Nexonav/Nexonav IV

Nexonav: Each enteric-coated tab contains: Esomeprazole Magnesium Trihydrate Eq. to Esomeprazole 40 mg.
Nexonav IV: Each vial contains: Esomeprazole Sodium equivalent to Esomeprazole 40 mg.
Each ampoule contains: Sodium Chloride Injection 0.9% 10 mL.
White or almost white lyophilized mass filled in clear glass.
Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity.

Nexonav: Pharmacology: Esomeprazole is a compound that inhibits gastric acid secretion and is indicated in the treatment of gastroesophageal reflux disease (GERD), the healing of erosive esophagitis, and H. pylori eradication to reduce the risk of duodenal ulcer recurrence. Esomeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic properties, but that suppress gastric acid secretion by specific inhibition of the H⁺/K⁺ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, Esomeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.
Pharmacokinetics: Absorption: At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single close of 40 mg.
Distribution: Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 ì mol/L. The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L.
Metabolism: Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole lack anti secretory activity. The major part of esomeprazole's metabolism is dependent upon the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP 3A4 which forms the sulphone metabolite.
Excretion: The plasma elimination half-life of esomeprazole 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 esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces.
Nexonav IV: Pharmacotherapeutic group: Drugs for acid-related disorders, proton pump inhibitor.
Pharmacology: Pharmacodynamics: Mechanism of Action: Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K+-ATPase C the acid pump and inhibits both basal and stimulated acid secretion.
Pharmacodynamic effects: After 5 days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours respectively, over 24 hours in symptomatic GERD patients. The effect is similar irrespective of whether esomeprazole is administered orally or intravenously.
Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown after oral administration of esomeprazole.
During intravenous administration of 80 mg esomeprazole as a bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/h for 23.5 hours, intragastric pH above 4, and pH above 6 was maintained for a mean time of 21 hours and 11-13 hours, respectively, over 24 hours in healthy subjects.
Healing of reflux oesophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after 4 weeks, and in 93% after 8 weeks of oral treatment.
During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours.
Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in both children and adults during long-term treatment with orally administered esomeprazole. The findings are considered to be of no clinical significance.
During long-term oral treatment with antisecretory drugs, gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
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, in hospitalised patients, possibly also Clostridium difficile.
Pediatric population: Results from the pediatric studies further show that 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 month old infants, respectively, reduced the mean percentage of time with intra-oesophageal pH < 4.
The safety profile appeared to be similar to that seen in adults.
In a study in pediatric GERD patients (<1 to 17 years of age) receiving long-term PPI treatment, 61% of the children developed minor degrees of ECL cell hyperplasia with no known clinical significance and with no development of atrophic gastritis or carcinoid tumours.
Pharmacokinetics: Distribution:The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprazole is 97% plasma protein bound.
Metabolism: Esomeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma.
Elimination: The parameters as follows reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolizers.
Total plasma clearance is about 17 L/h after a single dose and about 9 L/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once daily dosing.
Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once daily administration.
The major metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.
Linearity/non-linearity: Total exposure (AUC) increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite.
Following repeated doses of 40 mg administered as intravenous injections, the mean peak plasma concentration is approx. 13.6 micromol/L. The mean peak plasma concentration after corresponding oral doses is approx. 4.6 micromol/L. A smaller increase (of approx. 30%) can be seen in total exposure after intravenous administration compared to oral administration. There is a dose-linear increase in total exposure following intravenous administration of esomeprazole as a 30-minute infusion (40 mg, 80 mg or 120 mg) followed by a continuous infusion (4 mg/h or 8 mg/h) over 23.5 hours.
Special patient populations: Poor metabolizers: Approximately 2.9 ±1.5% of the population lacks a functional CYP2C19 enzyme and is called poor metabolizers. In these individuals, the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once daily administration of 40 mg oral esomeprazole, the mean total exposure was approximately 100% higher in poor metabolizers than in subjects with a functional CYP2C19 enzyme (extensive metabolizers). Mean peak plasma concentrations were increased by about 60%. Similar differences have been seen for intravenous administration of esomeprazole. These findings have no implications for the posology of esomeprazole.
Hepatic impairment: The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate is decreased in patients with severe liver dysfunction resulting in a doubling of the total exposure of esomeprazole. Therefore, a maximum dose of 20 mg should not be exceeded in GERD patients with severe dysfunction. For patients with bleeding ulcers and severe liver impairment, following an initial bolus dose of 80 mg, a maximum continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient. Esomeprazole or its major metabolites do not show any tendency to accumulate with once daily dosing.
Renal impairment: No studies have been performed in patients with decreased renal function. The metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Elderly: The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).
Pediatric population: In a randomized, open-label, multi-national, repeated dose study, esomeprazole was given as a once-daily 3-minute injection over four days. The study included a total of 59 pediatric patients 0 to 18 years old of which 50 patients (7 children in the age group 1 to 5 years) completed the study and were evaluated for the pharmacokinetics of esomeprazole.
The table as follows describes the systemic exposure to esomeprazole following the intravenous administration as a 3-minute injection in pediatric patients and adult healthy subjects. The values in the table are geometric means (range). The 20 mg dose for adults was given as a 30-minute infusion. The C_ss,max was measured 5 minutes post-dose in all pediatric groups and max7 minutes post-dose in adults on the 40 mg dose, and after stop of infusion in adults on the 20 mg dose. (See table.)

Click on icon to see table/diagram/image

Model based predictions indicate that C_ss,max following intravenous administration of esomeprazole as a 10-minute, 20-minute and 30-minute infusions will be reduced by on average 37% to 49%, 54% to 66% and 61% to 72%, respectively, across all age and dose groups compared to when the dose is administered as a 3-minute injection.

Nexonav: For the treatment of peptic ulcer disease, and other conditions where inhibition of gastric acid secretion may be beneficial, including aspiration syndrome, Healing of Erosive Esophagitis, dyspepsia, gastro-esophageal reflux disease, Zollinger Ellison Syndrome.
Nexonav IV: Treatment of peptic ulcer disease, NSAID associated ulceration, gastroesophageal reflux disease and Zollinger-Ellison syndrome.

Nexonav: The usual dose for adults is 1 to 2 capsules once a day.
Dyspepsia: 10 mg or 20 mg daily for 2 to 4 weeks.
Gastro-oesophageal Reflux Disease: 20 mg to 40 mg once daily for 4 to 12 weeks, or maximum daily dose of 40 mg given 4 to 12 weeks.
Erosive reflux oesophagitis: 40 mg once daily for 4 weeks.
Peptic ulcer disease: 20 mg once daily or 40 mg daily in severe cases. Treatment is continued for 4 weeks for duodenal and 8 weeks for gastric ulcer. A dose of 10 mg to 20 mg once daily may be given for maintenance.
Zollinger Ellison Syndrome: The recommended initial dosage is Esomeprazole 40 mg twice daily. The dosage should then be individually adjusted and treatment continues as long as clinically indicated. Based on the clinical data available, the majority of patients can be controlled on doses between 80 and 160 mg esomeprazole daily. With doses above 80 mg daily, the dose should be divided and given twice-daily.
NSAID-Associated Ulceration: 20 mg daily.
Or as prescribed by the physician.
Nexonav IV: The recommended adult dose of Esomeprazole I.V is either 20 or 40 mg given once daily by intravenous injection (no less than 3 minutes) or intravenous infusion (10 to 30 minutes). Esomeprazole I.V. should not be administered concomitantly with any other medications through the same intravenous site and/or tubing. The intravenous line should always be flushed with either 0.9% Sodium Chloride Injection USP, Lactated Ringer Injection USP, or 5% Dextrose Injection USP, both prior to and after administration of Esomeprazole I.V. for Injection.
Or as prescribed by physician.

Nexonav IV: There is very limited experience to date with deliberate overdose. The symptoms described in connection with an oral dose of 280 mg were gastrointestinal symptoms and weakness. Single oral doses of 80 mg esomeprazole and intravenous doses of 308 mg esomeprazole over 24 hours were uneventful. No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

Nexonav: Hypersensitivity to the active substance or to any of the excipients.
Nexonav IV: Esomeprazole for Injection is contraindicated in patients with known hypersensitivity to the formulation.

Nexonav: Patients know that antacids may be used while taking Esomeprazole, Esomeprazole can interfere with antiretroviral drugs and drugs that are affected by gastric pH changes.
Use in Pregnancy: Esomeprazole is not recommended in pregnancy.
Nexonav IV: Do not use Esomeprazole if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged. If you also take an imidazole antifungal (eg, ketoconazole), take it at least 2 hours before using Esomeprazole.

Nexonav: Pregnancy: Esomeprazole is not recommended in pregnancy.
Nexonav IV: Pregnancy: Clinical data on exposed pregnancies with esomeprazole are insufficient. With the racemic mixture, omeprazole data on a larger number of exposed pregnancies from epidemiological studies indicate no malformative nor foetotoxic effect. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/fetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development. Caution should be exercised when prescribing esomeprazole to pregnant women.
A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicated no malformative or foeto/neonatal toxicity of esomeprazole. Use is recommended only if clearly needed and the benefit outweighs the risk.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
Breastfeeding: It is not known whether esomeprazole is excreted in human breast milk, there is insufficient information on the effects of esomeprazole in newborns/infants. Esomeprazole should not be used during breastfeeding.

Nexonav: Esomeprazole, like other PPIs, is well-tolerated. The most common side effects are diarrhea, nausea, vomiting, headaches, rash and dizziness. Nervousness, abnormal heartbeat, muscle pain, weakness, leg cramps and water retention occur infrequently.
Nexonav IV: Common Side effects: Constipation; diarrhea; dry mouth; gas; headache; nausea; pain, swelling, or redness at the injection site; stomach pain.
Severe Side effects: Severe allergic reactions (rash; hives; itching; difficulty of breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); chest pain; fast heartbeat; fever, chills, or sore throat; red, swollen, blistered, or peeling skin; unusual bruising or bleeding; unusual tiredness. Seek medical attention right away if any of these severe side effects occur.

Nexonav: Esomeprazole potentially can increase the concentration in blood of diazepam by decreasing the elimination of diazepam in the liver. Esomeprazole may have fewer drug interactions than omeprazole.
The absorption of certain drugs may be affected by stomach acidity. Therefore, esomeprazole and other PPIs that reduce stomach acid also reduce the absorption and concentration in blood of ketoconazole and increase the absorption and concentration in blood of digoxin. This may lead to reduced effectiveness of ketoconazole or increased digoxin toxicity, respectively. Through unknown mechanisms, esomeprazole may increase blood levels of saquinavir and reduce blood levels of nelfinavir and atazanavir. Therefore, nelfinavir or atazanavir should not be administered with esomeprazole, and physicians should consider reducing the dose of saquinavir in order to avoid side effects from saquinavir.
Nexonav IV: Effects of esomeprazole on the pharmacokinetics of other medicinal product: Protease inhibitors: Omeprazole has been reported to interact with some protease inhibitors. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the protease inhibitors. Other possible interaction mechanisms are via inhibition of CYP2C19.
For atazanavir and nelfinavir, due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir is not recommended and concomitant administration with esomeprazole and nelfinavir is contraindicated.
For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg qd).
Methotrexate: When given together with PPIs, methotrexate levels have been reported to increase in some patients. In high-dose methotrexate administration a temporary withdrawal of esomeprazole may need to be considered.
Tacrolimus: Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus. A reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed.
Medicinal products with pH dependent absorption: Gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of medicinal products with a gastric pH dependent absorption. As with other medicinal products that decrease intragastric acidity, the absorption of medicinal products such as ketoconazole, itraconazole and erlotinib can decrease and the absorption of digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is given at high doses in elderly patients. Therapeutic medicinal product monitoring of digoxin should then be reinforced.
Medicinal products metabolised by CYP2C19: Esomeprazole inhibits CYP2C19, the major esomeprazole-metabolising enzyme. Thus, when esomeprazole is combined with medicinal products metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these medicinal products may be increased and a dose reduction could be needed. No in vivo interaction studies have been performed with the high dose intravenous regimen (80 mg + 8 mg/h). The effect of esomeprazole on drugs metabolised by CYP2C19 may be more pronounced during this regimen, and patients should be monitored closely for adverse effects during the 3-day intravenous treatment period.
Diazepam: Concomitant oral administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam.
Phenytoin: Concomitant oral administration of 40 mg esomeprazole and phenytoin resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.
Voriconazole: Omeprazole as well as Esomeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C_max and AUC by 15% and 41% respectively.
Cilostazol: Omeprazole as well as esomeprazole act as inhibitors of CYP2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased C_max and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.
Cisapride: In healthy volunteers, concomitant oral administration of 40 mg esomeprazole and cisapride resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t_1/2) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole.
Warfarin: Concomitant oral administration of 40 mg esomeprazole to warfarin-treated patients in a clinical trial showed that coagulation times were within the accepted range. However, post-marketing of oral esomeprazole, a few isolated cases of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives.
Clopidogrel: Results from studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40% and resulting in decreased maximum inhibition of (ADP induced) platelet aggression by an average of 14%.
When clopidogrel was given together with a fixed dose combination of esomeprazole 20 mg + ASA 81 mg compared to clopidogrel alone in a study in health subjects there was a decreased exposure by almost 40% of the active metabolite of clopidogrel. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were the same in the clopidogrel and the clopidogrel + the combined (esomeprazole + ASA) product groups.
Inconsistent data on the clinical implications of a PK/PD interaction of esomeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution concomitant use of clopidogrel should be discouraged.
Effects of other medicinal products on the pharmacokinetics of esomeprazole: Medicinal products which inhibit CYP2C19 and/or CYP3A4: Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant oral administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg b.i.d.), resulted in a doubling of the exposure (AUC) to esomeprazole. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUC by 280%. A dose adjustment of esomeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.
Medicinal products which induce CYP2C19 and/or CYP3A4: Medicinal products known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.
Pediatric population: Interaction studies have only been performed in adults.

Nexonav IV: Direction for Reconstitution: Reconstitute with 10 mL of 0.9% Sodium Chloride Injection.
Reconstituted solution may be stored at room temperature and must be used within 24 hours from the time of initial reconstitution.

Store at temperatures not exceeding 30°C.

Antacids, Antireflux Agents & Antiulcerants

A02BC05 - esomeprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

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