Nexium 40 mg gastro-resistant tablets booklet

4.1 Therapeutic Indications

Nexium tablets are indicated in adults for:

• Gastroesophageal Reflux Disease (GERD), including the treatment of erosive reflux oesophagitis.
• Prolonged treatment after intravenous (i.v.) induced prevention of rebleeding of peptic ulcers.
• Treatment of Zollinger-Ellison Syndrome.

Nexium tablets are indicated in adolescents aged 12 years and older for:

• Gastroesophageal Reflux Disease (GERD), including the treatment of erosive reflux oesophagitis.

4.2 Posology and Method of Administration

Adults

Gastroesophageal Reflux Disease (GERD):

• Treatment of erosive reflux oesophagitis: 40 mg once daily for 4 weeks. An additional 4 weeks of treatment is recommended for patients whose oesophagitis has not healed or who have persistent symptoms.

Prolonged treatment after i.v. prevention of rebleeding of peptic ulcers:

• 40 mg once daily for 4 weeks.

Treatment of Zollinger-Ellison Syndrome:

• The recommended initial dosage is Nexium 40 mg twice daily. The dosage should then be individually adjusted, with treatment continuing as long as clinically indicated. Most patients can be controlled on doses between 80 to 160 mg daily. For doses exceeding 80 mg per day, the dose should be divided and administered twice daily.

Special Populations

Renal impairment:

• Dose adjustment is not required. However, patients with severe renal insufficiency should be treated with caution.

Hepatic impairment:

• Dose adjustment is not required for mild to moderate impairment. In severe hepatic impairment, a maximum dose of 20 mg should not be exceeded.

Elderly:

• No dose adjustment is required.

Paediatric Population

Adolescents aged 12 years and older

Gastroesophageal Reflux Disease (GERD):

• Treatment of erosive reflux oesophagitis: 40 mg once daily for 4 weeks. An additional 4 weeks of treatment is recommended for patients whose oesophagitis has not healed or who have persistent symptoms.

Children under 12 years:

• For patients aged 1 to 11, refer to the Nexium sachet Summary of Product Characteristics (SmPC).

Method of Administration

• Tablets should be swallowed whole with liquid. They should not be chewed or crushed. For patients with difficulty swallowing, the tablets can be dispersed in half a glass of non-carbonated water, stirred until disintegrated, and consumed immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed.
• For patients unable to swallow, the tablets can be dispersed in non-carbonated water and administered via a gastric tube. It is important to test the appropriateness of the selected syringe and tube. For preparation and administration instructions, see section 6.6.

4.3 Contraindications

• Hypersensitivity to esomeprazole, substituted benzimidazoles, or any of the excipients listed in section 6.1.
• Concomitant use with nelfinavir (see section 4.5).

4.4 Special Warnings and Precautions for Use

• In the presence of alarm symptoms (e.g. unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, or melaena) or suspicion of gastric ulcer, malignancy should be excluded, as treatment with Nexium may mask symptoms and delay diagnosis.
• Long-term use: Patients on long-term treatment should be regularly monitored, especially if treated for more than a year.
• On-demand treatment: Patients should be advised to contact their physician if symptoms change.
• Helicobacter pylori eradication: Possible drug interactions with the components of the triple therapy (including clarithromycin) should be considered.
• Gastrointestinal infections: Treatment with proton pump inhibitors may slightly increase the risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).
• Vitamin B12 absorption: Nexium may reduce the absorption of vitamin B12 during long-term use, especially in patients with risk factors for deficiency.
• Hypomagnesaemia: Prolonged treatment with PPIs can lead to hypomagnesaemia, especially after three months to a year of use. Symptoms such as fatigue, convulsions, and arrhythmia should prompt monitoring of magnesium levels.

 

Summary of Safety Profile

• Most common adverse reactions: headache, abdominal pain, diarrhoea, nausea.
• Safety profile consistent across different formulations, indications, and populations.
• No dose-related adverse effects identified.

Tabulated List of Adverse Reactions

System Organ Class	Frequency	Undesirable Effect
Blood/Lymphatic	Rare	Leukopenia, thrombocytopenia
	Very rare	Agranulocytosis, pancytopenia
Immune System	Rare	Hypersensitivity (fever, angioedema, anaphylactic reaction/shock)
Metabolism	Uncommon	Peripheral oedema
	Rare	Hyponatraemia
	Not known	Hypomagnesaemia, hypocalcaemia, hypokalaemia
Psychiatric	Uncommon	Insomnia
	Rare	Agitation, confusion, depression
	Very rare	Aggression, hallucinations
Nervous System	Common	Headache
	Uncommon	Dizziness, paraesthesia, somnolence
	Rare	Taste disturbance
Gastrointestinal	Common	Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting
	Rare	Stomatitis, gastrointestinal candidiasis
	Not known	Microscopic colitis
Hepatobiliary	Uncommon	Increased liver enzymes
	Rare	Hepatitis with/without jaundice
	Very rare	Hepatic failure, encephalopathy (in patients with liver disease)
Skin	Uncommon	Dermatitis, rash, urticaria
	Rare	Alopecia, photosensitivity
Musculoskeletal	Uncommon	Fracture (hip, wrist, spine)
	Rare	Arthralgia, myalgia
Renal	Very rare	Interstitial nephritis, renal failure
General	Rare	Malaise, increased sweating

 

Nexium 40 mg gastro-resistant tablets have been associated with various adverse reactions across different systems. Blood and lymphatic disorders, such as leukopenia and thrombocytopenia, are rare, while agranulocytosis and pancytopenia are very rare. Hypersensitivity reactions like fever, angioedema, and anaphylactic shock have been reported rarely. In terms of metabolism, uncommon reactions include peripheral oedema, with rare cases of hyponatraemia and unknown frequency of hypomagnesaemia, hypocalcaemia, and hypokalaemia. Psychiatric disorders such as insomnia are uncommon, while agitation, confusion, and depression are rare, and aggression or hallucinations are very rare. Common nervous system effects include headaches, with uncommon dizziness, paraesthesia, and somnolence, and rare disturbances in taste. Gastrointestinal symptoms like abdominal pain, constipation, diarrhoea, flatulence, and nausea/vomiting are common, with rare instances of stomatitis and gastrointestinal candidiasis. Microscopic colitis has also been reported but with unknown frequency. Hepatobiliary issues, such as increased liver enzymes, are uncommon, while hepatitis, with or without jaundice, is rare, and hepatic failure or encephalopathy in patients with liver disease is very rare. Skin reactions, including dermatitis, rash, and urticaria, are uncommon, while alopecia and photosensitivity are rare. Uncommon musculoskeletal reactions include fractures of the hip, wrist, or spine, with rare cases of arthralgia and myalgia. Very rare renal disorders include interstitial nephritis and renal failure. General adverse effects like malaise and increased sweating are rare.

Reporting Suspected Reactions

Healthcare professionals are encouraged to report adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard or via Google Play/Apple App Store).

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5.1 Pharmacodynamic Properties

• ATC Code: A02B C05
• Esomeprazole, an S-isomer of omeprazole, reduces gastric acid by inhibiting the H+K+-ATPase enzyme in parietal cells.
• Onset: Within 1 hour after oral dosing.
• Effectiveness: Maintains intragastric pH >4 for extended durations, crucial for GERD patients.
• Efficacy: 78-93% healing rate for reflux esophagitis within 8 weeks; 90% success rate for H. pylori eradication when combined with antibiotics.

5.2 Pharmacokinetic Properties

• Absorption: Rapid, with peak plasma levels 1-2 hours after dosing.
• Distribution: 97% plasma protein binding.
• Metabolism: Primarily through the CYP2C19 and CYP3A4 pathways.
• Elimination: Primarily via urine as metabolites; minimal renal excretion of the parent drug.

Absorption

Esomeprazole is acid-labile and is administered orally as enteric-coated granules. In vivo conversion to the R-isomer is negligible. Absorption is rapid, with peak plasma levels occurring 1-2 hours post-dose. The absolute bioavailability is 64% after a single 40 mg dose, increasing to 89% with repeated daily administration. For a 20 mg dose, the bioavailability is 50%, increasing to 68% with repeated use. Food intake delays and decreases esomeprazole absorption but has no significant effect on intragastric acidity.

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.

Biotransformation

Esomeprazole is metabolized by the cytochrome P450 system (CYP). Most of its metabolism depends on the polymorphic CYP2C19, forming hydroxy- and desmethyl metabolites. Another isoform, CYP3A4, metabolizes esomeprazole into its main metabolite, esomeprazole sulphone.

Elimination

For extensive CYP2C19 metabolizers, total plasma clearance is approximately 17 l/h after a single dose, decreasing to about 9 l/h after repeated dosing. The plasma elimination half-life is about 1.3 hours after repeated administration. Esomeprazole is completely eliminated between doses with no accumulation. About 80% of an oral dose is excreted as metabolites in the urine, with the rest excreted in feces. Less than 1% of the parent drug is found in urine.

Linearity/Non-linearity

The pharmacokinetics of esomeprazole have been studied at doses up to 40 mg twice daily. Repeated administration leads to a dose-dependent, more than proportional increase in the area under the plasma concentration-time curve (AUC). This is likely due to the inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite.

Poor Metabolizers

Approximately 2.9 ± 1.5% of the population lacks a functional CYP2C19 enzyme. In these individuals, metabolism is likely catalyzed by CYP3A4. After repeated 40 mg daily doses, the AUC is approximately 100% higher in poor metabolizers, and peak plasma concentrations are 60% higher compared to extensive metabolizers. These findings do not affect the posology of esomeprazole.

Gender

Following a single 40 mg dose, the AUC is approximately 30% higher in females than males. No significant gender differences are observed with repeated dosing.

Hepatic Impairment

Patients with mild to moderate liver dysfunction may experience reduced metabolism of esomeprazole, with severe dysfunction resulting in a doubled AUC. In such cases, the daily dose should not exceed 20 mg. There is no tendency for accumulation with daily dosing in patients with hepatic impairment.

Renal Impairment

No studies have been performed in patients with decreased renal function. Since the kidney is responsible for excreting esomeprazole metabolites, renal impairment is not expected to affect esomeprazole metabolism.

Elderly

No significant changes in esomeprazole metabolism occur in elderly subjects (71-80 years).

Paediatric Population

In adolescents (12-18 years), the pharmacokinetics of esomeprazole after repeated doses (20 mg and 40 mg) are similar to those in adults.

6.1 List of Excipients

• Glycerol monostearate 40-55
• Hyprolose
• Hypromellose
• Iron oxide (reddish-brown) (E 172)
• Magnesium stearate
• Methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30%
• Microcrystalline cellulose
• Synthetic paraffin
• Macrogol
• 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

Do not store above 30°C. Keep the container tightly closed to protect from moisture. Store in the original packaging to prevent moisture exposure.

6.5 Nature and Contents of Container

• Polyethylene bottle with tamper-proof polypropylene screw cap, equipped with a desiccant capsule.
• Aluminium blister packs.
• Available in various sizes, from 2 to 140 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal and Other Handling

No special requirements for disposal.