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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
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.
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
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
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
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
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
returned to baseline levels within four weeks after discontinuation of therapy.
Enterochromaffin-like (ECL) Cell Effects
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
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
ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.
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.
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
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)
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.
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.
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
adjustment based on age is not necessary.
Esomeprazole is contraindicated in patients with known hypersensitivity to substituted
benzimidazoles. Concomitant administration of Clarithromycin with pimozide is
The pharmacokinetics of esomeprazole have not been studied in patients < 18 years of
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
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
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:
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
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.
The potential effects of esomeprazole on fertility and reproductive performance were
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
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
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
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
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
NeksiumTM I.V. 40 mg for Injection is supplied as a freeze-dried powder containing 40
Safety and effectiveness in pediatric patients have not been established.
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.
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 -
GLENMARK GENERICS LTD.
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Journal of Clinical Neuroscience (2003) 10(3), 338–339ª 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0967-5868(03)00010-9Treatment of painful peripheral neuroma by vein implantationR.J. Mobbs BSc(MED) MB BS, M. Vonau MB BS FRACS, P. Blum MB BS FRACSDepartment of Neurosurgery, Institute of Neurological Sciences, The Prince of Wales Hospital, Sydney, AustraliaSummary Painful n
GENITOURINARY COMPLICATIONS Two of the very important genitourinary complications of diabetes are urinary tract infections and erectile dysfunction . Urinary Tract Infections: Diabetes is a risk factor for urinary tract infections (UTIs). UTIs are much more common in women than men, whether they have diabetes or not. Although the reason for the association between diabetes and UTIs