Actions of Nexopral in details
Pharmacology: Nexopral reduces gastric acid secretion through a unique mechanism of action. It is a specific inhibitor of the gastric proton pump in the parietal cell. It is rapidly acting and produces reversible control of gastric acid secretion with once daily dosing.
Pharmacokinetics: Absorption and Distribution: Nexopral is acid labile and is administered orally as enteric-coated granules. In vivo conversion to the R-isomer is negligible. Absorption of Nexopral is rapid, with peak plasma levels occurring approximately 1-2 hours after dose.
The absolute bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once daily administration. For 20 mg Nexopral the corresponding values are 50% and 68%, respectively. The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Nexopral is 97% plasma protein bound.
Food intake both delays and decreases the absorption of Nexopral although this has no significant influence on the effect of Nexopral on intragastric acidity.
Metabolism and Excretion: Nexopral is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of Nexopral is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of Nexopral. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of Nexopral sulphone, the main metabolite in plasma.
How should I take Nexopral?
Take Nexopral strontium exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.
Nexopral strontium comes with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.
It may take several days before Nexopral strontium begins to relieve stomach pain. To help relieve this pain, antacids may be taken with Nexopral strontium, unless your doctor has told you not to use them.
Take Nexopral strontium at least 1 hour before a meal and for the full time of treatment, even if you begin to feel better after a few days.
If you are taking Nexopral strontium to treat an ulcer with an H. pylori infection, take it together with the antibiotics (eg, amoxicillin, clarithromycin).
To use the capsule:
- Swallow the capsule whole. Do not crush or chew it.
- If the capsule cannot be swallowed, open it and sprinkle the contents on one tablespoonful of applesauce. Do not heat the applesauce. Swallow the mixture right away. Do not chew or crush the granules. Throw away any remaining mixture.
To use the capsule with a nasogastric (NG) tube:
- Open the capsule and empty the granules into a 60 mL catheter-tipped syringe and mix it with 50 mL of water.
- Shake the syringe well for 15 seconds. Hold the syringe with the tip up and check the granules in the tip.
- Deliver the mixture into the nasogastric tube.
- Do not inject the granules if they have dissolved or have broken into pieces.
- Flush the tube with more water to rinse all of the medicine into the stomach.
Dosing
The dose of Nexopral strontium will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Nexopral strontium. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For oral dosage form (delayed-release capsules):
- To prevent NSAID-associated gastric ulcer:
- Adults—24.65 or 49.3 milligrams (mg) once a day for up to 6 months. Your doctor may adjust your dose if needed.
- Children—Use and dose must be determined by your doctor.
- To treat duodenal ulcers with H. pylori infection:
- Adults—49.3 milligrams (mg) once a day for 10 days. The dose is usually taken together with amoxicillin and clarithromycin. Your doctor may adjust your dose if needed.
- Children—Use and dose must be determined by your doctor.
- To treat erosive esophagitis:
- Adults—24.65 or 49.3 milligrams (mg) once a day for 4 to 8 weeks. Your doctor may adjust your dose if needed.
- Children—Use and dose must be determined by your doctor.
- To treat gastroesophageal reflux disease (GERD):
- Adults—24.65 milligrams (mg) once a day for 4 to 8 weeks. Your doctor may adjust your dose if needed.
- Children—Use and dose must be determined by your doctor.
- To treat Zollinger-Ellison syndrome:
- Adults—49.3 milligrams (mg) two times a day. Your doctor may adjust your dose if needed.
- Children—Use and dose must be determined by your doctor.
- To prevent NSAID-associated gastric ulcer:
Missed Dose
If you miss a dose of Nexopral strontium, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Storage
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Nexopral administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
This medicine is usually given for 4 to 8 weeks only. Your doctor may recommend a second course of treatment if you need additional healing time.
Take each dose with a full glass (8 ounces) of water.
Nexopral should be taken at least one hour before a meal.
Do not crush, chew, break, or open a delayed-release capsule. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time.
You may open the delayed-release capsule and sprinkle the medicine into a spoonful of pudding or applesauce to make swallowing easier. Swallow this mixture right away without chewing. Do not save the mixture for later use. Discard the empty capsule.
Nexopral can be given through a nasogastric (NG) feeding tube. Open the capsule and sprinkle the medicine into a 60-milliliter syringe. Mix in 50 milliliters of water. Place the plunger into the syringe and shake the mixture well. Make sure there are no medicine granules stuck in the tip of the syringe. Attach the syringe to the NG tube and push the plunger down to empty the syringe into the tube. Then flush the tube with more water to wash the contents down.
Take this medication for the full prescribed length of time. Your symptoms may improve before the condition is fully treated.
Call your doctor if your symptoms do not improve or if they get worse while you are taking this medicine.
This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using Nexopral.
Store at room temperature away from moisture and heat.
Nexopral pharmacology
Mechanism of Action
Nexopral is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, Nexopral blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion.
Pharmacodynamics
Antisecretory Activity
The effect of Nexopral magnesium on intragastric pH was determined in patients with symptomatic gastroesophageal reflux disease in two separate studies. In the first study of 36 patients, Nexopral magnesium 40 mg and 20 mg capsules were administered over 5 days. The results are shown in Table 3:
Table 3: Effect on Intragastric pH on Day 5 (N = 36)
| ||
| Parameter | Nexopral Magnesium 40 mg | Nexopral Magnesium 20 mg |
| % Time Gastric pH > 4* (Hours) | 70%† (16.8 h) | 53% (12.7 h) |
| Coefficient of variation | 26% | 37% |
| Median 24 Hour pH | 4.9† | 4.1 |
| Coefficient of variation | 16% | 27% |
In a second study, the effect on intragastric pH of Nexopral magnesium 40 mg administered once daily over a five day period was similar to the first study, (% time with pH > 4 was 68% or 16.3 hours).
Serum Gastrin Effects
The effect of Nexopral magnesium on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6 to 12 months. The mean fasting gastrin level increased in a dose-related manner. This increase reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.
Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop Nexopral treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.
Enterochromaffin-like (ECL) Cell Effects
In 24 month carcinogenicity studies of omeprazole in rats, a dose-related significant occurrence of gastric ECL cell 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.
Human gastric biopsy specimens have been obtained from more than 3,000 patients (both children and adults) treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients.
In over 1,000 patients treated with Nexopral magnesium (10, 20 or 40 mg/day) up to 6 to 12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.
Endocrine Effects
Nexopral magnesium had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other effects of Nexopral magnesium on the endocrine system were assessed using omeprazole studies. Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin, or secretin.
Pharmacokinetics
Absorption
Nexopral magnesium delayed-release capsules and Nexopral magnesium for delayed-release oral suspension contain a bioequivalent enteric-coated granule formulation of Nexopral magnesium. Bioequivalency is based on a single dose (40 mg) study in 94 healthy male and female volunteers under fasting condition. After oral administration, peak plasma levels (Cmax) occur at approximately 1.5 hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to Nexopral increases from 4.32 micromol*hr/L on Day 1 to 11.2 micromol*hr/L on Day 5 after 40 mg once daily dosing.
The AUC after administration of a single 40 mg dose of Nexopral magnesium is decreased by 43% to 53% after food intake compared to fasting conditions. Nexopral magnesium should be taken at least one hour before meals.
The pharmacokinetic profile of Nexopral magnesium was determined in 36 patients with symptomatic gastroesophageal reflux disease following repeated once daily administration of 20 mg and 40 mg capsules of Nexopral magnesium over a period of five days. The results are shown in Table 4:
Table 4: Pharmacokinetic Parameters of Nexopral Magnesium on Day 5 Following
Oral Dosing for 5 Days
| ||
| Parameter*(CV) | Nexopral Magnesium 40 mg | Nexopral Magnesium 20 mg |
| AUC (micromol·h/L) | 12.6 (42%) | 4.2 (59%) |
| Cmax (micromol/L) | 4.7 (37%) | 2.1 (45%) |
| Tmax (h) | 1.6 | 1.6 |
| t1/2 (h) | 1.5 | 1.2 |
Distribution
Nexopral is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 micromol/L. The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L.
Elimination
Metabolism
Nexopral is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of Nexopral lack antisecretory activity. The major part of Nexopral’s metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite. CYP2C19 isoenzyme exhibits polymorphism in the metabolism of Nexopral, since some 3% of Caucasians and 15 to 20% of Asians lack CYP2C19 and are termed Poor Metabolizers. At steady state, the ratio of AUC in Poor Metabolizers to AUC in the rest of the population (Extensive Metabolizers) is approximately 2.
Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the liver, resulting in higher plasma levels of the S- than of the R-isomer.
Excretion
The plasma elimination half-life of Nexopral is approximately 1 to 1.5 hours. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of Nexopral is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces.
Combination Therapy With Antimicrobials
Nexopral magnesium 40 mg once daily was given in combination with clarithromycin 500 mg twice daily and amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady state AUC and Cmax of Nexopral increased by 70% and 18%, respectively during triple combination therapy compared to treatment with Nexopral alone. The observed increase in Nexopral exposure during coadministration with clarithromycin and amoxicillin is not expected to produce significant safety concerns.
The pharmacokinetic parameters for clarithromycin and amoxicillin were similar during triple combination therapy and administration of each drug alone. However, the mean AUC and Cmax for 14-hydroxyclarithromycin increased by 19% and 22%, respectively, during triple combination therapy compared to treatment with clarithromycin alone. This increase in exposure to 14-hydroxyclarithromycin is not considered to be clinically significant.
Concomitant Use with Clopidogrel
Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and Nexopral (40 mg p.o. once daily) when coadministered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite.
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.
Specific Populations
Age: Geriatric Population
The AUC and Cmax values were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment based on age is not necessary.
Age: Pediatric Population
1 to 11 Years of Age
The pharmacokinetics of Nexopral were studied in pediatric patients with GERD aged 1 to 11 years. Following once daily dosing for 5 days, the total exposure (AUC) for the 10 mg dose in patients aged 6 to 11 years was similar to that seen with the 20 mg dose in adults and adolescents aged 12 to 17 years. The total exposure for the 10 mg dose in patients aged 1 to 5 years was approximately 30% higher than the 10 mg dose in patients aged 6 to 11 years. The total exposure for the 20 mg dose in patients aged 6 to 11 years was higher than that observed with the 20 mg dose in 12 to 17 year-olds and adults, but lower than that observed with the 40 mg dose in 12 to 17 year-olds and adults. See Table 6.
Table 6: Summary of PK Parameters in 1 to 11 Year Olds with GERD Following 5 Days of Once-Daily
Oral Nexopral Treatment
| |||
| 1 to 5 Year Olds | 6 to 11 Year Olds | ||
| Parameter | 10 mg (N = 8) | 10 mg (N = 7) | 20 mg (N = 6) |
| AUC (micromol·h/L)* | 4.83 | 3.70 | 6.28 |
| Cmax (micromol/L)* | 2.98 | 1.77 | 3.73 |
| tmax (h)† | 1.44 | 1.79 | 1.75 |
| t½λz (h)* | 0.74 | 0.88 | 0.73 |
| Cl/F (L/h)* | 5.99 | 7.84 | 9.22 |
12 to 17 Years of Age
The pharmacokinetics of Nexopral magnesium were studied in 28 adolescent patients with GERD aged 12 to 17 years inclusive, in a single center study. Patients were randomized to receive Nexopral magnesium 20 mg or 40 mg once daily for 8 days. Mean Cmax and AUC values of Nexopral were not affected by body weight or age; and more than dose-proportional increases in mean Cmax and AUC values were observed between the two dose groups in the study. Overall, Nexopral magnesium pharmacokinetics in adolescent patients aged 12 to 17 years were similar to those observed in adult patients with symptomatic GERD. See Table 7.
Table 7: Comparison of PK Parameters in 12 to 17 Year Olds with GERD and Adults With Symptomatic GERD Following the Repeated Daily
Oral Dose Administration of Esomeprazole1
| 12 to 17 Year Olds (N = 28) | Adults (N = 36) | |||
| 20 mg | 40 mg | 20 mg | 40 mg | |
| AUC (micromol·h/L) | 3.65 | 13.86 | 4.2 | 12.6 |
| Cmax (micromol/L) | 1.45 | 5.13 | 2.1 | 4.7 |
| tmax (h) | 2 | 1.75 | 1.6 | 1.6 |
| t½λz (h) | 0.82 | 1.22 | 1.2 | 1.5 |
| Data presented are geometric means for AUC, Cmax and t½λz, and median value for tmax. | ||||
1. Duration of treatment for 12 to 17 year olds and adults were 8 days and 5 days, respectively. Data were obtained from two independent studies.
Gender
The AUC and Cmax values were slightly higher (13%) in females than in males at steady state. Dosage adjustment based on gender is not necessary.
Hepatic Insufficiency
The steady state pharmacokinetics of Nexopral obtained after administration of 40 mg once daily to 4 patients each with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe (Child-Pugh Class C) liver insufficiency were compared to those obtained in 36 male and female GERD patients with normal liver function. In patients with mild and moderate hepatic insufficiency, the AUCs were within the range that could be expected in patients with normal liver function. In patients with severe hepatic insufficiency the AUCs were 2 to 3 times higher than in the patients with normal liver function. No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency (Child-Pugh Classes A and B). However, in patients with severe hepatic insufficiency (Child-Pugh Class C) a dose of 20 mg once daily should not be exceeded.
Renal Insufficiency
The pharmacokinetics of Nexopral magnesium in patients with renal impairment are not expected to be altered relative to healthy volunteers as less than 1% of Nexopral is excreted unchanged in urine.
Other Pharmacokinetic Observations
Coadministration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of Nexopral.
Studies evaluating concomitant administration of Nexopral and either naproxen (non-selective NSAID) or rofecoxib (COX-2 selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of Nexopral or these NSAIDs.
Microbiology
Nexopral magnesium, amoxicillin, and clarithromycin triple therapy has been shown to be active against most strains of Helicobacter pylori (H. pylori) in vitro and in clinical infections.
Helicobacter pylori: Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology, and minimum inhibitory concentrations (MICs) were determined.
Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC ≥ 1 mcg/mL) to H. pylori was 15% (66/445) at baseline in all treatment groups combined. A total of > 99% (394/395) of patients had H. pylori isolates that were considered to be susceptible (MIC ≤ 0.25 mcg/mL) to amoxicillin at baseline. One patient had a baseline H. pylori isolate with an amoxicillin MIC = 0.5 mcg/mL.
Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes: The baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results at the Day 38 visit are shown in Table 8:
Table 8: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes1 for Triple Therapy - (Nexopral magnesium 40 mg once daily/amoxicillin 1000 mg twice daily/clarithromycin 500 mg twice daily for 10 days)
| Clarithromycin Pretreatment Results | H. pylori negative (Eradicated) | H. pylori positive (Not Eradicated) Post-treatment susceptibility results | |||
| S2 | I2 | R2 | No MIC | ||
| 162 | 4 | 0 | 2 | 14 |
| 1 | 0 | 0 | 0 | 0 |
| 13 | 1 | 0 | 13 | 2 |
- 1.
- Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test results
- 2.
- Susceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC = 0.5 mcg/mL, Resistant (R) MIC ≥ 1 mcg/mL
Patients not eradicated of H. pylori following Nexopral magnesium/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, when possible. Patients with clarithromycin resistant H. pylori should not be re-treated with a clarithromycin-containing regimen.
Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: In the Nexopral magnesium/amoxicillin/clarithromycin clinical trials, 83% (176/212) of the patients in the Nexopral magnesium/amoxicillin/clarithromycin treatment group who had pretreatment amoxicillin susceptible MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori, and 17% (36/212) were not eradicated of H. pylori. Of the 36 patients who were not eradicated of H. pylori on triple therapy, 16 had no post-treatment susceptibility test results and 20 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Fifteen of the patients who were not eradicated of H. pylori on triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. There were no patients with H. pylori isolates who developed treatment emergent resistance to amoxicillin.
Susceptibility Test for Helicobacter pylori: For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.
Effects on Gastrointestinal Microbial Ecology: Decreased gastric acidity due to any means, including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile in hospitalized patients.
References
- DailyMed. "ESOMEPRAZOLE STRONTIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Esomeprazole: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Esomeprazole: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
