Neostigmine Injection BP 2.5mg in 1ml

1. Name Of The Medicinal Product

Neostigmine Injection BP 2.5mg in 1ml.

2. Qualitative And Quantitative Composition

Each 1ml of solution contains neostigmine methylsulphate BP

3. Pharmaceutical Form

Clear, colourless, sterile aqueous solution intended for parenteral administration to human beings.

4. Clinical Particulars

4.1 Therapeutic Indications

Neostigmine inhibits cholinesterase enzyme activity and thus potentiates the physiological actions of acetylcholine.

Neostigmine Injection BP has the following indications : Antagonist to non-depolarising neuromuscular blockade; myasthenia gravis; paralytic ileus; post-operative urinary retention.

4.2 Posology And Method Of Administration

Routes of administration : Intramuscular, subcutaneous or slow intravenous injection.

When administering Neostigmine Injection BP, a syringe of atropine sulphate should always be available to counteract possible severe cholinergic reactions. Where the intravenous route is used, administration must be by very slow injection.

Antagonist to non-depolarising neuromuscular blockade.

Generally, reversal of neuromuscular blockade should not be attempted until there are signs of spontaneous recovery from paralysis. The patient should be well ventilated and a patent airway maintained until normal respiration is fully restored.

Adults and children : A single dose of Neostigmine Injection BP 0.05 - 0.07mg/kg bodyweight and atropine sulphate 0.02 - 0.03mg/kg body-weight, by slow intravenous injection over 60 seconds, will usually achieve complete reversal of non-depolarising neuromuscular blockade within 5 - 15 minutes. Additional neostigmine may be required but a total of 5mg for adults and 2.5mg for children should not be exceeded. The two drugs are often administered simultaneously, but in patients with bradycardia the pulse rate should be increased to about 80/minute with atropine before giving the neostigmine.

Although the speed of recovery from neuromuscular blockade is determined mainly by the intensity of the block at the time of antagonism, it is also influenced by other factors such as the presence of drugs (e.g. anaesthetics, antibiotics, antiarrhythmic agents) and physiological changes (e.g. electrolyte and acid-base disturbances, renal impairment). Because these factors may prevent successful reversal of blockade or may lead to re-curarisation following apparently successful reversal, it is essential that patients be observed carefully until such possibilities have been excluded.

MYASTHENIA GRAVIS

Adults: Doses of 1 - 2.5mg may be given by intramuscular or subcutaneous injection at intervals during the day when strength is most needed. The usual duration of action of a dose is 2 - 4 hours. The total daily dose is usually in the range of 5 - 20mg, but higher doses may be required by some patients.

Newborn infants: Neonatal myasthenia may be treated with an initial dose of 0.1mg intramuscularly. Thereafter, the dosage should be titrated individually and is usually in the range 0.05 - 0.25mg by injection. Treatment is not usually needed beyond eight weeks of age, except in the rare conditions of congenital and familial infantile myasthenia.

Older children: A dose of 0.2 - 0.5mg may be given by injection as required. The dosage should be adjusted according to the response.

OTHER INDICATIONS

Adults: The usual dose is 0.5 - 2.5mg by subcutaneous or intramuscular injection.

Children: The usual dose is 0.125 - 1mg by injection.

The frequency of these doses may be varied according to the needs of the patient.

Elderly: There are no specific dosage recommendations for elderly patients.

4.3 Contraindications

Neostigmine should not be administered to patients with gastro-intestinal or urinary obstruction. Neostigmine should not be given to patients with a known hypersensitivity to the drug. Neostigmine should not be used in conjunction with depolarising muscle relaxants such as suxamethonium, as the neuromuscular blockade may be potentiated and prolonged apnoea may result.

4.4 Special Warnings And Precautions For Use

Neostigmine should be used with particular caution in patients with mytonic dystrophy, bronchial asthma, bradycardia, recent coronary occlusion, hypotension, vagotonia, peptic ulceration, epilepsy or Parkinsonism.

Care should be taken in patients with hyperthyroidism, renal impairment (dose reduction might be required).

Bradycardia may occur, possibly to a serious degree, with intravenous injection of neostigmine unless atropine is given simultaneously. The requirement for neostigmine is usually decreased after thymectomy, or when additional therapy (steroids, immunosuppressant drugs) is given.

Neostigmine should not be administered during cyclopropane or halothane anaesthesia, although it may be used after withdrawal of these agents.

Although there is no evidence to suggest that neostigmine has any special effects in elderly patients, these patients may be more susceptible to dysrhythmias than younger adults.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

• Anti-arrhythmic: Effects of neostigmine antagonised by procainamide and quinidine; possibly antagonized by propafenone;

• Antibacterials: Effects of neostigmine antagonised by aminoglycosides, clindamycin and polymyxins;

• Antimalarials: Effects of neostigmine may be diminished because of potential for chloroquine and hydroxychloroquine to increase symptoms of myasthenia gravis;

• Antimuscarinics: Effects of parasympathomimetics antagonised by antimuscarinics;

• Beta-blockers: Effects of neostigmine antagonised by propranolol;

• Lithium: Effects of neostigmine antagonised by lithium;

• Muscle Relaxants Neostigmine enhances effects of suxamethonium.

Neostigmine antagonises effects of non-depolarising muscle relaxants.

Atropine is an antidote to the muscarinic effects of neostigmine.

4.6 Pregnancy And Lactation

The safety of neostigmine in pregnancy and lactation has not been established. Although experience with neostigmine in pregnant patients with myasthenia gravis has revealed no untoward effects of the drug on the course of pregnancy, the possible hazard to mother and child must be weighed against the potential benefits in individual cases. Although only negligible amounts of neostigmine appear to be excreted in breast milk, consideration should be given to the possible effects on the breast-fed infant.

4.7 Effects On Ability To Drive And Use Machines

Nil.

4.8 Undesirable Effects

Possible side effects may include nausea, vomiting, increased salivation, diarrhoea, abdominal cramps and bradycardia. Allergic reactions have been reported.

4.9 Overdose

Overdosage may lead to a 'cholinergic crisis' characterised by both muscarinic and nicotinic effects. Signs of overdosage due to muscarinic effects may include abdominal cramps, increased peristalsis, diarrhoea, nausea and vomiting, involuntary defecation and urination, sweating, salivation, increased bronchial secretions, miosis, bradycardia and hypotension.

Nicotinic effects may include involuntary twitching, fasciculations and generalised weakness. Muscle weakness is a symptom both of cholinergic crisis and of myastheni gravis. It is extremely important to distinguish between these two conditions as their treatments are radically different.

Atropine sulphate 1 - 2mg intravenously is an antidote to the muscarinic effects of neostigmine. Supportive treatment should be given as required; artificial respiration should be instituted if respiratory depression is severe.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Acetylcholine is a chemical transmitter with a wide range of actions within the body. Its action is transient as it is rapidly destroyed by cholinesterase. Neostigmine inhibits cholinesterase and thus prolongs and intensifies the physiological actions of acetylcholine.

The main actions of neostigmine that are of therapeutic importance are concerned with the skeletal neuromuscular junction, the intestine and the smooth muscle of the urinary tract. Neostigmine reverses the antagonism caused by non-depolarising neuro-muscular blocking agents. The drug augments the motor activity of the small and large bowel and it causes contraction of smooth muscle fibres of the ureters and urinary bladder.

5.2 Pharmacokinetic Properties

Neostigmine is a quaternary ammonium compound and is poorly absorbed from the gastrointestinal tract. Following parenteral administration as the methylsulphate, neostigmine is metabolised partly by hydrolysis of the ester linkage and is excreted in the urine both as unchanged drug and as metabolites. The half-life of neostigmine is only one to two hours.

5.3 Preclinical Safety Data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Dilute Sulphuric Acid BP

Water for Injections BP

6.2 Incompatibilities

None known.

6.3 Shelf Life

4 years

6.4 Special Precautions For Storage

Keep in outer carton.

Do not store above 25°C.

6.5 Nature And Contents Of Container

1ml, amber glass ampoules, glass type 1 Ph. Eur. Packed in cardboard cartons to contain 10 x 1ml ampoules.

6.6 Special Precautions For Disposal And Other Handling

For SC, IV, or IM injection.

Use as directed by the physician.

If only part used, discard the remaining solution.

ADMINISTRATIVE DATA

7. Marketing Authorisation Holder

Antigen International Ltd.,

Roscrea,

Co. Tipperary,

Ireland.

8. Marketing Authorisation Number(S)

PL 2848/5916R.

9. Date Of First Authorisation/Renewal Of The Authorisation

1997

10. Date Of Revision Of The Text

April 2008

Neoclarityn 0.5 mg / ml syrup

1. Name Of The Medicinal Product

Neoclarityn 0.5 mg/ml syrup

2. Qualitative And Quantitative Composition

Each ml of syrup contains 0.5 mg desloratadine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Syrup

4. Clinical Particulars

4.1 Therapeutic Indications

Neoclarityn is indicated for the relief of symptoms associated with:

- allergic rhinitis (see section 5.1)

- urticaria (see section 5.1)

4.2 Posology And Method Of Administration

Neoclarityn may be taken without regard to mealtime for the relief of symptoms associated with allergic rhinitis (including intermittent and persistent allergic rhinitis) and urticaria (see section 5.1).

The prescriber should be aware that most cases of rhinitis below 2 years of age are of infectious origin (see section 4.4) and there are no data supporting the treatment of infectious rhinitis with Neoclarityn.

Children 1 through 5 years of age: 2.5 ml (1.25 mg) Neoclarityn syrup once a day.

Children 6 through 11 years of age: 5 ml (2.5 mg) Neoclarityn syrup once a day.

In adults and adolescents (12 years of age and over): 10 ml (5 mg) Neoclarityn syrup once a day.

There is limited clinical trial efficacy experience with the use of desloratadine in adolescents 12 through 17 years of age (see sections 4.8 and 5.1).

Intermittent allergic rhinitis (presence of symptoms for less than 4 days per week or for less than 4 weeks) should be managed in accordance with the evaluation of patient's disease history and the treatment could be discontinued after symptoms are resolved and reinitiated upon their reappearance.

In persistent allergic rhinitis (presence of symptoms for 4 days or more per week and for more than 4 weeks), continued treatment may be proposed to the patients during the allergen exposure periods.

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients, or to loratadine.

4.4 Special Warnings And Precautions For Use

Efficacy and safety of Neoclarityn syrup in children under 1 year of age have not been established.

In children below 2 years of age, the diagnosis of allergic rhinitis is particularly difficult to distinguish from other forms of rhinitis. The absence of upper respiratory tract infection or structural abnormalities, as well as patient history, physical examinations, and appropriate laboratory and skin tests should be considered.

Approximately 6 % of adults and children 2- to 11-year old are phenotypic poor metabolisers of desloratadine and exhibit a higher exposure (see section 5.2). The safety of Neoclarityn syrup in children 2- to 11-years of age who are poor metabolisers is the same as in children who are normal metabolisers. The effects of Neoclarityn syrup in poor metabolisers < 2 years of age have not been studied.

In the case of severe renal insufficiency, Neoclarityn should be used with caution (see section 5.2).

This medicinal product contains sucrose and sorbitol; thus, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This medicinal product contains the colouring agent E110 which may cause allergic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically relevant interactions were observed in clinical trials with Neoclarityn tablets in which erythromycin or ketoconazole were co-administered (see section 5.1).

In a clinical pharmacology trial, Neoclarityn tablets taken concomitantly with alcohol did not potentiate the performance impairing effects of alcohol (see section 5.1).

4.6 Pregnancy And Lactation

Desloratadine was not teratogenic in animal studies. The safe use of the medicinal product during pregnancy has not been established. The use of Neoclarityn during pregnancy is therefore not recommended.

Desloratadine is excreted into breast milk, therefore the use of Neoclarityn is not recommended in breastfeeding women.

4.7 Effects On Ability To Drive And Use Machines

In clinical trials that assessed the driving ability, no impairment occurred in patients receiving desloratadine. However, patients should be informed that very rarely some people experience drowsiness, which may affect their ability to drive or use machines.

4.8 Undesirable Effects

In clinical trials in a paediatric population, Neoclarityn syrup was administered to a total of 246 children aged 6 months through 11 years. The overall incidence of adverse events in children 2 through 11 years of age was similar for the Neoclarityn syrup and the placebo groups. In infants and toddlers aged 6 to 23 months, the most frequent adverse events reported in excess of placebo were diarrhoea (3.7 %), fever (2.3 %) and insomnia (2.3 %).

At the recommended dose, in clinical trials involving adults and adolescents in a range of indications including allergic rhinitis and chronic idiopathic urticaria, undesirable effects with Neoclarityn were reported in 3 % of patients in excess of those treated with placebo. The most frequent of adverse events reported in excess of placebo were fatigue (1.2 %), dry mouth (0.8 %) and headache (0.6 %). Other undesirable effects reported very rarely during the post-marketing period are listed in the following table.

Psychiatric disorders	Hallucinations
Nervous system disorders	Dizziness, somnolence, insomnia, psychomotor hyperactivity, seizures
Cardiac disorders	Tachycardia, palpitations
Gastrointestinal disorders	Abdominal pain, nausea, vomiting, dyspepsia, diarrhoea
Hepatobiliary disorders	Elevations of liver enzymes, increased bilirubin, hepatitis
Musculoskeletal and connective tissue disorders	Myalgia
General disorders	Hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnoea, pruritus, rash, and urticaria)

4.9 Overdose

In the event of overdose, consider standard measures to remove unabsorbed active substance.

Symptomatic and supportive treatment is recommended.

Based on a multiple dose clinical trial in adults and adolescents, in which up to 45 mg of desloratadine was administered (nine times the clinical dose), no clinically relevant effects were observed.

Desloratadine is not eliminated by haemodialysis; it is not known if it is eliminated by peritoneal dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antihistamines – H₁ antagonist, ATC code: R06A X27

Desloratadine is a non-sedating, long-acting histamine antagonist with selective peripheral H₁-receptor antagonist activity. After oral administration, desloratadine selectively blocks peripheral histamine H₁-receptors because the substance is excluded from entry to the central nervous system.

Desloratadine has demonstrated antiallergic properties from in vitro studies. These include inhibiting the release of proinflammatory cytokines such as IL-4, IL-6, IL-8, and IL-13 from human mast cells/basophils, as well as inhibition of the expression of the adhesion molecule P-selectin on endothelial cells. The clinical relevance of these observations remains to be confirmed.

Efficacy of Neoclarityn syrup has not been investigated in separate paediatric trials. Safety of Neoclarityn syrup was demonstrated in three paediatric trials. Children, 1-11 years of age, who were candidates for antihistamine therapy received a daily desloratadine dose of 1.25 mg (1 through 5 years of age) or 2.5 mg (6 through 11 years of age). Treatment was well tolerated as documented by clinical laboratory tests, vital signs, and ECG interval data, including QTc. When given at the recommended doses, the plasma concentrations of desloratadine (see section 5.2) were comparable in the paediatric and adult populations. Thus, since the course of allergic rhinitis/chronic idiopathic urticaria and the profile of desloratadine are similar in adults and paediatric patients, desloratadine efficacy data in adults can be extrapolated to the paediatric population.

In a multiple dose clinical trial, in adults and adolescents, in which up to 20 mg of desloratadine was administered daily for 14 days, no statistically or clinically relevant cardiovascular effect was observed. In a clinical pharmacology trial, in adults and adolescents, in which desloratadine was administered to adults at a dose of 45 mg daily (nine times the clinical dose) for ten days, no prolongation of QTc interval was seen.

Desloratadine does not readily penetrate the central nervous system. In controlled clinical trials, at the recommended dose of 5 mg daily for adults and adolescents, there was no excess incidence of somnolence as compared to placebo. Neoclarityn tablets given at a single daily dose of 7.5 mg to adults and adolescents did not affect psychomotor performance in clinical trials. In a single dose study performed in adults, desloratadine 5 mg did not affect standard measures of flight performance including exacerbation of subjective sleepiness or tasks related to flying.

In clinical pharmacology trials in adults, co-administration with alcohol did not increase the alcohol-induced impairment in performance or increase in sleepiness. No significant differences were found in the psychomotor test results between desloratadine and placebo groups, whether administered alone or with alcohol.

No clinically relevant changes in desloratadine plasma concentrations were observed in multiple-dose ketoconazole and erythromycin interaction trials.

Efficacy of Neoclarityn syrup has not been investigated in paediatric trials in children less than 12 years of age.

In adult and adolescent patients with allergic rhinitis, Neoclarityn tablets were effective in relieving symptoms such as sneezing, nasal discharge and itching, as well as ocular itching, tearing and redness, and itching of palate. Neoclarityn effectively controlled symptoms for 24 hours. The efficacy of Neoclarityn tablets has not been clearly demonstrated in trials with adolescent patients 12 through 17 years of age.

In addition to the established classifications of seasonal and perennial, allergic rhinitis can alternatively be classified as intermittent allergic rhinitis and persistent allergic rhinitis according to the duration of symptoms. Intermittent allergic rhinitis is defined as the presence of symptoms for less than 4 days per week or for less than 4 weeks. Persistent allergic rhinitis is defined as the presence of symptoms for 4 days or more per week and for more than 4 weeks.

Neoclarityn tablets were effective in alleviating the burden of seasonal allergic rhinitis as shown by the total score of the rhino-conjunctivitis quality of life questionnaire. The greatest amelioration was seen in the domains of practical problems and daily activities limited by symptoms.

Chronic idiopathic urticaria was studied as a clinical model for urticarial conditions, since the underlying pathophysiology is similar, regardless of etiology, and because chronic patients can be more easily recruited prospectively. Since histamine release is a causal factor in all urticarial diseases, desloratadine is expected to be effective in providing symptomatic relief for other urticarial conditions, in addition to chronic idiopathic urticaria, as advised in clinical guidelines.

In two placebo-controlled six week trials in patients with chronic idiopathic urticaria, Neoclarityn was effective in relieving pruritus and decreasing the size and number of hives by the end of the first dosing interval. In each trial, the effects were sustained over the 24 hour dosing interval. As with other antihistamine trials in chronic idiopathic urticaria, the minority of patients who were identified as non-responsive to antihistamines was excluded. An improvement in pruritus of more than 50 % was observed in 55 % of patients treated with desloratadine compared with 19 % of patients treated with placebo. Treatment with Neoclarityn also significantly reduced interference with sleep and daytime function, as measured by a four-point scale used to assess these variables.

5.2 Pharmacokinetic Properties

Desloratadine plasma concentrations can be detected within 30 minutes of desloratadine administration in adults and adolescents. Desloratadine is well absorbed with maximum concentration achieved after approximately 3 hours; the terminal phase half-life is approximately 27 hours. The degree of accumulation of desloratadine was consistent with its half-life (approximately 27 hours) and a once daily dosing frequency. The bioavailability of desloratadine was dose proportional over the range of 5 mg to 20 mg.

In a series of pharmacokinetic and clinical trials, 6 % of the subjects reached a higher concentration of desloratadine. The prevalence of this poor metaboliser phenotype was comparable for adult (6 %) and paediatric subjects 2- to 11-year old (6 %), and greater among Blacks (18 % adult, 16 % paediatric) than Caucasians (2 % adult, 3 % paediatric) in both populations.

In a multiple-dose pharmacokinetic study conducted with the tablet formulation in healthy adult subjects, four subjects were found to be poor metabolisers of desloratadine. These subjects had a C_max concentration about 3-fold higher at approximately 7 hours with a terminal phase half-life of approximately 89 hours.

Similar pharmacokinetic parameters were observed in a multiple-dose pharmacokinetic study conducted with the syrup formulation in paediatric poor metaboliser subjects 2- to 11-year old diagnosed with allergic rhinitis. The exposure (AUC) to desloratadine was about 6-fold higher and the C_max was about 3 to 4 fold higher at 3-6 hours with a terminal half-life of approximately 120 hours. Exposure was the same in adult and paediatric poor metabolisers when treated with age-appropriate doses. The overall safety profile of these subjects was not different from that of the general population. The effects of Neoclarityn syrup in poor metabolizers < 2 years of age have not been studied.

Desloratadine is moderately bound (83 % - 87 %) to plasma proteins. There is no evidence of clinically relevant active substance accumulation following once daily adult and adolescent dosing of desloratadine (5 mg to 20 mg) for 14 days.

In a single dose, crossover study of desloratadine, the tablet and the syrup formulations were found to be bioequivalent.

In separate single dose studies, at the recommended doses, paediatric patients had comparable AUC and C_max values of desloratadine to those in adults who received a 5 mg dose of desloratadine syrup.

The enzyme responsible for the metabolism of desloratadine has not been identified yet, and therefore, some interactions with other medicinal products can not be fully excluded. Desloratadine does not inhibit CYP3A4 in vivo, and in vitro studies have shown that the medicinal product does not inhibit CYP2D6 and is neither a substrate nor an inhibitor of P-glycoprotein.

In a single dose trial using a 7.5 mg dose of desloratadine, there was no effect of food (high-fat, high caloric breakfast) on the disposition of desloratadine. In another study, grapefruit juice had no effect on the disposition of desloratadine.

5.3 Preclinical Safety Data

Desloratadine is the primary active metabolite of loratadine. Non-clinical studies conducted with desloratadine and loratadine demonstrated that there are no qualitative or quantitative differences in the toxicity profile of desloratadine and loratadine at comparable levels of exposure to desloratadine.

Non-clinical data with desloratadine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction. The lack of carcinogenic potential was demonstrated in studies conducted with desloratadine and loratadine.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene glycol,

sorbitol,

citric acid anhydrous,

sodium citrate,

sodium benzoate,

disodium edetate,

purified water,

sucrose,

natural and artificial flavour (bubblegum),

orange colour E110.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 30°C. Store in the original package.

6.5 Nature And Contents Of Container

Neoclarityn syrup is supplied in bottles of 30, 50, 60, 100, 120, 150, 225, and 300 ml in type III amber glass bottles closed with a childproof polypropylene cap. The caps have a liner made of Low Density Polyethylene (LDPE), polyethylene foam, ethylenevinylacetate (EVA), and polyvinylidene chloride (PvDC). LDPE is the product contact surface.

Supplied with a rigid, transparent, polystyrene measuring spoon, calibrated at 2.5 ml and 5 ml.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

SP Europe

Rue de Stalle 73

B-1180 Bruxelles

Belgium

8. Marketing Authorisation Number(S)

EU/1/00/161/014-021

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 15 January 2001

Date of last renewal: 15 January 2006

10. Date Of Revision Of The Text

31 March 2008

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/

11. LEGAL CATEGORY

Prescription Only Medicine

Neoclarityn Syrup/03-08/15

Neurontin Capsules and Tablets

1. Name Of The Medicinal Product

Neurontin 100mg Hard Capsules

Neurontin 300mg Hard Capsules

Neurontin 400mg Hard Capsules

Neurontin 600mg Film-coated Tablets

Neurontin 800mg Film-coated Tablets

2. Qualitative And Quantitative Composition

Each 100 mg hard capsule contains 100 mg gabapentin.

Each 300mg hard capsule contains 300 mg gabapentin.

Each 400mg hard capsule contains 400 mg gabapentin.

Each 600 mg film-coated tablet contains 600 mg gabapentin.

Each 800 mg film-coated tablet contains 800 mg gabapentin.

Excipients:

Each 100 mg hard capsule contains 13 mg lactose (as monohydrate).

Each 300 mg hard capsule contains 41 mg lactose (as monohydrate).

Each 400 mg hard capsule contains 54 mg lactose (as monohydrate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Neurontin Hard Capsules

Capsule, hard

Neurontin 100 mg Hard Capsules:	A two-piece, white opaque hard capsule, imprinted with 'Neurontin 100 mg' and 'PD' and containing a white to off-white powder.
Neurontin 300 mg Hard Capsules:	A two-piece, yellow opaque hard capsule, imprinted with 'Neurontin 300 mg' and 'PD' and containing a white to off-white powder.
Neurontin 400 mg Hard Capsules:	A two-piece, orange opaque hard gelatin capsule, imprinted with 'Neurontin 400 mg' and 'PD' and containing a white to off-white powder.

Neurontin Film-Coated Tablets

Neurontin 600 mg Film-coated Tablets:	White, elliptical film-coated tablets with a bisecting score on both sides and debossed with “NT” and “16” on one side.
Neurontin 800 mg Film-coated Tablets:	White, elliptical film-coated tablets with a bisecting score on both sides and debossed with “NT” and “26” on one side.

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Epilepsy

Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults and children aged 6 years and above (see section 5.1).

Gabapentin is indicated as monotherapy in the treatment of partial seizures with and without secondary generalization in adults and adolescents aged 12 years and above.

Treatment of peripheral neuropathic pain

Gabapentin is indicated for the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia in adults.

4.2 Posology And Method Of Administration

For oral use.

Gabapentin can be given with or without food and should be swallowed whole with sufficient fluid-intake (e.g. a glass of water).

For all indications a titration scheme for the initiation of therapy is described in Table 1, which is recommended for adults and adolescents aged 12 years and above. Dosing instructions for children under 12 years of age are provided under a separate sub-heading later in this section.

Table 1
DOSING CHART – INITIAL TITRATION
Day 1	Day 2	Day 3
300 mg once a day	300 mg two times a day	300 mg three times a day

Discontinuation of gabapentin

In accordance with current clinical practice, if gabapentin has to be discontinued it is recommended this should be done gradually over a minimum of 1 week independent of the indication.

Epilepsy

Epilepsy typically requires long-term therapy. Dosage is determined by the treating physician according to individual tolerance and efficacy.

Adults and adolescents:

In clinical trials, the effective dosing range was 900 to 3600 mg/day. Therapy may be initiated by titrating the dose as described in Table 1 or by administering 300 mg three times a day (TID) on Day 1. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300 mg/day increments every 2-3 days up to a maximum dose of 3600 mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day is a total of 2 weeks, and to reach 3600 mg/day is a total of 3 weeks. Dosages up to 4800 mg/day have been well tolerated in long-term open-label clinical studies. The total daily dose should be divided in three single doses, the maximum time interval between the doses should not exceed 12 hours to prevent breakthrough convulsions.

Children aged 6 years and above:

The starting dose should range from 10 to 15 mg/kg/day and the effective dose is reached by upward titration over a period of approximately three days. The effective dose of gabapentin in children aged 6 years and older is 25 to 35 mg/kg/day. Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The total daily dose should be divided in three single doses, the maximum time interval between doses should not exceed 12 hours.

It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin therapy. Further, gabapentin may be used in combination with other antiepileptic medicinal products without concern for alteration of the plasma concentrations of gabapentin or serum concentrations of other antiepileptic medicinal products.

Peripheral neuropathic pain

Adults

The therapy may be initiated by titrating the dose as described in Table 1. Alternatively, the starting dose is 900 mg/day given as three equally divided doses. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300 mg/day increments every 2-3 days up to a maximum dose of 3600 mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day is a total of 2 weeks, and to reach 3600 mg/day is a total of 3 weeks.

In the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia, efficacy and safety have not been examined in clinical studies for treatment periods longer than 5 months. If a patient requires dosing longer than 5 months for the treatment of peripheral neuropathic pain, the treating physician should assess the patient's clinical status and determine the need for additional therapy.

Instruction for all areas of indication

In patients with poor general health, i.e., low body weight, after organ transplantation etc., the dose should be titrated more slowly, either by using smaller dosage strengths or longer intervals between dosage increases.

Use in elderly patients (over 65 years of age)

Elderly patients may require dosage adjustment because of declining renal function with age (see Table 2). Somnolence, peripheral oedema and asthenia may be more frequent in elderly patients.

Use in patients with renal impairment

Dosage adjustment is recommended in patients with compromised renal function as described in Table 2 and/or those undergoing haemodialysis. Gabapentin 100 mg capsules can be used to follow dosing recommendations for patients with renal insufficiency.

Table 2
DOSAGE OF GABAPENTIN IN ADULTS BASED ON RENAL FUNCTION
Creatinine Clearance (ml/min)	Total Daily Dosea (mg/day)
	900-3600
50-79	600-1800
30-49	300-900
15-29	150b-600
<15c	150b-300

a Total daily dose should be administered as three divided doses. Reduced dosages are for patients with renal impairment (creatinine clearance < 79 ml/min).

b To be administered as 300 mg every other day.

c For patients with creatinine clearance <15 ml/min, the daily dose should be reduced in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 ml/min should receive one-half the daily dose that patients with a creatinine clearance of 15 ml/min receive).

Use in patients undergoing haemodialysis

For anuric patients undergoing haemodialysis who have never received gabapentin, a loading dose of 300 to 400 mg, then 200 to 300 mg of gabapentin following each 4 hours of haemodialysis, is recommended. On dialysis-free days, there should be no treatment with gabapentin.

For renally impaired patients undergoing haemodialysis, the maintenance dose of gabapentin should be based on the dosing recommendations found in Table 2. In addition to the maintenance dose, an additional 200 to 300 mg dose following each 4-hour haemodialysis treatment is recommended.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for gabapentin.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

If a patient develops acute pancreatitis under treatment with gabapentin, discontinuation of gabapentin should be considered (see section 4.8).

Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsant agents in epileptic patients may precipitate status epilepticus (see section 4.2)..

As with other antiepileptic medicinal products, some patients may experience an increase in seizure frequency or the onset of new types of seizures with gabapentin.

As with other anti-epileptics, attempts to withdraw concomitant anti-epileptics in treatment refractive patients on more than one anti-epileptic, in order to reach gabapentin monotherapy have a low success rate.

Gabapentin is not considered effective against primary generalized seizures such as absences and may aggravate these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizures including absences.

No systematic studies in patients 65 years or older have been conducted with gabapentin. In one double blind study in patients with neuropathic pain, somnolence, peripheral oedema and asthenia occurred in a somewhat higher percentage in patients aged 65 years or above, than in younger patients. Apart from these findings, clinical investigations in this age group do not indicate an adverse event profile different from that observed in younger patients.

The effects of long-term (greater than 36 weeks) gabapentin therapy on learning, intelligence, and development in children and adolescents have not been adequately studied. The benefits of prolonged therapy must therefore be weighed against the potential risks of such therapy.

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)

Severe, life-threatening, systemic hypersensitivity reactions such as Drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking antiepileptic drugs including gabapentin (see section 4.8).

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Gabapentin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Laboratory tests

False positive readings may be obtained in the semi-quantitative determination of total urine protein by dipstick tests. It is therefore recommended to verify such a positive dipstick test result by methods based on a different analytical principle such as the Biuret method, turbidimetric or dye-binding methods, or to use these alternative methods from the beginning.

Neurontin hard capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Neurontin Capsules.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In a study involving healthy volunteers (N=12), when a 60

No interaction between gabapentin and phenobarbital, phenytoin, valproic acid, or carbamazepine has been observed.

Gabapentin steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving these anti-epileptic agents.

Coadministration of gabapentin with oral contraceptives containing norethindrone and/or ethinyl estradiol, does not influence the steady-state pharmacokinetics of either component.

Coadministration of gabapentin with antacids containing aluminium and magnesium, reduces gabapentin bioavailability up to 24%.. It is recommended that gabapentin be taken at the earliest two hours following antacid administration.

Renal excretion of gabapentin is unaltered by probenecid.

A slight decrease in renal excretion of gabapentin that is observed when it is coadministered with cimetidine is not expected to be of clinical importance.

4.6 Pregnancy And Lactation

Risk related to epilepsy and antiepileptic medicinal products in general

The risk of birth defects is increased by a factor of 2 – 3 in the offspring of mothers treated with an antiepileptic medicinal product. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practised whenever possible. Specialist advice should be given to women who are likely to become pregnant or who are of childbearing potential and the need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child. Developmental delay in children of mothers with epilepsy has been observed rarely. It is not possible to differentiate if the developmental delay is caused by genetic, social factors, maternal epilepsy or the antiepileptic therapy.

Risk related to gabapentin

There are no adequate data from the use of gabapentin in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Gabapentin should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus.

No definite conclusion can be made as to whether gabapentin is associated with an increased risk of congenital malformations when taken during pregnancy, because of epilepsy itself and the presence of concomitant antiepileptic medicinal products during each reported pregnancy.

Gabapentin is excreted in human milk. Because the effect on the breast-fed infant is unknown, caution should be exercised when gabapentin is administered to a breast-feeding mother. Gabapentin should be used in breast-feeding mothers only if the benefits clearly outweigh the risks.

4.7 Effects On Ability To Drive And Use Machines

Gabapentin may have minor or moderate influence on the ability to drive and use machines. Gabapentin acts on the central nervous system and may cause drowsiness, dizziness or other related symptoms. Even, if they were only of mild or moderate degree, these undesirable effects could be potentially dangerous in patients driving or operating machinery. This is especially true at the beginning of the treatment and after increase in dose.

4.8 Undesirable Effects

The adverse reactions observed during clinical studies conducted in epilepsy (adjunctive and monotherapy) and neuropathic pain have been provided in a single list below by class and frequency (very common (

Additional reactions reported from post-marketing experience are included as frequency Not known (cannot be estimated from the available data) in italics in the list below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Body System	Adverse drug reactions
Infections and infestations
Very Common	Viral infection
Common	Pneumonia, respiratory infection, urinary tract infection, infection, otitis media
Blood and the lymphatic system disorders
Common	leucopenia
Not known	thrombocytopenia
Immune system disorders
Uncommon	allergic reactions (e.g. urticaria)
Not Known	hypersensitivity syndrome, a systemic reaction with a variable presentation that can include fever, rash, hepatitis, lymphadenopathy, eosinophilia, and sometimes other signs and symptoms
Metabolism and Nutrition Disorders
Common	anorexia, increased appetite
Psychiatric disorders
Common	hostility, confusion and emotional lability, depression, anxiety, nervousness, thinking abnormal
Not known	hallucinations
Nervous system disorders
Very Common	somnolence, dizziness, ataxia
Common Uncommon	convulsions, hyperkinesias, dysarthria, amnesia, tremor, insomnia, headache, sensations such as paresthesia, hypaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes hypokinesia
Not known	other movement disorders (e.g. choreoathetosis, dyskinesia, dystonia)
Eye disorders
Common	visual disturbances such as amblyopia, diplopia
Ear and Labyrinth disorders
Common	vertigo
Not known	tinnitus
Cardiac disorders
Uncommon	palpitations
Vascular disorders
Common	hypertension, vasodilatation
Respiratory, thoracic and mediastinal disorders
Common	dyspnoea, bronchitis, pharyngitis, cough, rhinitis
Gastrointestinal disorders
Common	vomiting, nausea, dental abnormalities, gingivitis, diarrhea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence
Not known	pancreatitis
Hepatobiliary disorders
Not known	hepatitis, jaundice
Skin and subcutaneous tissue disorders
Common	facial oedema, purpura most often described as bruises resulting from physical trauma, rash, pruritus, acne
Not known	Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia, drug rash with eosinophilia and systemic symptoms (see section 4.4)
Musculoskeletal, connective tissue and bone disorders
Common	arthralgia, myalgia, back pain, twitching
Not known	myoclonus
Renal and urinary disorder
Not known	acute renal failure, incontinence
Reproductive system and breast disorders
Common	impotence
Not known	breast hypertrophy, gynaecomastia
General disorders and administration site conditions
Very Common	fatigue, fever
Common	peripheral oedema, abnormal gait, asthenia, pain, malaise, flu syndrome
Uncommon Not known	generalized oedema withdrawal reactions (mostly anxiety, insomnia, nausea, pains, sweating), chest pain. Sudden unexplained deaths have been reported where a causal relationship to treatment with gabapentin has not been established.
Investigations
Common Uncommon	WBC (white blood cell count) decreased, weight gain elevated liver function tests SGOT (AST), SGPT (ALT) and bilirubin
Not known	blood glucose fluctuations in patients with diabetes
Injury and poisoning
Common	accidental injury, fracture, abrasion

Under treatment with gabapentin cases of acute pancreatitis were reported. Causality with gabapentin is unclear (see section 4.4).

In patients on haemodialysis due to end-stage renal failure, myopathy with elevated creatine kinase levels has been reported.

Respiratory tract infections, otitis media, convulsions and bronchitis were reported only in clinical studies in children. Additionally, in clinical studies in children, aggressive behaviour and hyperkinesias were reported commonly.

4.9 Overdose

Acute, life-threatening toxicity has not been observed with gabapentin overdoses of up to 49 grams. Symptoms of the overdoses included dizziness, double vision, slurred speech, drowsiness, lethargy and mild diarrhoea. All patients recovered fully with supportive care. Reduced absorption of gabapentin at higher doses may limit drug absorption at the time of overdosing and, hence, minimise toxicity from overdoses.

Overdoses of gabapentin, particularly in combination with other CNS depressant medications, may result in coma.

Although gabapentin can be removed by haemodialysis, based on prior experience it is not usually required. However, in patients with severe renal impairment, haemodialysis may be indicated.

An oral lethal dose of gabapentin was not identified in mice and rats given doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, laboured breathing, ptosis, hypoactivity, or excitation.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic groups: Other antiepileptics ATC code: N03AX12

The precise mechanism of action of gabapentin is not known.

Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but its mechanism of action is different from that of several other active substances that interact with GABA synapses including valproate, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA uptake inhibitors, GABA agonists, and GABA prodrugs. In vitro studies with radiolabeled gabapentin have characterized a novel peptide binding site in rat brain tissues including neocortex and hippocampus that may relate to anticonvulsant and analgesic activity of gabapentin and its structural derivatives.

The binding site for gabapentin has been identified as the alpha₂-delta subunit of voltage-gated calcium channels.

Gabapentin at relevant clinical concentrations does not bind to other common drug or neurotransmitter receptors of the brain including GABA_A, GABA_B, benzodiazepine, glutamate, glycine or N-methyl-d-aspartate receptors.

Gabapentin does not interact with sodium channels in vitro and so differs from phenytoin and carbamazepine. Gabapentin partially reduces responses to the glutamate agonist N-methyl-D-aspartate (NMDA) in some test systems in vitro, but only at concentrations greater than 100 μM, which are not achieved in vivo. Gabapentin slightly reduces the release of monoamine neurotransmitters in vitro. Gabapentin administration to rats increases GABA turnover in several brain regions in a manner similar to valproate sodium, although in different regions of brain. The relevance of these various actions of gabapentin to the anticonvulsant effects remains to be established. In animals, gabapentin readily enters the brain and prevents seizures from maximal electroshock, from chemical convulsants including inhibitors of GABA synthesis, and in genetic models of seizures.

A clinical trial of adjunctive treatment of partial seizures in paediatric subjects ranging in age from 3 to 12 years, showed a numerical but not statistically significant difference in the 50% responder rate in favour of the gabapentin group compared to placebo. Additional post-hoc analyses of the responder rates by age did not reveal a statistically significant effect of age, either as a continuous or dichotomous variable (age groups 3-5 and 6-12 years).

The data from this additional post-hoc analysis are summarised in the table below:

Response (
Age Category	Placebo	Gabapentin	P-Value
< 6 Years Old	4/21 (19.0%)	4/17 (23.5%)	0.7362
6 to 12 Years Old	17/99 (17.2%)	20/96 (20.8%)	0.5144

*The modified intent to treat population was defined as all patients randomised to study medication who also had evaluable seizure diaries available for 28 days during both the baseline and double-blind phases.

5.2 Pharmacokinetic Properties

Absorption

Following oral administration, peak plasma gabapentin concentrations are observed within 2 to 3 hours. Gabapentin bioavailability (fraction of dose absorbed) tends to decrease with increasing dose. Absolute bioavailability of a 300 mg capsule is approximately 60%. Food, including a high-fat diet, has no clinically significant effect on gabapentin pharmacokinetics.

Gabapentin pharmacokinetics are not affected by repeated administration. Although plasma gabapentin concentrations were generally between 2 μg/ml and 20 μg/ml in clinical studies, such concentrations were not predictive of safety or efficacy. Pharmacokinetic parameters are given in Table 3.

Table 3

Summary of gabapentin mean (%CV) steady-state pharmacokinetic parameters following every eight hours administration

Pharmacokinetic parameter	300 mg (N = 7)	400 mg (N = 14)	800 mg (N=14)
	Mean	%CV	Mean	%CV	Mean	%CV
Cmax (μg/ml)	4.02	(24)	5.74	(38)	8.71	(29)
tmax (hr)	2.7	(18)	2.1	(54)	1.6	(76)
T1/2 (hr)	5.2	(12)	10.8	(89)	10.6	(41)
AUC (0-8) μg•hr/ml)	24.8	(24)	34.5	(34)	51.4	(27)
Ae% (%)	NA	NA	47.2	(25)	34.4	(37)
Cmax = Maximum steady state plasma concentration tmax = Time for Cmax T1/2 = Elimination half-life AUC(0-8) = Steady state area under plasma concentration-time curve from time 0 to 8 hours postdose Ae% = Percent of dose excreted unchanged into the urine from time 0 to 8 hours postdose NA = Not available

Distribution

Gabapentin is not bound to plasma proteins and has a volume of distribution equal to 57.7 litres. In patients with epilepsy, gabapentin concentrations in cerebrospinal fluid (CSF) are approximately 20% of corresponding steady-state trough plasma concentrations. Gabapentin is present in the breast milk of breast-feeding women.

Metabolism

There is no evidence of gabapentin metabolism in humans. Gabapentin does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism.

Elimination

Gabapentin is eliminated unchanged solely by renal excretion. The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours.

In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin elimination-rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.

Gabapentin is removed from plasma by haemodialysis. Dosage adjustment in patients with compromised renal function or undergoing haemodialysis is recommended (see section 4.2).

Gabapentin pharmacokinetics in children were determined in 50 healthy subjects between the ages of 1 month and 12 years. In general, plasma gabapentin concentrations in children > 5 years of age are similar to those in adults when dosed on a mg/kg basis.

Linearity/Non-linearity

Gabapentin bioavailability (fraction of dose absorbed) decreases with increasing dose which imparts non-linearity to pharmacokinetic parameters which include the bioavailability parameter (F) e.g. Ae%, CL/F, Vd/F. Elimination pharmacokinetics (pharmacokinetic parameters which do not include F such as CLr and T1/2), are best described by linear pharmacokinetics. Steady state plasma gabapentin concentrations are predictable from single-dose data.

5.3 Preclinical Safety Data

Carcinogenesis

Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell tumours was found only in male rats at the highest dose. Peak plasma drug concentrations in rats at 2000 mg/kg are 10 times higher than plasma concentrations in humans given 3600 mg/day. The pancreatic acinar cell tumours in male rats are low-grade malignancies, did not affect survival, did not metastasize or invade surrounding tissue, and were similar to those seen in concurrent controls. The relevance of these pancreatic acinar cell tumours in male rats to carcinogenic risk in humans is unclear.

Mutagenesis

Gabapentin demonstrated no genotoxic potential. It was not mutagenic in vitro in standard assays using bacterial or mammalian cells. Gabapentin di

NEXIUM 20 mg Tablets

1. Name Of The Medicinal Product

NEXIUM^® 20 mg Tablets

2. Qualitative And Quantitative Composition

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

Excipients: Sucrose 28 mg.

For a full list of excipients see section 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

Adults

NEXIUM tablets are indicated for:

Gastro-Oesophageal Reflux Disease (GORD)

- treatment of erosive reflux oesophagitis

- long-term management of patients with healed oesophagitis to prevent relapse

- symptomatic treatment of gastro-oesophageal reflux disease (GORD)

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.

Patients requiring continued NSAID therapy

Healing of gastric ulcers associated with NSAID therapy.

Prevention of gastric and duodenal ulcers associated with NSAID therapy, in patients at risk.

Treatment of Zollinger Ellison Syndrome

Adolescents from the age of 12 years

Gastro-Oesophageal Reflux Disease (GORD)

- treatment of erosive reflux oesophagitis

- long-term management of patients with healed oesophagitis to prevent relapse

- symptomatic treatment of gastro-oesophageal reflux disease (GORD)

In combination with antibiotics in treatment of duodenal ulcer caused by Helicobacter pylori

4.2 Posology And Method Of Administration

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

For patients who have difficulty in swallowing, the tablets can also be dispersed in half a glass of non-carbonated water. No other liquids should be used as the enteric coat may be dissolved. Stir until the tablets disintegrate and drink the liquid with the pellets 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 who cannot swallow, the tablets can be dispersed in non-carbonated water and administered through a gastric tube. It is important that the appropriateness of the selected syringe and tube is carefully tested. For preparation and administration instructions see section 6.6.

Adults and adolescents from the age of 12 years.

Gastro-Oesophageal Reflux Disease (GORD)

- treatment of erosive reflux oesophagitis

40 mg once daily for 4 weeks.

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

- long-term management of patients with healed oesophagitis to prevent relapse

20 mg once daily.

- symptomatic treatment of gastro-oesophageal reflux disease (GORD)

20 mg once daily in patients without oesophagitis. 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 20 mg once daily. In adults, an on demand regimen taking 20 mg once daily, when needed, can be used. In NSAID treated patients at risk of developing gastric and duodenal ulcers, subsequent symptom control using an on demand regimen is not recommended.

Adults

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.

Patients requiring continued NSAID therapy

Healing of gastric ulcers associated with NSAID therapy: The usual dose is 20 mg once daily. The treatment duration is 4-8 weeks.

Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: 20 mg once daily.

Treatment of Zollinger Ellison Syndrome

The recommended initial dosage is Nexium 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 to 160 mg esomeprazole daily. With doses above 80 mg daily, the dose should be divided and given twice-daily.

Adolescents from the age of 12 years

Treatment of duodenal ulcer caused by Helicobacter pylori

When selecting appropriate combination therapy, consideration should be given to official national, regional and local guidance regarding bacterial resistance, duration of treatment (most commonly 7 days but sometimes up to 14 days), and appropriate use of antibacterial agents. The treatment should be supervised by a specialist.

The posology recommendation is:

Weight	Posology
30 - 40 kg	Combination with two antibiotics: Nexium 20 mg, amoxicillin 750 mg and clarithromycin 7.5 mg/kg body weight are all administered together twice daily for one week.
> 40 kg	Combination with two antibiotics: Nexium 20 mg, amoxicillin 1 g and clarithromycin 500 mg are all administered together twice daily for one week.

Children below the age of 12 years

For posology in patients aged 1 to 11 reference is made to the Nexium sachet SmPC.

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.

Esomeprazole should not be used concomitantly with nelfinavir (See section 4.5).

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.

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

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).

Co-administration of esomeprazole with atazanavir is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; esomeprazole 20 mg should not be exceeded.

Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.

Interference with laboratory tests

Increased CgA level may interfere with investigations for neuroendocrine tumours. To avoid this interference, esomeprazole treatment should be temporarily stopped for at least five days before CgA measurements.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Effects of esomeprazole on the pharmacokinetics of other drugs

Medicinal products with pH dependent absorption

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 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 drug monitoring of digoxin should then be reinforced.

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, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, C_max and C_min). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg qd) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared with the exposure observed with atazanavir 300 mg/ritonavir 100 mg qd without omeprazole 20 mg qd. Co-administration of omeprazole (40 mg qd) reduced mean nelfinavir AUC, C_max and C_min by 36–39 % and mean AUC, C_max and C_min for the pharmacologically active metabolite M8 was reduced by 75-92%. For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg qd). Treatment with omeprazole 20 mg qd had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with esomeprazole 20 mg qd had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg qd had no effect on the exposure of lopinavir (with concomitant ritonavir). 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.

Drugs metabolised by CYP2C19

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. Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C_max and AUC by 15% and 41%, respectively.

Concomitant 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, 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.

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 (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 (see also section 4.4).

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

Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.

In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from observational and clinical studies.

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. 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.

Drugs 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.

4.6 Pregnancy And Lactation

For Nexium, clinical data on exposed pregnancies are insufficient. With the racemic mixture omeprazole data on a larger number of exposed pregnancies stemmed from epidemiological studies indicate no malformative nor foetotoxic effects. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/foetal 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 and post-marketing. None was found to be dose-related. The reactions are classified according to frequency very common > 1/10; common >1/100 to <1/10; uncommon >1/1,000 to <1/100; rare >1/10,000 to <1/1,000; very rare <1/10,000; not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Rare: Leukopenia, thrombocytopenia

Very rare: Agranulocytosis, pancytopenia

Immune system disorders

Rare: Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock

Metabolism and nutrition disorders

Uncommon: Peripheral oedema

Rare: Hyponatraemia

Very rare: Hypomagnesaemia

Psychiatric disorders

Uncommon: Insomnia

Rare: Agitation, confusion, depression

Very rare: Aggression, hallucinations

Nervous system disorders

Common: Headache

Uncommon: Dizziness, paraesthesia, somnolence

Rare: Taste disturbance

Eye disorders

Rare: Blurred vision

Ear and labyrinth disorders

Uncommon: Vertigo

Respiratory, thoracic and mediastinal disorders

Rare: Bronchospasm

Gastrointestinal disorders

Common: Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting

Uncommon: Dry mouth

Rare: Stomatitis, gastrointestinal candidiasis

Hepatobiliary disorders

Uncommon: Increased liver enzymes

Rare: Hepatitis with or without jaundice

Very rare: Hepatic failure, encephalopathy in patients with pre-existing liver disease

Skin and subcutaneous tissue disorders

Uncommon: Dermatitis, pruritus, rash, urticaria

Rare: Alopecia, photosensitivity

Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)

Musculoskeletal, connective tissue and bone disorders

Rare: Arthralgia, myalgia

Very rare: Muscular weakness

Renal and urinary disorders

Very rare: Interstitial nephritis

Reproductive system and breast disorders

Very rare: Gynaecomastia

General disorders and administration site conditions

Rare: Malaise, increased sweating

4.9 Overdose

There is very limited experience to date with deliberate overdose. The symptoms described in connection with 280 mg were gastrointestinal symptoms and weakness. 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

Pharmacotherapeutic group: Proton Pump Inhibitor

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 GORD 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 oesophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after four weeks, and in 93% after eight weeks.

One weeks 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. Chromogranin A (CgA) also increases due to decreased gastric acidity.

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.

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.

In two studies with ranitidine as an active comparator, Nexium showed better effect in healing of gastric ulcers in patients using NSAIDs, including COX-2 selective NSAIDs.

In two studies with placebo as comparator, Nexium showed better effect in the prevention of gastric and duodenal ulcers in patients using NSAIDs (aged >60 and/or with previous ulcer), including COX-2 selective NSAIDs.

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 40 mg and increases to 89% after repeated once daily administration. For 20 mg 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 pharmacokinetics of esomeprazole has been studied in doses up to 40 mg b.i.d. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a more than dose proportional increase in AUC 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 2.9 ±1.5% 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 40 mg 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.

Impaired organ function

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 20 mg 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.

Paediatric

Adolescents 12-18 years:

Following repeated dose administration of 20 mg and 40 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma concentration (t_max) in 12 to 18 year-olds was similar to that in adults for both esomeprazole doses.

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

hyprolose

hypromellose

iron oxide (20 mg & 40 mg tablets: reddish-brown; 20 mg tablets: yellow) (E 172)

magnesium stearate

methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30 per cent

cellulose microcrystalline

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.

18 months in climate zones III-IV.

6.4 Special Precautions For Storage

Do not store above 30°C.

Keep the container tightly closed (bottle) in order to protect from moisture. Store in the original package (blister) in order to protect from moisture.

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

Administration through gastric tube

1. Put the tablet into an appropriate syringe and fill the syringe with approximately 25 mL water and approximately 5 mL air. For some tubes, dispersion in 50 mL water is needed to prevent the pellets from clogging the tube.

2. Immediately shake the syringe for approximately 2 minutes to disperse the tablet.

3. Hold the syringe with the tip up and check that the tip has not clogged.

4. Attach the syringe to the tube whilst maintaining the above position.

5. Shake the syringe and position it with the tip pointing down. Immediately inject 5–10 mL into the tube. Invert the syringe after injection and shake (the syringe must be held with the tip pointing up to avoid clogging of the tip).

6. Turn the syringe with the tip down and immediately inject another 5–10 mL into the tube. Repeat this procedure until the syringe is empty.

7. Fill the syringe with 25 mL of water and 5 mL of air and repeat step 5 if necessary to wash down any sediment left in the syringe. For some tubes, 50 mL water is needed.

7. Marketing Authorisation Holder

AstraZeneca UK Limited,

600 Capability Green

Luton, LU1 3LU, UK.

8. Marketing Authorisation Number(S)

PL 17901/0068

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 10 March 2005

Date of latest renewal: 10 March 2010

10. Date Of Revision Of The Text

30 September 2011