Nexium Tablets 20mg

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1. Name Of The Medicinal Product

NEXIUM® 20 mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains: 20mg esomeprazole (as magnesium trihydrate).

For excipients see 6.1.

3. Pharmaceutical Form

Gastro-resistant tablet

20 mg: A light pink, oblong, biconvex, film-coated tablet engraved 20 mg on one side and

4. Clinical Particulars 4.1 Therapeutic Indications

NEXIUM tablets are indicated for:

Gastroesophageal Reflux Disease (GERD)

• treatment of erosive reflux esophagitis

• long-term management of patients with healed esophagitis to prevent relapse

• symptomatic treatment of gastroesophageal reflux disease (GERD)

In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori and

• healing of Helicobacter pylori associated duodenal ulcer and

• prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers.

4.2 Posology And Method Of Administration

The tablets should be swallowed whole with liquid. The tablets should not be chewed or crushed.

Gastroesophageal Reflux Disease (GERD)

• treatment of erosive reflux esophagitis

40 mg once daily for 4 weeks.

An additional 4 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms.

• long-term management of patients with healed esophagitis to prevent relapse

20 mg once daily.

• symptomatic treatment of gastroesophageal reflux disease (GERD)

20 mg once daily in patients without esophagitis. If symptom control has not been achieved after four weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen taking 20 mg once daily, when needed.

In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori and

• healing of Helicobacter pylori associated duodenal ulcer and

• prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers.

20 mg NEXIUM with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days.

Children

NEXIUM should not be used in children since no data is available.

Impaired renal function

Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution. (See Section 5.2).

Impaired hepatic function

Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum dose of 20 mg NEXIUM should not be exceeded. (See section 5.2).

Elderly

Dose adjustment is not required in the elderly.

4.3 Contraindications

Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of the formulation.

4.4 Special Warnings And Precautions For Use

In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with NEXIUM may alleviate symptoms and delay diagnosis.

Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. When prescribing esomeprazole for on-demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole should be considered. See section 4.5

When prescribing esomeprazole for eradication of Helicobacter pylori possible drug interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for clarithromycin should be considered when the triple therapy is used in patients concurrently taking other drugs metabolised via CYP3A4 such as cisapride.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of esomeprazole on the pharmacokinetics of other drugs

The decreased intragastric acidity during treatment with esomeprazole, might increase or decrease the absorption of drugs if the mechanism of absorption is influenced by gastric acidity. In common with the use of other inhibitors of acid secretion or antacids, the absorption of ketoconazole and itraconazole can decrease during treatment with esomeprazole.

Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with drugs metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these drugs may be increased and a dose reduction could be needed. This should be considered especially when prescribing esomeprazole for on-demand therapy. Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. Concomitant administration of 40 mg esomeprazole 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.

In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life(t1/2) 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 (see also section 4.4).

Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin, quinidine or warfarin.

Effects of other drugs on the pharmacokinetics of esomeprazole

Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg b.i.d.), resulted in a doubling of the exposure (AUC) to esomeprazole. Dose adjustment of esomeprazole is not required.

4.6 Pregnancy And Lactation

For esomeprazole no clinical data on exposed pregnancies are available. 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 to pregnant women.

It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore NEXIUM should not be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

No effects have been observed.

4.8 Undesirable Effects

The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole. None was found to be dose-related.

Common

Headache, abdominal pain, diarrhoea, flatulence, nausea/vomiting, constipation.

(>1/100, <1/10)

 

 

 

 

 

Uncommon

Dermatitis, pruritus, urticaria, dizziness, dry mouth

(>1/1000, <1/100)

 

 

The following adverse drug reactions have been observed for the racemate (omeprazole) and may occur with esomeprazole:

Central and peripheral nervous system

Paraesthesia, somnolence, insomnia, vertigo. Reversible mental confusion, agitation, aggression, depression and hallucinations, predominantly in severely ill patients.

Endocrine

Gynaecomastia.

Gastrointestinal

Stomatitis and gastrointestinal candidiasis.

Haematological

Leukopenia, thrombocytopenia, agranulocytosis and pancytopenia.

Hepatic

Increased liver enzymes, encephalopathy in patients with pre-existing severe liver disease; hepatitis with or without jaundice, hepatic failure.

Musculoskeletal

Arthralgia, muscular weakness and myalgia.

Skin

Rash, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), alopecia.

Other

Malaise. Hypersensitivity reactions e.g. angioedema, fever, bronchospasm, interstitial nephritis and anaphylactic shock. Increased sweating, peripheral oedema, blurred vision, taste disturbance and hyponatraemia.

4.9 Overdose

There is no experience to date with deliberate overdose. Data are limited but single doses of 80 mg esomeprazole 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.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC Code: A02B C05

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.

Site and 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 – the acid pump and inhibits both basal and stimulated acid secretion.

Effect on gastric acid secretion

After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg esomeprazole once daily for five days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6 – 7 hours after dosing on day five.

After five 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 proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.

Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.

Therapeutic effects of acid inhibition

Healing of reflux esophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after four weeks, and in 93% after eight weeks.

One week treatment with esomeprazole 20 mg b.i.d. and appropriate antibiotics, results in successful eradication of H. pylori in approximately 90% of patients.

After eradication treatment for one week there is no need for subsequent monotherapy with antisecretory drugs for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.

Other effects related to acid inhibition

During treatment with antisecretory drugs serum gastrin increases in response to the decreased acid secretion.

An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in some patients during long-term treatment with esomeprazole.

During long-term 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.

5.2 Pharmacokinetic Properties

Absorption and distribution

Esomeprazole is acid labile and is administered orally as enteric-coated granules. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. The absolute bioavailability is 64% after a single dose of 40mg and increases to 89% after repeated once-daily administration. For 20mg esomeprazole 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. Esomeprazole is 97% plasma protein bound.

Food intake both delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.

Metabolism and excretion

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.

The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.

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. The area under the plasma concentration-time curve 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 an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite. 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.

Special patient populations

Approximately 1-2% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%. These findings have no implications for the posology of esomeprazole.

The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).

Following a single dose of 40mg esomeprazole the mean area under the plasma concentration-time curve is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the posology of esomeprazole.

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 area under the plasma concentration-time curve of esomeprazole. Therefore, a maximum of 20mg should not be exceeded in patients with severe dysfunction. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing.

No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.

5.3 Preclinical Safety Data

Preclinical bridging studies reveal no particular hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction. Carcinogenicity studies in the rat with the racemic mixture have shown gastric ECL-cell hyperplasia and carcinoids. These gastric effects in the rat are the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid and are observed after long-term treatment in the rat with inhibitors of gastric acid secretion.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Glycerol monostearate 40-55, hydroxypropyl cellulose, hypromellose, iron oxide (reddish-brown, yellow) (E 172), magnesium stearate, methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30 per cent, cellulose microcrystalline, synthetic paraffin, macrogol 6000, polysorbate 80, crospovidone, sodium stearyl fumarate, sugar spheres (sucrose and maize starch), talc, titanium dioxide (E 171), triethyl citrate.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Keep the container tightly closed (bottle). Store in the original package (blister).

6.5 Nature And Contents Of Container

- Polyethylene bottle with a tamper proof, polypropylene screw cap equipped with a desiccant capsule.

- Aluminium blister package.

20 mg, 40 mg: Bottles of 2, 5, 7, 14, 15, 28, 30, 56, 60, 100, 140(5x28) tablets.

20 mg, 40 mg: Blister packs in wallet and/or carton of 3, 7, 7x1, 14, 15, 25x1, 28, 30, 50x1, 56, 60, 90, 98, 100x1, 140 tablets

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

AstraZeneca UK Limited

Kings Langley

Hertfordshire

WD4 8DH

United Kingdom

8. Marketing Authorisation Number(S)

PL 17901/0068

9. Date Of First Authorisation/Renewal Of The Authorisation

27th July 2000

10. Date Of Revision Of The Text

July 2000

Nexium Tablets 20mg

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