tacrolimus may result in increased tacrolimus blood levels.
6. Combination therapy with clarithromycin
Combined treatment with esomeprazole, clarithromycin and amoxicillin can lead to increased blood levels of esomeprazole and 14-hydroxyclarithromycin.
Combination therapy with cisapride, pimozide, astemizole, terfenadine, ergotamine, or dihydroergotamine is prohibited [see instructions for clarithromycin].
7. Methotrexate
Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that the combination of PPIs and methotrexate (primarily at high doses; see Methotrexate Prescribing Information) may increase serum concentrations of methotrexate and/or its metabolites and prolong the duration of high serum concentrations. However, no formal drug interaction studies have been conducted with methotrexate and PPIs.
Elevated methotrexate levels have been reported in some patients when co-administered with PPIs. Temporary withdrawal of esomeprazole may be considered when treating with high doses of methotrexate.
[Drug overdose].
There is very limited experience with overdose of esomeprazole. Symptoms associated with the 280 mg dose have been gastrointestinal symptoms and weakness. There were no abnormal reactions to a single dose of 80 mg estramiprazole. There is no known specific antidote. Esomeprazole is extensively bound to plasma proteins, making it difficult to dialyze. Treatment of any overdose poisoning should be symptomatic management and systemic supportive therapy.
[Pharmacology and Toxicology
Pharmacological effects
Esomeprazole is a proton pump inhibitor, the S-isomer of omeprazole, which blocks the final step of gastric acid secretion by specifically inhibiting the H+-K+ ATPase of gastric lining cells. The S-isomer and R-isomer of omeprazole are converted to the active ingredient in the acidic environment of gastric lining cells. Esomeprazole inhibits gastric acid secretion in a dose-dependent manner at daily doses in the range of 20-40 mg.
Toxicological studies
Genotoxicity:
Esomeprazole Ames test, in vivo rat bone marrow cell chromosome aberration test, and mouse micronucleus test results were negative; Esomeprazole in vitro human lymphocyte chromosome aberration test results were positive. The results of omeprazole in vitro human lymphocyte chromosome aberration test, in vivo mouse bone marrow cell chromosome aberration test and in vivo mouse micronucleus test were positive.
Reproductive toxicity:
The results of the omeprazole test were used to assess the reproductive toxicity of estramiprazole.
Fertility and reproductive behavior were not significantly abnormal in rats given orally 138 mg/kg/day of omeprazole (approximately 34 times the human oral dose of 40 mg based on body surface area).
The oral administration of omeprazole to pregnant rats at 138 mg/kg/day (about 34 times the human oral dose of 40 mg based on body surface area) and to pregnant rabbits at 69 mg/kg/day (about 34 times the human oral dose of 40 mg based on body surface area) did not reveal any potential teratogenic effect of omeprazole.
In rabbits given omeprazole at 6.9-69.1 mg/kg/day (approximately 3.4-34 times the human oral dose of 40 mg on a body surface area basis), dose-dependent increases in embryonic mortality, fetal resorption and abortion were observed.
Dose-dependent embryo/fetus toxicity and postnatal developmental toxicity were observed in the offspring of parental rats given omeprazole at 13.8-138.0 mg/kg/day (approximately 3.4-34 times the human oral dose of 40 mg on a body surface area basis).
Carcinogenicity:
The carcinogenicity of estramiprazole was assessed by the results of the omeprazole test.
In two 2-year carcinogenicity tests in rats, omeprazole doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (approximately 0.4-34 times the human oral dose of 40 mg based on body surface area) resulted in dose-dependent development of gastrointestinal chromophobe (ECL) cell carcinoids in both males and females; the incidence was significantly higher in females than in males, The incidence of omeprazole was significantly higher in females than in males, and the blood concentration of omeprazole was higher in females than in males. Gastric carcinoid tumors were rare in untreated animals, while ECL cell proliferation was observed in both female and male treated groups.
In another study, female rats were given omeprazole at 13.8 mg/kg/day (approximately 3.4 times the oral dose of 40 mg in humans based on body surface area) for 1 year, after which the drug was discontinued for 1 year, and no carcinoid tumors were observed. One rat (2%) developed gastric adenocarcinoma, which was not seen in male and female rats at 2 years of dosing. Historically, no similar tumors have been documented in this genus of rats, and since only one case occurred, the significance is difficult to determine. In a 52-week toxicity test in SD rats, omeprazole doses of 0.4, 2, and 16 mg/kg/day (approximately 0.1-3.9 times the oral dose of 40 mg in humans based on body surface area) resulted in a small number of brain astrocytomas in males, but not in females. In a 2-year carcinogenicity test in SD rats, astrocytomas were not observed in males and females at the highest dose of 140.8 mg/kg/day (approximately 34 times the oral dose of 40 mg in humans, based on body surface area).
In the 78-week carcinogenicity test in omeprazole mice, no increase in tumor incidence was observed, but the results of this test were inconclusive. p53(+/-) transgenic mice showed negative results in the 26-week carcinogenicity test.
Juvenile animal studies:
Juvenile rats were given esomeprazole magnesium at doses of 70-280 mg/kg/day (approximately 17-68 times the human oral dose of 40 mg based on body surface area) for 28 consecutive days from postnatal day 7 to day 35, with a recovery period of 14 days. The results showed that the number of dead animals increased in the highest dose group. In addition, at 140 mg/kg/day (approximately 34 times the human oral dose of 40 mg based on body surface area) and higher doses, a decrease in body weight and weight gain, a decrease in femur weight and length, and an effect on overall growth were observed.
Similar results were observed for esomeprazole strontium at equimolar doses.
Pharmacokinetics
Absorption and distribution
Esomeprazole is unstable to acid and is administered orally in enteric-coated pellets. The amount of conversion to R-isomers in vivo is negligible. Esomeprazole is rapidly absorbed, with plasma concentrations peaking about 1~2 hours after oral administration. Absolute bioavailability was 64% after a single 40 mg dose and 89% after once-daily repeat dosing. the corresponding values for the 20 mg dose were 50% and 68%, respectively. The apparent volume of distribution at steady state in healthy subjects was approximately 0.22 L/kg body weight. The plasma protein binding of esomeprazole was 97%.
Feeding delayed and decreased the absorption of esomeprazole, but had no significant effect on the acidity-lowering effect of esomeprazole in the stomach.
Metabolism and excretion
Esomeprazole is completely metabolized by the cytochrome P450 enzyme system (CYP). Most of the metabolism of esomeprazole relies on the polymorphic CYP2C19, which generates the hydroxylated and demethylated metabolites of esomeprazole. The remainder relies on the metabolism of another specific isomer, CYP3A4, to generate esomeprazole sulfone, the latter being the major metabolite in plasma.
The following parameters primarily reflect the pharmacokinetic profile of individuals with normal CYP2C19 function, i.e., fast metabolizers.
Total plasma clearance is approximately 17 L/h after a single dose and approximately 9 L/h after multiple doses. plasma elimination half-life is approximately 1.3 hours after repeated once-daily dosing. The pharmacokinetics of esomeprazole 40 mg given twice daily have been studied. The area under the blood concentration-time curve (AUC) of esomeprazole increased after repeated administration. This increase was dose-dependent and resulted in a non-linear dose AUC relationship after multiple doses. This time and dose-dependence is due to first-pass metabolism and decreased total body clearance, which may be due to inhibition of CYP2C19 by esomeprazole and/or its metabolite esomeprazole sulfone. esomeprazole was completely eliminated from plasma without a tendency to accumulate between doses when administered as once daily.
The major metabolite of esomeprazole had no effect on gastric acid secretion. Nearly 80% of a single oral dose of esomeprazole is excreted as a metabolite in the urine, with the remainder excreted in the feces. Less than 1% of the drug in its original form is present in the urine.
Special patient populations
Approximately 2.9 ± 1.5% of individuals in Western populations lack the active CYP2C19 enzyme and are referred to as slow metabolizers, while in Asian populations, slow metabolizers make up approximately 13-23% of the population. Esomeprazole metabolism in this subset of individuals may be primarily catalyzed by CYP3A4. After repeated administration of esomeprazole 40 mg once daily, the mean area under the blood concentration-time curve (AUC) was nearly 100% higher in slow metabolizers than in individuals with active CYP2C19 (fast metabolizers), and the mean peak plasma concentration was increased by approximately 60%.
There were no significant changes in esomeprazole metabolism in the elderly (71 to 80 years).
After a single dose of esomeprazole 40 mg was given, the mean area under the blood concentration-time curve was approximately 30% higher in women than in men. No gender differences were observed after once-daily repeat dosing. These findings did not correlate with the dose of esomeprazole.
In patients with mild to moderate hepatic impairment, esomeprazole metabolism is diminished. The reduced metabolic rate in patients with severe hepatic impairment doubles the area under the blood concentration-time curve (AUC) of esomeprazole. Therefore, the maximum dose administered to patients with severe hepatic impairment should not exceed 20 mg. There is no tendency for esomeprazole or its major metabolites to accumulate when administered once daily.
Similar studies have not been conducted in patients with reduced renal function. Since the kidneys are responsible for the excretion of only the metabolites of esomeprazole and not the prodrug, no change in the metabolism of esomeprazole is expected in patients with renal impairment.
Storage]
Store under 25℃ in airtight storage.
Package】
Packed in high-density polyethylene bottle with built-in desiccant, 60 capsules/bottle, 1 bottle/box for oral solid drug.
Expiration date
24 months
Execution Standard
Approval number】
【Marketing license holder
Name
Name: Guangdong Dongyang Pharmaceutical Co.
Address
Address: North Industrial Zone, Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province
Postal Code: 523808
Telephone number: 0769-85370280
Fax number: 0769-85370206
Medical consulting phone number: 4006707855
Website: http://pharm.hec.cn/
【Manufacturer】
Company Name: Guangdong Dongyang Pharmaceutical Co.
Production Address: North Industrial Zone, Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province
Postal Code: 523808
Telephone number: 0769-85370280
Fax number: 0769-85370206
Website: http://pharm.hec.cn/
If you have any questions, you can contact directly with the drug marketing license holder.