Pd13970 leaflet neksium injection - sover g.cdr

For the use only of a Registered Medical Practitioner 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 (See DOSAGE AND ADMINISTRATION).
ESOMEPRAZOLE SODIUM POWDER
Renal Insufficiency
The pharmacokinetics of esomeprazole in patients with renal impairment are not
FOR SOLUTION FOR INJECTION
expected to be altered relative to healthy volunteers as less than 1% of esomeprazole is excreted unchanged in urine.
PHARMACODYNAMICS
Mechanism of Action
Esomeprazole 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
DESCRIPTION
pump, esomeprazole blocks the final step in acid production, thus reducing gastric The active ingredient in NEKSIUM I.V. (esomeprazole sodium) for Injection is (S)-5- acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition methoxy-2 [[(4-methoxy-3, 5-dimethyl-2-pyridinyl)-methyl] sulfinyl]-1 H benzimidazole sodium a compound that inhibits gastric acid secretion. Esomeprazole is the S-isomer of Antisecretory Activity
omeprazole, which is a mixture of the S- and R- isomers.
The effect of intravenous esomeprazole on intragastric pH was determined in two Its empirical formula is C17H18N3O3SNa with molecular weight of 367.4 g/mol (sodium salt) separate studies. In the first study, 20 mg of esomeprazole I.V. for Injection was and 345.4 g/mol (parent compound). Esomeprazole sodium is very soluble in water and administered intravenously once daily at constant rate over 30 minutes for 5 days. Twenty-two healthy subjects were included in the study. In the second study, 40 mg of The structural formula is:
esomeprazole I.V. for Injection was administered intravenously once daily at constant rate over 30 minutes for 5 days. Thirty-eight healthy subjects were included in the study.
Effect of esomeprazole IV for Injection dosing for 5 days on Intragastric pH on
PARAMETER
ESOMEPRAZOLE 20mg
ESOMEPRAZOLE 40mg
Esomeprazole I.V. for Injection is supplied as a sterile, freeze-dried, white to off-white, Gastric pH was measured over 24 hour period
porous cake or powder in a 10 mL vial, intended for intravenous administration after reconstitution with 0.9% Sodium Chloride Injection.
Serum Gastrin Effects
In oral studies, the effect of esomeprazole on serum gastrin concentrations was
COMPOSITION
evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 Each vial contains esomeprazole sodium equivalent to esomeprazole 40 mg (Suitably patients for up to 6-12 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 CLINICAL PHARMACOLOGY
returned to baseline levels within four weeks after discontinuation of therapy.
PHARMACOKINETICS
Enterochromaffin-like (ECL) Cell Effects
Absorption
There are no data available on the effects of intravenous esomeprazole on ECL cells. In The pharmacokinetic profile of esomeprazole I.V. for Injection 20 mg and 40 mg was 24-month carcinogenicity studies of oral omeprazole in rats, a dose-related significant determined in 24 healthy volunteers or the 20 mg dose and 38 healthy volunteers for the occurrence of gastric ECL cell carcinoid tumors and ECL cell hyperplasia was observed 40 mg dose following once daily administration of 20 mg and 40 mg of esomeprazole I.V. in both male and female animals (see PRECAUTIONS, Carcinogenesis, Mutagenesis, for Injection by constant rate over 30 minutes for five days. Impairment of Fertility). Carcinoid tumors have also been observed in rats subjected to The results are shown in the following table: 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 Pharmacokinetic parameters of esomeprazole following
than 3,000 patients treated orally with omeprazole in long-term clinical trials. The IV dosing for 5 days
incidence of ECL cell hyperplasia in these studies increased with time; however, no case PARAMETER
Esomeprazole IV 20mg
Esomeprazole IV 40mg
of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. In over 1,000 patients treated with esomeprazole (10, 20 or 40 mg/day) up to 6-12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed (µmol h/l)
ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.
Endocrine Effects
(µmol h/l)
Esomeprazole had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other effects of esomeprazole 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, Values represent the geometric mean 95% CI (Confidence Interval)
cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin.
Distribution
Clinical Studies
Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over Acid Suppression in Gastroesophageal Reflux Disease (GERD)
the concentration range of 2-20 µmol/L. The apparent volume of distribution at steady Four multicenter, open-label, two-period crossover studies were conducted to compare state in healthy volunteers is approximately 16 L.
the pharmacodynamic efficacy of the intravenous formulation of esomeprazole (20 mg Metabolism
and 40 mg) to that of esomeprazole Eenteric-coated tablets at corresponding doses in Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) patients with symptoms of GERD, with or without erosive esophagitis. enzyme system. The metabolites of esomeprazole lack antisecretory activity. The major The patients (n=206, 18 to 72 years old; 112 female; 110 Caucasian, 50 Black, 10 part of esomeprazole's metabolism is dependent upon the CYP2C19 isoenzyme, which Oriental, and 36 Other Race) were randomized to receive either 20 or 40 mg of forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on intravenous or oral esomeprazole once daily for 10 days (Period 1), and then were CYP3A4, which forms the sulphone metabolite. CYP2C19 isoenzyme exhibits switched in Period 2 to the other formulation for 10 days, matching their respective dose polymorphism in the metabolism of esomeprazole, since some 3% of Caucasians and 15-20% of Asians lack CYP2C19 and are termed Poor Metabolizers. At steady state, the The intravenous formulation was administered as a 3-minute injection in two of the ratio of AUC in Poor Metabolizers to AUC in the rest of the population (Extensive studies, and as a 15-minute infusion in the other two studies. Basal acid output (BAO) and metabolizers) is approximately 2. Following administration of equimolar doses, the S- maximal acid output (MAO) were determined 22-24 hours post-dose on Period 1, Day 11; and R isomers are metabolized differently by the liver, resulting in higher plasma levels of on Period 2, Day 3; and on Period 2, Day 11. BAO and MAO were estimated from 1-hour continuous collections of gastric contents prior to and following (respectively) Excretion
subcutaneous injection of 6.0 µg/kg of pentagastrin. Esomeprazole is excreted as metabolites primarily in urine but also in faeces. Less than In these studies, after 10 days of once daily administration, the intravenous dosage forms 1% of parent drug is excreted in the urine. Esomeprazole is completely eliminated from of esomeprazole 20 mg and 40 mg were similar to the corresponding oral dosage forms in plasma and there is no accumulation during once daily administration. The plasma their ability to suppress BAO and MAO in these GERD patients (see table below). elimination half-life of intravenous esomeprazole is approximately 1.1 to 1.4 hours and is There were no major changes in acid suppression when switching between intravenous prolonged with increasing dose of intravenous esomeprazole.
Special Populations
INDICATIONS
Investigations of age, gender, race, renal, and hepatic impairment and metabolizer status Neksium I.V. for Injection is indicated for the short-term treatment (up to 10 days) of have been made previously with oral esomeprazole. The pharmacokinetics of GERD patients with a history of erosive esophagitis as an alternative to oral therapy in esomeprazole is not expected to be affected differently by intrinsic or extrinsic factors patients when therapy with esomeprazole enteric-coated tablets is not possible or after intravenous administration compared to oral administration. The same recommendations for dose adjustment in special populations are suggested for When oral therapy is possible or appropriate, intravenous therapy with esomeprazole I.V. intravenous esomeprazole as for oral esomeprazole.
for Injection should be discontinued and the therapy should be continued orally.
Geriatric
NEKSIUM for injection is also indicated for prevention of bleeding following therapeutic In oral studies, the AUC and Cmax values were slightly higher (25% and 18%, endoscopy for acute bleeding gastric or duodenal ulcers.
respectively) in the elderly as compared to younger subjects at steady state. Dosage CONTRAINDICATIONS
adjustment based on age is not necessary. Esomeprazole is contraindicated in patients with known hypersensitivity to substituted Pediatric
benzimidazoles. Concomitant administration of Clarithromycin with pimozide is The pharmacokinetics of esomeprazole have not been studied in patients < 18 years of PRECAUTIONS
In oral studies, the AUC and Cmax values were slightly higher (13%) in females than in Symptomatic response to therapy with esomeprazole does not preclude the presence of males at steady state. Similar differences have been seen for intravenous administration gastric malignancy. Atrophic gastritis has been noted occasionally in gastric corpus of esomeprazole. Dosage adjustment based on gender is not necessary. biopsies from patients treated long-term with omeprazole, of which esomeprazole is an Hepatic Insufficiency
enantiomer. Treatment with esomeprazole I.V. for Injection should be discontinued as In oral studies, the steady state pharmacokinetics of esomeprazole obtained after soon as the patient is able to resume treatment with esomeprazole Enteric-coated 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 Drug Interactions
compared to those obtained in 36 male and female GERD patients with normal liver Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro function. In patients with mild and moderate hepatic insufficiency, the AUCs were within and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by esomeprazole (n=359) in trials irrespective of the relationship to esomeprazole are listed these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, Skin and appendages disorders: pruritus (1.1%);
warfarin, quinidine, clarithromycin or amoxicillin. Central and peripheral nervous system disorders: dizziness (2.5%), headache
Post-marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy. Increases in INR and Gastrointestinal system disorders: abdominal pain (5.8%), constipation (2.5%),
prothrombin time may lead to abnormal bleeding and even death. Patients treated with diarrhea (3.9%), dyspepsia (6.4%), flatulence (10.3%), mouth dry (3.9%), nausea proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. Esomeprazole may potentially interfere with Respiratory system disorders: respiratory infection (1.1%), sinusitis (1.7%);
CYP2C19, the major esomeprazole-metabolizing enzyme. Body as whole general disorders: AE associated with test procedure (23.1%); and
Coadministration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted Application site disorders: application site reaction (1.7%) (Including mild focal erythema in a 45% decrease in clearance of diazepam. Increased plasma levels of diazepam were observed 12 hours after dosing and onwards. However, at that time, the plasma levels of Intravenous treatment with esomeprazole 20 and 40 mg administered as an injection or diazepam were below the therapeutic interval, and thus this interaction is unlikely to be of as an infusion was found to have a safety profile similar to that of oral administration of clinical relevance. Coadministration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of esomeprazole. Concomitant administration of esomeprazole may reduce the plasma levels of OVERDOSAGE
atazanavir. Studies evaluating concomitant administration of esomeprazole and either The minimum lethal dose of esomeprazole sodium in rats after bolus administration was naproxen (non-selective NSAID) or rofecoxib (COX-2 selective NSAID) did not identify 310 mg/kg (about 62 times the human dose on a body surface area basis). The major any clinically relevant changes in the pharmacokinetic profiles of esomeprazole or these signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia and intermittent clonic convulsions. There have been some reports of Esomeprazole inhibits gastric acid secretion. Therefore, esomeprazole may interfere overdosage with oral esomeprazole. Reports have been received of overdosage with with the absorption of drugs where gastric pH is an important determinant of oral omeprazole in humans. Doses ranged up to 2,400 mg (120 times the usual bioavailability (e.g., ketoconazole, iron salts and digoxin).
recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry Carcinogenesis, Mutagenesis, Impairment of Fertility
mouth, and other adverse reactions similar to those seen in normal clinical experience. The carcinogenic potential of esomeprazole was assessed using omeprazole studies. In No specific antidote for esomeprazole is known. two 24-month oral carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, Since esomeprazole is extensively protein bound, it is not expected to be removed by 13.8, 44.0 and 140.8 mg/kg/day (about 0.7 to 57 times the human dose of 20 mg/day dialysis. In the event of overdosage, treatment should be symptomatic and supportive. expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose- As with the management of any overdose, the possibility of multiple drug ingestion should 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 DOSAGE AND ADMINISTRATION
treated groups of both sexes. In one of these studies, female rats were treated with 13.8 GERD with a history of Erosive Esophagitis
mg omeprazole/kg/day (about 5.6 times the human dose on a body surface area basis) The recommended adult dose is either 20 or 40 mg esomeprazole given once daily by for 1 year, and then followed for an additional year without the drug. No carcinoids were intravenous injection (no less than 3 minutes) or intravenous infusion (10 to 30 minutes). Esomeprazole I.V. for Injection should not be administered concomitantly with any other An increased incidence of treatment-related ECL cell hyperplasia was observed at the medications through the same intravenous site and or tubing. The intravenous line end of 1 year (94% treated vs. 10% controls). By the second year the difference between should always be flushed with either 0.9% Sodium Chloride Injection both prior to and treated and control rats was much smaller (46% vs 26%) but still showed more after administration of esomeprazole I.V. for Injection. Treatment with esomeprazole I.V. hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No for Injection should be discontinued as soon as the patient is able to resume treatment similar tumor was seen in male or female rats treated for 2 years. For this strain of rat no with esomeprazole Enteric-coated Tablets. Safety and efficacy of esomeprazole I.V. for similar tumor has been noted historically, but a finding involving only one tumor is difficult Injection as a treatment of GERD patients with a history of erosive esophagitis for more than 10 days have not been demonstrated (see INDICATIONS).
A 78-week oral mouse carcinogenicity study of omeprazole did not show increased tumor Prevention of bleeding following therapeutic endoscopy for acute bleeding gastric
occurrence, but the study was not conclusive. Esomeprazole was negative in the Ames or duodenal ulcers:
mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in 80 mg should be administered as a bolus intravenous infusion over 30 minutes, followed vivo mouse micronucleus test. Esomeprazole, however, was positive in the in vitro by a continuous intravenous infusion of 8 mg/h given over 3 days (72 hours).
human lymphocyte chromosome aberration test. Omeprazole was positive in the in vitro The parenteral treatment period should be followed by oral acid-suppression therapy.
human lymphocyte chromosome aberration test, the in vivo mouse bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. SPECIAL POPULATIONS
The potential effects of esomeprazole on fertility and reproductive performance were Geriatric: No dosage adjustment is necessary. (See CLINICAL PHARMACOLOGY,
assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times the human dose on a body surface area basis) was found to have no Renal Insufficiency: No dosage adjustment is necessary. (See CLINICAL
effect on reproductive performance of parental animals.
PHARMACOLOGY, Pharmacokinetics.)
Hepatic Insufficiency: No dosage adjustment is necessary in patients with mild to
Pregnancy
moderate liver impairment (Child Pugh Classes A and B). For patients with severe liver Teratogenic Effects. Pregnancy Category B
impairment (Child Pugh Class C), a dose of 20 mg of esomeprazole should not be Teratology studies have been performed in rats at oral doses up to 280 mg/kg/day (about exceeded (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) 57 times the human dose on a body surface area basis) and in rabbits at oral doses up to Gender: No dosage adjustment is necessary. (See CLINICAL PHARMACOLOGY,
86 mg/kg/day (about 35 times the human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole. There are, however, no adequate and well-controlled studies in pregnant women. PREPARATIONS FOR USE
Because animal reproduction studies are not always predictive of human response, this Intravenous Injection 40 mg over no less than 3 minutes
drug should be used during pregnancy only if clearly needed.
The freeze-dried powder should be reconstituted with 5 mL of 0.9% Sodium Chloride Teratology studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day Injection. Withdraw 5 mL of the reconstituted solution and administer as an intravenous (about 56 times the human dose on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 56 times the human dose on a body surface area basis) did not The reconstituted solution should be stored at room temperature up to 30 C and disclose any evidence for a teratogenic potential of omeprazole. administered within 12 hours after reconstitution. No refrigeration is required.
In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 5.5 to 56 times the Intravenous Infusion 40 mg over 10 to 30 minutes.
human dose on a body surface area basis) produced dose-related increases in embryo- A solution for intravenous infusion is prepared by first reconstituting the contents of one lethality, fetal resorptions, and pregnancy disruptions. vial with 5 mL of 0.9% Sodium Chloride Injection further diluting the resulting solution to a 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 The solution (admixture) should be administered as an intravenous infusion over a period mg/kg/day (about 5.6 to 56 times the human doses on a body surface area basis). of 10 to 30 minutes. No refrigeration is required. Esomeprazole I.V. for Injection should There are no adequate and well-controlled studies in pregnant women. Sporadic reports not be administered concomitantly with any other medications through the same have been received of congenital abnormalities occurring in infants born to women who have received omeprazole during pregnancy.
The intravenous line should always be flushed with either 0.9% Sodium Chloride Nursing Mothers
Injection both prior to and after administration of esomeprazole I.V. for Injection. The excretion of esomeprazole in milk has not been studied. However, omeprazole Parenteral drug products should be inspected visually for particulate matter and concentrations have been measured in breast milk of a woman following oral discoloration prior to administration, whenever solution and container permit.
administration of 20 mg. Because esomeprazole is likely to be excreted in human milk, Infusion 80 mg
because of the potential for serious adverse reactions in nursing infants from A solution for infusion is prepared by dissolving the content of two vials of Neksium 40 mg esomeprazole, and because of the potential for tumorigenicity shown for omeprazole in in up to 100 ml of 0.9% sodium chloride for intravenous use.
rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother PRESENTATION
NeksiumTM I.V. 40 mg for Injection is supplied as a freeze-dried powder containing 40
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Of the total number of patients who received oral esomeprazole in clinical trials, 1,459 Store in a cool, dry place and protect from light. were 65 to 74 years of age and 354 patients were≥ 75 years of age. No overall differences in safety and efficacy were observed between the elderly and If reconstituted solution contains any visible particulate matter do not use.
younger individuals, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some DATE OF REVISION
older individuals cannot be ruled out.
ADVERSE REACTIONS
Safety Experience with Intravenous esomeprazole: The safety of intravenous
esomeprazole is based on results from clinical trials conducted in three different populations including patients having symptomatic GERD with or without a history of erosive esophagitis (n=206), patients with erosive esophagitis (n=246) and healthy Adverse experiences occurring in >1% of patients treated with intravenous Further information is available on request from:
AstraZeneca Pharma India Ltd
'Avishkar', P B No. 2483, Off Bellary Road,
Hebbal, Bangalore - 560024. INDIA
GLENMARK GENERICS LTD.
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