Gliolan 30mg / ml powder for oral solution

1. Name Of The Medicinal Product

Gliolan 30 mg/ml powder for oral solution.

2. Qualitative And Quantitative Composition

One vial contains 1.17 g of 5-aminolevulinic acid, corresponding to 1.5 g 5-aminolevulinic acid hydrochloride (5-ALA HCl).

One ml of reconstituted solution contains 23.4 mg of 5-aminolevulinic acid, corresponding to 30 mg 5-aminolevulinic acid hydrochloride (5-ALA HCl).

3. Pharmaceutical Form

Powder for oral solution.

The powder is a white to off-white cake.

4. Clinical Particulars

4.1 Therapeutic Indications

Gliolan is indicated in adult patients for visualisation of malignant tissue during surgery for malignant glioma (WHO grade III and IV).

4.2 Posology And Method Of Administration

This medicinal product should only be used by experienced neurosurgeons conversant with surgery of malignant gliomas and in-depth knowledge of functional brain anatomy who have completed a training course in fluorescence-guided surgery.

The recommended dosage is 20 mg 5-aminolevulinic acid hydrochloride per kilogram body weight. The solution should be administered orally three hours (range 2-4 hours) before induction of anaesthesia. Use of 5-ALA under conditions other than the ones used in the clinical trials entail an undetermined risk.

Patients with renal or hepatic impairment

No studies have been performed in patients with clinically relevant hepatic or renal impairment. Therefore, this medicinal product should be used with caution in such patients.

Paediatric population

There is no experience in children

Elderly patients

There are no special instructions for use in elderly patients with regular organ function.

4.3 Contraindications

• Hypersensitivity to 5-aminolevulinic acid hydrochloride or porphyrins.

• Acute or chronic types of porphyria.

• Pregnancy (see sections 4.6 and 5.3)

4.4 Special Warnings And Precautions For Use

5-ALA-induced fluorescence of brain tissue does not provide information about the tissue's underlying neurological function. Therefore, resection of fluorescing tissue should be weighed up carefully against the neurological function of fluorescing tissue.

Special care must be taken in patients with a tumour in the immediate vicinity of an important neurological function and pre-existing focal deficits (e.g. aphasia, vision disturbances, paresis etc.) that do not improve on corticosteroid treatment. Fluorescence-guided resection in these patients has been found to impose a higher risk of critical neurological deficits. A safe distance to eloquent cortical areas and subcortical structures of at least 1 cm should be maintained independent of the degree of fluorescence.

In all patients with a tumour in the vicinity of an important neurological function, either pre- or intraoperative measures should be used to localise that function relative to the tumour in order to maintain safety distances.

After administration of this medicinal product, exposure of eyes and skin to strong light sources (e.g. operating illumination, direct sunlight or brightly focused indoor light) should be avoided for 24 hours.

Co-administration with other potentially phototoxic substances (e.g. tetracyclines, sulfonamides, fluoroquinolones, hypericin extracts) should be avoided (see also section 5.3).

Within 24 hours after administration, other potentially hepatotoxic medicinal products should be avoided.

In patients with pre-existing cardiovascular disease, this medicinal product should be used with caution since literature reports have shown decreased systolic and diastolic blood pressures, pulmonary artery systolic and diastolic pressures as well as pulmonary vascular resistance.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

One case of an increased phototoxic reaction (severe sunburn lasting for 5 days) has been reported in a patient after co-administration of 5-aminolevulinic acid and a hypericin extract (a known phototoxic agent).

Patients should not be exposed to any photosensitizing agent up to 2 weeks after administration of Gliolan.

4.6 Pregnancy And Lactation

Use in pregnancy

There are no adequate data from the use of this medicinal product in pregnant woman. Some limited animal studies suggest an embryotoxic acitivity of 5-ALA plus light exposure (see section 5.3). Therefore, this medicinal product should not be used during pregnancy.

Use in lactation

It is unknown whether 5-ALA or its metabolite PPIX are excreted in human breast milk. The excretion of 5-ALA or PPIX in milk has not been studied in animals. Breast-feeding should be interrupted for 24 hours after treatment with this medicinal product.

4.7 Effects On Ability To Drive And Use Machines

Gliolan has no influence on the ability to drive and use machines.

4.8 Undesirable Effects

Adverse reactions observed after the use of this medicinal product for fluorescence-guided glioma resection are divided into the following two categories:

- immediate reactions occurring after oral administration of the medicinal product before induction of anaesthesia (= active substance-specific side effects)

- combined effects of 5-ALA, anaesthesia, and tumour resection (= procedure-specific side effects).

Very common (

Common (

Uncommon (

Rare (

Very rare (

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Substance-specific side effects:

Cardiac disorders	Uncommon: Hypotension
Gastrointestinal disorders	Uncommon: Nausea
Skin and subcutaneous tissue disorders	Uncommon: Photosensitivity reaction, photodermatosis

Procedure-related side effects

The extent and frequency of procedure-related neurological side effects depend on the localisation of the brain tumour and the degree of resection of tumour tissue lying in eloquent brain areas (see section 4.4).

Blood and lymphatic system disorders	Very common: Anaemia, thrombocytopenia, leukocytosis
Nervous system disorders	Common: Neurological disorders (e.g. hemiparesis, aphasia, convulsions, hemianopsia) Very rare: Hypesthesia
Cardiac disorders	Uncommon: Hypotension
Vascular disorders	Common: Thromboembolism
Gastrointestinal disorders	Common : Vomiting, nausea Very rare: Diarrhoea
Hepatobiliary disorders	Very common: Blood bilirubin increased, Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma glutamyltransferase increased, Blood amylase increased

In a single-arm study including 21 healthy male volunteers, erythema of the skin could be provoked by direct exposure to UVA light up to 24 hours after oral application of 20 mg/kg body weight 5-ALA HCl. Possibly drug-related mild nausea was reported in 1out of 21 volunteers.

In another single-centre study, 21 patients with malignant glioma received 0.2, 2, or 20 mg/kg body weight 5-ALA HCl followed by fluorescence-guided tumour resection. The only adverse reaction reported in this trial was one case of mild sunburn occurring in a patient treated with the highest dose.

In a single-arm study including 36 patients with malignant glioma, drug-related adverse events were reported in 4 patients (one patient: mild diarrhoea, one patient: moderate hypesthesia, one patient: moderate chills, and one patient: arterial hypotension 30 minutes after application of 5-ALA HCl). All patients received the medicinal product in a dose of 20 mg/kg body weight and underwent fluorescence-guided resection. Follow-up time was 28 days.

In a comparative, unblinded phase-III trial (MCALS.3/GLI), 201 patients with malignant gliomas received 5-ALA HCl in a dose of 20 mg/kg body weight and 176 of these patients underwent fluorescence-guided resection with subsequent radiotherapy. 173 patients received standard resection without administration of the medicinal product and subsequent radiotherapy. Follow-up time comprised at least 180 days after administration. At least possibly related adverse reactions were reported in 2/201 (1.0 %) patients: mild vomiting 48 hours after surgery, and mild photosensitivity 48 hours after study surgery. Another patient accidentally received an overdose of the medicinal product (3000 mg instead of 1580 mg). Respiratory insufficiency, which was reported in this patient, was managed by adaptation of ventilation and resolved completely. A more pronounced transient increase of liver enzymes without clinical symptoms was observed in the 5-ALA HCl- treated patients. Peak values occurred between 7 and 14 days after administration. Increased levels of amylase, total bilirubin, and leukocytes, but decreased levels of thrombocytes and erythrocytes were observed, however differences between treatment groups were not statistically significant.

4.9 Overdose

Within a clinical trial, a 63 year old patient with known cardiovascular disease was accidentally given an overdose of 5-ALA HCl (3000 mg instead of 1580 mg). During surgery he developed respiratory insufficiency, which was managed by adaptation of ventilation. After surgery the patient also displayed facial erythema. It was stated that the patient had been exposed to more light than permitted for the trial. Respiratory insufficiency and erythema completely resolved.

In the event of overdose, supportive measures should be provided as necessary, including sufficient protection from strong light sources (e.g. direct sunlight).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: sensitisers used in photodynamic therapy, ATC code: L01XD04

5-aminolevulinic acid (5-ALA), the active substance of Gliolan, is a natural biochemical precursor of heme that is metabolised in a series of enzymatic reactions to fluorescent porphyrins, particularly protoporphyrin IX (PPIX). 5-ALA synthesis is regulated by an intracellular pool of free heme via a negative feedback mechanism.

Systemic administration of 5-ALA results in an overload of the cellular porphyrin metabolism and accumulation of PPIX in various epithelia and cancer tissues. Malignant glioma tissue (WHO grade III and IV, e.g. glioblastoma multiforme, gliosarcoma or anaplastic astrocytoma) has also been demonstrated to synthesise and accumulate porphyrins in response to 5-ALA administration. The concentration of PPIX is significantly lower in white matter than in cortex and tumour. Tissue surrounding the tumour and normal brain may also be affected. However, 5-ALA induced PPIX formation is significantly higher in malignant tissue than in normal brain.

In contrast, in low-grade tumours (WHO-grade I and II, e.g. medulloblastoma, oligodendroglioma) no fluorescence could be observed after application of the active substance. Brain metastases revealed inconsistent or no fluorescence.

The phenomenon of PPIX accumulation in WHO grade III and IV malignant gliomas may be explained by higher 5-ALA uptake into the tumour tissue or an altered pattern of expression or activity of enzymes (e.g. Ferrochelatase) involved in haemoglobin biosynthesis in tumour cells. Explanations for higher 5-ALA uptake include a disrupted blood-brain barrier, increased neo-vascularisation, and the overexpression of membrane transporters in glioma tissue.

After excitation with blue light (λ=400-410 nm), PPIX is strongly fluorescent (peak at λ=635 nm) and can be visualised after appropriate modifications to a standard neurosurgical microscope.

Fluorescence emission can be classified as intense (solid) red fluorescence (corresponds to vital, solid tumour tissue) and vague pink fluorescence (corresponds to infiltrating tumour cells), whereas normal brain tissue lacking enhanced PPIX levels reflects the violet-blue light and appears blue.

In a phase I/II-trial including 21 patients, a dose-efficacy relationship between the dose levels and the extent and quality of fluorescence in the tumour core was detected: Higher doses of 5-ALA HCl enhanced the fluorescence quality and the fluorescence extent of the tumour core compared to demarcation of the tumour core under standard white illumination in a monotone, non-falling fashion. The highest dose (20 mg/kg body weight) was determined to be the most efficient.

A positive predictive value of tissue fluorescence of 84.8 % (90 % CI: 70.7 %-93.8 %) was found. This value was defined as the percentage of patients with positive tumour cell identification in all biopsies taken from areas of weak and strong fluorescence. The positive predictive value of strong fluorescence was higher (100.0 %; 90 % CI: 91.1 %-100.0 %) than of weak fluorescence (83.3 %; 90 % CI: 68.1 %-93.2 %). Results were based on a phase-II trial including 33 patients receiving 5-ALA HCl in a dose of 20 mg/kg body weight.

The resulting fluorescence was used as an intraoperative marker for malignant glioma tissue with the aim of improving the surgical resection of these tumours.

In a phase-III trial with 349 patients with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomised to fluorescence-guided resection after administration of 20 mg/kg body weight 5-ALA HCl or conventional resection under white light. Contrast-enhancing tumour was resected in 64 % of patients in the experimental group compared to 38 % in the control-group (p<0.001).

At the visit six months after tumour resection, 20.5 % of 5-ALA-treated-patients and 11 % of patients who underwent standard surgery were alive at the six-month visit without progression. The difference was statistically significant using the chi-square test (p=0.015).

No significant increase in overall survival has been observed in this study, however, the trial was not powered to detect such a difference.

5.2 Pharmacokinetic Properties

General characteristics

This medicinal product shows good solubility in aqueous solutions. After ingestion, 5-ALA itself is not fluorescent but is taken up by tumour tissue (see section 5.1) and is intracellularily metabolised to fluorescent porphyrins, predominantly protoporphyrin IX (PPIX).

Absorption

5-ALA HCl as drinking solution is rapidly and completely absorbed and peak plasma levels of 5-ALA are reached 0.5–2 hours after oral administration of 20 mg/kg body weight. Plasma levels return to baseline values 24 hours after administration of an oral dose of 20 mg/kg body weight. The influence of food has not been investigated because this medicinal product is generally given on empty stomach prior to induction of anaesthesia.

Distribution and Biotransformation

5-ALA is preferentially taken up by the liver, kidney, endothelials and skin as well as by malignant gliomas (WHO grade III and IV) and metabolised to fluorescent PPIX. Four hours after oral administration of 20 mg/kg body weight 5-ALA HCl, the maximum PPIX plasma level is reached. PPIX plasma levels rapidly decline during the subsequent 20 hours and are not detectable anymore 48 hours after administration. At the recommended oral dose of 20 mg/kg body weight, tumour to normal brain fluorescence ratios are usually high and offer lucid contrast for visual perception of tumour tissue under violet-blue light for at least 9 hours.

Besides tumour tissue, faint fluorescence of the choroid plexus was reported. 5-ALA is also taken up and metabolised to PPIX by other tissues, e.g. liver, kidneys or skin (see section 4.4). Plasma protein binding of 5-ALA is unknown.

Elimination

5-ALA is eliminated quickly with a terminal half-life of 1-3 hours. Approximately 30 % of an orally administered dose of 20 mg/kg body weight are excreted unchanged in urine within 12 hours.

Linearity/non-linearity

There is dose proportionality between AUC_0-inf. of 5-ALA values and different oral doses of this medicinal product.

Patients with renal or hepatic impairment

Pharmacokinetics of 5-ALA in patients with renal or liver impairment has not been investigated.

5.3 Preclinical Safety Data

Standard safety pharmacology experiments were performed under light protection in the mouse, rat and dog. 5-ALA HCl administration does not influence the function of the gastro-intestinal and central nervous systems. A slight increase in saluresis cannot be excluded.

Single administration of high doses of 5-ALA HCl to mice or rats leads to unspecific findings of intolerance without macroscopic abnormalities or signs of delayed toxicity. Repeat-dose toxicity studies performed in rats and dogs demonstrate dose-dependent adverse reactions affecting changes in bile duct histology (non-reversible within a 14 day recovery period), transient increase in transaminases, LDH, total bilirubin, total cholesterin, creatinine, urea and vomiting (only in dogs). Signs of systemic toxicity (cardiovascular and respiratory parameters) occurred at higher doses in the anaesthetised dog: at 45 mg/kg body weight intravenously a slight decrease in peripheral arterial blood pressure and systolic left ventricular pressure was recorded. Five minutes after administration, the baseline values had been reached again. The cardiovascular effects seen are considered to be related to the intravenous route of administration.

Phototoxicity observed after 5-ALA HCl treatment in vitro and in vivo is obviously closely related to dose- and time- dependent induction of PPIX synthesis in the irradiated cells or tissues. Destruction of sebaceous cells, focal epidermal necrosis with a transient acute inflammation and diffuse reactive changes in the keratinocytes as well as transient secondary oedema and inflammation of dermis are observed. Light exposed skin recovered completely except for a persistent reduction in the number of hair follicles. Accordingly, general light protective measures of eyes and skin are recommended for at least 24 hours after administration of this medicinal product.

Although pivotal studies on the reproductive and developmental behaviour of 5-ALA have not been performed, it can be concluded that 5-ALA induced porphyrin synthesis may lead to embryotoxic activity in mouse, rat and chick embryos only under the condition of direct concomitant light exposure. This medicinal product should, therefore, not be administered to pregnant women. Excessive single dose treatment of rats with 5-ALA reversibly impaired male fertility for two weeks after dosing.

The majority of genotoxicity studies performed in the dark do not reveal a genotoxic potential of 5-ALA. The compound potentially induces photogenotoxicity after subsequent irradiation or light exposure which is obviously related to the induction of porphyrin synthesis.

Long-term in vivo carcinogenicity studies have not been conducted. However, considering the therapeutic indication, a single oral treatment with 5-ALA HCl might not be related to any serious potential carcinogenic risk.

6. Pharmaceutical Particulars

6.1 List Of Excipients

None

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years

The reconstituted solution is physically-chemically stable for 24 hours at 25ºC.

6.4 Special Precautions For Storage

Keep the vial in the outer carton in order to protect from light.

For storage conditions of the reconstituted product see section 6.3.

6.5 Nature And Contents Of Container

Colourless type II glass vial, with rubber stopper.

Pack sizes: 1, 2 and 10 vials of powder.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The oral solution is prepared by dissolving the amount of powder of one vial in 50 ml of tap water. The reconstituted solution is a clear and colourless to slightly yellowish fluid.

Any unused product or waste material should be disposed of in accordance with local requirements.

Single use vial – discard any content remaining after first use.

7. Marketing Authorisation Holder

m e d a c

Gesellschaft für klinische

Spezialpräparate mbH

Fehlandtstraße 3

D-20354 Hamburg, Germany

Tel. + 49 4103 8006 0

Fax: +49 4103 8006 100

8. Marketing Authorisation Number(S)

EU/1/07/413/001-003

9. Date Of First Authorisation/Renewal Of The Authorisation

07.09.2007

10. Date Of Revision Of The Text

07.09.2007

Gliclazide 80mg Tablets

1. Name Of The Medicinal Product

Glimil 80mg Tablets / Gliclazide 80mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 80mg Gliclazide

3. Pharmaceutical Form

Glimil (Gliclazide) 80mg Tablets are presented as white round tablets with 'G 80' on one side and score line on other side.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of maturity onset diabetes mellitus.

4.2 Posology And Method Of Administration

Adults: The total daily dose may vary from 40 to 320mg taken orally. The dose should be adjusted according to the individual patient's response, commencing with 40 - 80mg daily (½ to 1 tablets) and increasing until adequate control is achieved. A single dose should not exceed 160mg (2 tablets). When higher dose is required, Gliclazide should be taken twice daily and according to the main meals of the day.

In obese patients or those not showing adequate response to Gliclazide alone, additional therapy may be required.

Elderly: Plasma clearance of gliclazide is not altered in the elderly and steady state plasma levels can therefore be expected to be similar to those in adults under 65 years. Clinical experience in the elderly to date shows that gliclazide is effective and well tolerated. Care should be exercised, however, when prescribing sulphonylureas in the elderly due to possible age-related increased risk of hypoglycaemia.

Children: Gliclazide, as with other sulphonylureas, is not indicated for the treatment of juvenile onset diabetes mellitus.

4.3 Contraindications

Gliclazide is contra indicated in:

- Juvenile onset diabetes

- Diabetes complicated by ketosis and acidosis

- Pregnancy

- Diabetes undergoing surgery, after severe trauma or during infections

- Patients known to have hypersensitivity to other sulphonylureas and related drugs

- Diabetes pre-coma and coma

- Severe renal or hepatic insufficiency

4.4 Special Warnings And Precautions For Use

Care should be exercised in patients with hepatic impairment and a small starting dose should be used with careful patient monitoring.

All sulphonylurea drugs are capable of producing moderate or severe hypoglycaemia. As with other sulphonylureas, hypoglycaemia will occur if the patient's dietary intake is reduced or if they are receiving a larger dose of Gliclazide than required, particularly in the following conditions;

- In patients controlled by diet alone

- In cases of accidental overdose

- When calorie or glucose intake is deficient

- In patients with hepatic and/or renal impairment, however, in long-term clinical trials, patients with renal insufficiency have been treated satisfactorily, using gliclazide at reduced doses.

In order to reduce the risk of hypoglycaemia it is therefore recommended;

- To initiate treatment for non-insulin dependent diabetics by diet alone, if this is possible;

- To take into account the age of the patient: blood sugar levels not strictly controlled by

diet alone might be acceptable in the elderly;

- To adjust the dose of Gliclazide according to the blood glucose response and to the 24 hour urinary glucose during the first days of treatment.

Dosage adjustments may be necessary;

- On the occurrence of mild symptoms of hypoglycaemia (seating, pallor, hunger pangs, tachycardia, sensation of malaise). Such findings should be treated with oral glucose and adjustments made in drug dosage and/or meal patterns;

- On the occurrence of severe hypoglyceemic reactions (coma or neurological impairment, see overdose)

- Loss of control of blood glucose (hyperglycaemia). When a patient stabilised on any diabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control may occur. At such times, it may be necessary to progressively increase the dosage of Gliclazide and if this is insufficient, to discontinue the treatment and to administer insulin.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Care should be taken when giving Gliclazide with drugs, which are known to alter the diabetic state or potentiate the drug's action. The hypoglycaemic effect of Gliclazide may be potentiated by phenylbutazone, salicylates, sulphonamides, coumarin derivatives, MAOIs, beta adrenergic blocking agents, tetracycline compounds, chloramphenicol, clofibrate, disopyramide, miconazole (oral forms) and cimetidine.

It may be diminished by corticosteroids, oral contraceptives, thiazide diuretics, phenothiazine derivatives, thyroid hormones and abuse of laxatives.

4.6 Pregnancy And Lactation

Pregnancy: 'See Contra-indications'

Nursing mothers: It has not yet been established whether gliclazide is transferred to human milk. However, other sulphonylureas have been found in milk and there is no evidence to suggest that gliclazide differs from the group in this respect.

4.7 Effects On Ability To Drive And Use Machines

Patients should be informed that their concentration may be affected if their diabetes is not satisfactorily controlled, especially at the beginning of treatment (see other special warnings and precautions).

4.8 Undesirable Effects

Hypoglycaemia (see special warnings and precautions).

Abnormalities of hepatic functions are not uncommon during gliclazide therapy. There are rare reports of hepatic failure, hepatitis and jaundice following treatment with gliclazide.

Mild gastro-intestinal disturbances including nausea, dyspepsia, diarrhoea and constipation have been reported, but this type of adverse reaction can be avoided, if Gliclazide is taken during the meal.

Skin reactions including rash, pruritis, erythmea, bullous eruption, blood dyscarsia including anaemia, leucopenia, thrombocytopenia and granulocytopenia have been during treatment with gliclazide but are not known to be directly attributable to the drug.

4.9 Overdose

The symptoms to be expected with an overdose would be hypoglycaemia. The treatment is gastric lavage and correction of the hypoglycaemia by appropriate means with continued monitoring of the patient's blood sugar until the effect of the drug has ceased.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Gliclazide is a hypoglycaemic sulphonylurea differing from other related compounds by the addition of an azabicyclo octane ring. Oral sulphonylureas act by stimulating the release of insulin from beta cells, but they may also have long term extrapancreatic effects that reduce hepatic glucose production and increase the number of peripheral insulin receptors. Sulphonylureas are effective only in individuals with functional beta cells.

In man, apart from having a similar hypoglycaemic effect to the other sulphonylureas, gliclazide has been shown to reduce platelet adhesiveness and aggregation and increase fibrinolytic activity. These factors are thought to be implicated in the pathogenesis of long-term complications of diabetes mellitus.

5.2 Pharmacokinetic Properties

The drug is well absorbed and its half-life in man is approximately 10 - 12 hours. Gliclazide is metabolised in the liver to inactive metabolites; less than 5% of the dose is excreted unchanged in the urine. Although there is a dose-dependent relationship between gliclazide and plasma concentrations, no clear correlation with hypoglycaemic activity exists.

5.3 Preclinical Safety Data

No further relevant information.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate	Ph. Eur.
Silicon dioxide	Ph. Eur.
Pregelatinised maize starch	Ph. Eur.
Talc	Ph. Eur.
Magnesium stearate	Ph. Eur.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

The tablets are packaged into polyvinyl chloride (PVC)/aluminium foil blister packs. Boxes of 28 tablets or 60 tablets are available.

Boxes of 28 tablets contain 2 blister packs each of 14 tablets. Boxes of 60 tablets contain 6 blister packs each of 10 tablets or 3 blister packs each of 20 tablets or 4 blister packs each of 15 tablets.

6.6 Special Precautions For Disposal And Other Handling

No special instructions. Tablets to be taken as directed by a physician.

7. Marketing Authorisation Holder

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

8. Marketing Authorisation Number(S)

PL 16363/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

10 June 1999

10. Date Of Revision Of The Text

28/05/2007

Gaviscon Double Action Tablets

1. Name Of The Medicinal Product

Gaviscon Double Action Tablets.

2. Qualitative And Quantitative Composition

Each tablet contains sodium alginate 250 mg, sodium bicarbonate 106.5 mg and calcium carbonate 187.5 mg.

Excipients:	Aspartame (E951) 5.863mg per tablet Carmoisine Lake (E122) 0.375mg per tablet

For a full list of excipients, see Section 6.1.

3. Pharmaceutical Form

Chewable tablet.

A flat, circular, bi-layer tablet with bevelled edges. One layer of the tablet is pink and slightly mottled, and the other white.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of acid related symptoms of gastro-oesophageal reflux such as acid regurgitation, heartburn and indigestion, for example following meals or during pregnancy.

4.2 Posology And Method Of Administration

For oral administration, after being thoroughly chewed.

Adults and children 12 years and over: Two to four tablets after meals and at bedtime, up to four times per day.

Children under 12 years: Should be given only on medical advice.

Elderly: No dose modifications necessary for this age group.

4.3 Contraindications

This medicinal product is contraindicated in patients with known or suspected hypersensitivity to the active substances or to any of the excipients.

4.4 Special Warnings And Precautions For Use

The sodium content of a two-tablet dose is 110.75 mg (4.82 mmol). This should be taken into account when a highly restricted salt diet is recommended, e.g. in some cases of congestive cardiac failure and renal impairment.

Each two-tablet dose contains 150 mg (3.75 mmol) of calcium. Care needs to be taken in treating patients with hypercalcaemia, nephrocalcinosis and recurrent calcium containing renal calculi.

Due to its aspartame content this product should not be given to patients with phenylketonuria.

If symptoms do not improve after seven days, the clinical situation should be reviewed.

Prolonged use should be avoided.

As with other antacid products, taking Gaviscon Double Action Tablets can mask the symptoms of other more serious, underlying medical conditions.

Gaviscon Double Action Tablets should not be used in the following cases:

• Patients with server/impaired renal function/-insufficiency

• Patients with hypophosphatemia

There is a possibility of reduced efficacy in patients with very low levels of gastric acid.

There is increased risk for hypernatremia in children with gastroenteritis or suspected renal insufficiency.

Treatment of children younger than 12 years of age is not generally recommended, except on medical advice.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Due to the presence of calcium carbonate which acts as an antacid, a time-interval of 2 hours should be considered between Gaviscon intake and the administration of other medicinal products, especially H2-antihistaminics, tetracyclines, digoxine, fluoroquinolone, iron salt, ketoconazole, neuroleptics, thyroxine, penicilamine, beta-blockers (atenolol, metoprolol, propanolol), glucocorticoid, chloroquine and diphosphonates.

4.6 Pregnancy And Lactation

Open controlled studies in 281 pregnant women did not demonstrate any significant adverse effects of Gaviscon on the course of pregnancy or on the health of the foetus/new-born child. Based on this and previous experience, the medicinal product may be used during pregnancy and lactation. Nevertheless, taking into account the presence of calcium carbonate it is recommended to limit the treatment duration as much as possible.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Very rarely (<1/10,000) patients sensitive to the ingredients may develop allergic manifestations such as urticaria or bronchospasm, anaphylactic or anaphylactoid reactions.

Ingestion of large quantities of calcium carbonate may cause alkalosis, hypercalcaemia, acid rebound, milk alkali syndrome or constipation. These usually occur following larger than recommended dosages

4.9 Overdose

In the event of overdosage, symptomatic treatment should be given. The patient may notice abdominal distension.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: A02BX, Other drugs for peptic ulcer and gastro-oesophageal reflux disease.

The medicinal product is a combination of two antacids (calcium carbonate and sodium bicarbonate) and an alginate.

On ingestion, the medicinal product reacts rapidly with gastric acid to form a raft of alginic acid gel having a near neutral pH and which floats on the stomach contents effectively impeding gastro-oesophageal reflux. In severe cases the raft itself may be refluxed into the oesophagus, in preference to the stomach contents, and exert a demulcent effect.

Calcium carbonate neutralises gastric acid to provide fast relief from indigestion and heartburn. This effect is increased by the addition of sodium bicarbonate which also has a neutralising action. The total neutralising capacity of the product at the lowest dose of two tablets is approximately 10 mEqH⁺.

5.2 Pharmacokinetic Properties

The mode of action of the medicinal product is physical and does not depend on absorption into the systemic circulation.

5.3 Preclinical Safety Data

No pre-clinical findings of any relevance to the prescriber have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Macrogol 20,000

Mannitol (E421)

Copovidone

Acesulfame K

Aspartame (E951)

Mint Flavour

Carmoisine Lake (E122)

Magnesium stearate

Xylitol DC (contains carmellose sodium)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

Polypropylene container: Use within 3 months of opening.

6.4 Special Precautions For Storage

Blister trays: Do not store above 30°C. Store in the original package to protect from moisture.

Flip-top lid containers: Do not store above 25°C. Store in the original package to protect from moisture.

6.5 Nature And Contents Of Container

Unprinted, glass, clear, thermoformable laminate of uPVC/PE/PVdC with aluminium foil lidding blisters packed into cartons.

Blister tray containing 2, 4, 6 or 8 sealed tablets. Pack sizes: 4, 6, 8, 16, 24, 32, 48, 60, 62, 64 and 80 chewable tablets.

Coloured, opaque, injection-moulded, polypropylene flip-top lid containers containing 8, 10, 12 or 16 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Limited,

Dansom Lane,

Hull, HU8 7DS,

United Kingdom.

8. Marketing Authorisation Number(S)

PL 00063/0157

9. Date Of First Authorisation/Renewal Of The Authorisation

27/01/2011

10. Date Of Revision Of The Text

27/01/2011

Gaviscon Double Action Mint

1. Name Of The Medicinal Product

Gaviscon Double Action Mint.

2. Qualitative And Quantitative Composition

Each 10 ml dose contains sodium alginate 500 mg, sodium bicarbonate 213 mg and calcium carbonate 325 mg.

Excipients : Methyl parahydroxybenzoate (E218) and Propyl parahydroxybenzoate (E216). For a full list of excipients, see Section 6.1.

3. Pharmaceutical Form

Oral suspension.

Opaque, off-white to cream viscous suspension.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of symptoms of gastro-oesophageal reflux such as acid regurgitation, heartburn and indigestion, for example following meals or during pregnancy, and for symptoms of excess stomach acid (hyperacidity).

4.2 Posology And Method Of Administration

For oral administration.

Adults and children 12 years and over: 10-20 ml after meals and at bedtime, up to four times per day.

Children under 12 years: Should be given only on medical advice.

Elderly: No dose modifications necessary for this age group.

4.3 Contraindications

Hypersensitivity to any of the ingredients, including the esters of hydroxybenzoates (parabens).

4.4 Special Warnings And Precautions For Use

Each 20 ml dose has a sodium content of 254.5 mg (11.06 mmol). This should be taken into account when a highly restricted salt diet is recommended, e.g. in some cases of congestive cardiac failure and renal impairment.

Each 20 ml contains 260 mg (6.5 mmol) of calcium. Care needs to be taken in treating patients with hypercalcaemia, nephrocalcinosis and recurrent calcium containing renal calculi.

Treatment of children younger than 12 years of age is not generally recommended, except on medical advice.

If symptoms do not improve after seven days, the clinical situation should be reviewed.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Due to the presence of calcium carbonate which act as an antacid, a time-interval of 2 hours should be considered between Gaviscon intake an the administration of other medicinal products, especially H2-antihistaminics tetracyclines, digoxine, fluoroquinolone, iron salt, ketoconazole, neuroleptics, thyroxine, penicilamine, beta-blockers (atenolol, metoprolol, propanolol), glucocorticoid, chloroquine, and diphosphonates.

.

4.6 Pregnancy And Lactation

Open controlled studies in 281 pregnant women did not demonstrate any significant adverse effects of Gaviscon on the course of pregnancy or on the health of the foetus/new-born child. Based on this and previous experience the medicinal product may be used during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Very rarely (<1/10,000) patients sensitive to the ingredients may develop allergic manifestations such as urticaria or bronchospasm, anaphylactic or anaphylactoid reactions.

Ingestion of large quantities of calcium carbonate may cause alkalosis, hypercalcaemia, acid rebound, milk alkali syndrome or constipation. These usually occur following larger than recommended dosages.

4.9 Overdose

In the event of overdosage symptomatic treatment should be given. The patient may notice abdominal distension.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: A02BX, Other drugs for peptic ulcer and gastro-oesophageal reflux disease.

The medicinal product is a combination of two antacids (calcium carbonate and sodium bicarbonate) and an alginate.

On ingestion, the medicinal product reacts rapidly with gastric acid to form a raft of alginic acid gel having a near neutral pH and which floats on the stomach contents effectively impeding gastro-oesophageal reflux. In severe cases the raft itself may be refluxed into the oesophagus, in preference to the stomach contents and exert a demulcent effect.

Calcium carbonate neutralises gastric acid to provide fast relief from indigestion and heartburn. This effect is increased by the addition of sodium bicarbonate which also has a neutralising action. The total neutralising capacity of the product at the lowest dose of 10 ml is approximately 10 mEqH+.

5.2 Pharmacokinetic Properties

The mode of action of the medicinal product is physical and does not depend on absorption into the systemic circulation.

5.3 Preclinical Safety Data

No pre-clinical findings of any relevance to the prescriber have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Carbomer

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Saccharin sodium

Mint flavour

Sodium hydroxide

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Two years.

Use within six months of opening.

6.4 Special Precautions For Storage

Do not store above 30°C. Do not refrigerate or freeze.

6.5 Nature And Contents Of Container

Amber glass bottles with a polypropylene cap with a polyethylene tamper-evident band lined with expanded polyethylene wad and containing 150, 200, 300 and 600 ml.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Limited, Dansom Lane, Hull, HU8 7DS, United Kingdom.

8. Marketing Authorisation Number(S)

PL 00063/0552.

9. Date Of First Authorisation/Renewal Of The Authorisation

24/06/2008

10. Date Of Revision Of The Text

14/09/2010

Gabitril 5mg, Gabitril 10mg, Gabitril 15mg (Cephalon (UK) Limited)

1. Name Of The Medicinal Product

Gabitril^® 5 mg film-coated tablets

Gabitril^® 10 mg film-coated tablets

Gabitril^® 15 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each Gabitril 5 mg tablet contains:

Tiagabine anhydrous, INN 5 mg (as hydrochloride monohydrate)

Each Gabitril 10 mg tablet contains:

Tiagabine anhydrous, INN 10 mg (as hydrochloride monohydrate)

Each Gabitril 15 mg tablet contains:

Tiagabine anhydrous, INN 15 mg (as hydrochloride monohydrate)

3. Pharmaceutical Form

5 mg: Tablet. White, round biconvex film-coated tablet embossed on one side with '251'.

10 mg: Tablet. White, oval biconvex film-coated tablet embossed on one side with '252'.

15 mg: Tablet. White, oval biconvex film-coated tablet embossed on one side with '253'.

4. Clinical Particulars

4.1 Therapeutic Indications

Gabitril is an anti-epileptic drug indicated as add-on therapy for partial seizures with or without secondary generalisation where control is not achieved by optimal doses of at least one other anti-epileptic drug.

4.2 Posology And Method Of Administration

Gabitril should be taken orally with meals.

Dosing schemes may need to be individualised based upon a patient's particular characteristics such as age and concomitant medications.

Concomitant use with drugs involving CYP 3A4/5 metabolism: As CYP3A4/5 is involved in the metabolism of tiagabine, it is recommended that the dose of tiagabine is adjusted when it is taken in combination with CYP3A4/5 inducers (see section 4.5 Interactions with other medicinal products and other forms of interactions).

Following a given dose of tiagabine, the estimated plasma concentration in non-induced patients is more than twice that in patients receiving enzyme-inducing agents. To achieve similar systemic exposures of tiagabine, non-induced patients require lower and less frequent doses of tiagabine than induced patients. These patients may also require a slower titration of tiagabine compared to that of induced patients.

Adults and children over 12 years: The initial daily dose is 5-10 mg tiagabine, followed by weekly increments of 5-10 mg/day. The usual maintenance dose in patients taking enzyme-inducing drugs is 30-45 mg/day. In patients not taking enzyme-inducing drugs, the maintenance dose should initially be reduced to 15-30 mg/day. The initial daily dose should be taken as a single dose or divided into two doses. The daily maintenance dose should be divided into two or three single doses.

Children under 12 years: There is no experience with Gabitril in children under 12 years of age and as such Gabitril should not be used in this age group.

Use in the elderly: There is limited information available on the use of Gabitril in elderly patients, but pharmacokinetics of tiagabine are unchanged, hence there should be no need for dose modification.

Patients with renal insufficiency: Renal insufficiency does not affect the pharmacokinetics of tiagabine, therefore the dosage does not need to be modified in this type of patient.

Patients with impaired liver function: Tiagabine is metabolised in the liver and since the pharmacokinetics of tiagabine in patients with mild to moderate impaired liver function is modified (see Section 5.2), the Gabitril dosage should be adjusted by reducing the individual doses and/or prolonging the dose intervals.

Gabitril should not be used in patients with severely impaired hepatic function (see Section 4.3).

4.3 Contraindications

Gabitril should not be given to patients with a history of hypersensitivity to tiagabine or one of the excipients.

Severely impaired liver function.

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 Gabitril.

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.

Post-marketing reports have shown that Gabitril use has been associated with new onset seizures and status epilepticus in patients without epilepsy. Confounding factors that may have contributed to development of seizures include underlying medical conditions or concomitant medications that can reduce seizure threshold, reported overdose and manner of dose administration (e.g. high dosage, fast titration rate).

Safety and effectiveness of Gabitril have not been established for any indication other than as adjunctive therapy for partial seizures in adults and adolescents over 12 years.

Gabitril is eliminated by hepatic metabolism and therefore caution should be exercised when administering the product to patients with impaired hepatic function. Reduced doses and/or dose intervals should be used and patients should be monitored closely for adverse events such as dizziness and tiredness.

Although Gabitril may slightly prolong the CNS depressant effect of triazolam, this interaction is unlikely to be relevant to clinical practice.

Anti-epileptic agents that induce hepatic enzymes (such as phenytoin, carbamazepine, phenobarbital and primidone) enhance the metabolism of tiagabine. Consequently, patients taking enzyme-inducing drugs may require doses of tiagabine above the usual dose range.

Although there is no evidence of withdrawal seizures following Gabitril, it is recommended to taper off treatment over a period of 2-3 weeks.

Serious rash, including vesiculobullous rash, has occured in patients receiving Gabitril (see section 4.8 Undesirable effects).

Spontaneous bruising has been reported. Therefore, if bruising is observed full blood count, including platelet count is to be performed.

Rare cases of visual field defects have been reported with tiagabine. If visual symptoms develop, the patient should be referred to an ophthalmologist for further evaluation including perimetry.

Gabitril tablets contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Anti-epileptic agents that induce hepatic enzymes (such as phenytoin, carbamazepine, phenobarbital and primidone) enhance the metabolism of tiagabine. The plasma concentration of tiagabine may be reduced by a factor 1.5-3 by concomitant use of these drugs.

Gabitril does not have any clinically significant effect on the plasma concentrations of phenytoin, carbamazepine, phenobarbital, warfarin, digoxin, theophylline and hormones from oral contraceptive pills. Gabitril reduces the plasma concentration of valproate by about 10%, and cimetidine increases the bioavailability of tiagabine by about 5%. Neither of these findings are considered clinically important and do not warrant a dose modification.

4.6 Pregnancy And Lactation

Animal experiments have not shown a teratogenic effect of tiagabine. Studies in animals have however, revealed peri- and post-natal toxicity of tiagabine at very high doses.

Clinical experience of the use of Gabitril in pregnant women is limited.

No information on Gabitril during breast-feeding is available.

Consequently, as a precautionary measure, it is preferable not to use Gabitril during pregnancy or breast-feeding unless in the opinion of the physician, the potential benefits of treatment outweigh the potential risks.

4.7 Effects On Ability To Drive And Use Machines

Gabitril may cause dizziness or other CNS related symptoms, especially during initial treatment. Therefore caution should be shown by patients driving vehicles or operating machinery.

4.8 Undesirable Effects

Adverse events are mainly CNS related.

A full list of adverse reactions reported with Gabitril during clinical studies and post marketing experience is shown in the table below. Adverse reactions are listed below as MedDRA preferred term by system organ class and frequency (frequencies are defined as: very common

The following undesirable effects have been reported with Gabitril:

System Organ Class	Frequency	Undesirable effects
Nervous system disorders	Very common	Dizziness, tremor
Common	Ataxia, abnormal gait, speech disorder
Uncommon	Somnolence
Rare	Non-convulsive status epilepticus
Not known	Encephalopathy
Psychiatric disorders	Very common	Nervousness (non-specific)
Common	Concentration difficulties, depressed mood, emotional lability, confusion, insomnia, hostility/aggression
Uncommon	Depression, psychosis
Rare	Hallucinations, delusion
Injury, poisoning and procedural complications	Common	Accidental injury
General disorders and administration site conditions	Very common	Tiredness
Eye disorders	Common	Vision blurred
Rare	Visual field defects
Skin and subcutaneous tissue disorders	Uncommon	Dermatitis bullous, bruising
Not known	Vesiculobullous rash, exfoliative dermatitis
Gastrointestinal disorders	Very common	Nausea
Common	Diarrhoea, vomiting, abdominal pain
Musculoskeletal and connective tissue disorders	Common	Muscle twitching

In patients with a history of serious behavioural problems there is a risk of recurrence of these symptoms during treatment with Gabitril, as occurs with certain other anti-epileptic drugs.

Although not statistically significant, routine laboratory screening during placebo controlled studies showed a low white blood cell count (<2.5 x 10⁹ per litre) more frequently during Gabitril treatment (4.1%) than placebo (1.5%).

Postmarketing reports have shown that Gabitril use has been associated with new onset seizures and status epilepticus in patients without epilepsy (see section 4.4 Special warnings and special precautions for use).

4.9 Overdose

Symptoms most often accompanying Gabitril overdose, alone or in combination with other drugs, have included seizures, including status epilepticus, in patients with and without underlying seizure disorders, respiratory depression, respiratory arrest, coma, loss of consciousness, spike wave stupor, encephalopathy, amnesia, confusion, disorientation, somnolence, dyskinesia, myoclonus, tremors, ataxia or incoordination, dizziness, nystagmus, impaired speech, headache, psychotic disorder, hallucinations, hostility, aggression, agitation, vomiting, hypersalivation, bradycardia, tachycardia, ST wave changes, hypertension, hypotension and urinary incontinence. In more severe instances, mute and withdrawn appearance of the patient, risk of convulsion have been reported.

From post-marketing experience, there have been no reports of fatal overdoses involving Gabitril alone (doses up to 720 mg), although a number of patients required intubation and ventilatory support as part of the management of their status epilepticus.

Standard medical observation and supportive care should be given. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of more than 2 mg/kg.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Gabitril is an anti-epileptic drug.

Tiagabine is a potent and selective inhibitor of both neuronal and glial GABA uptake, which results in an increase in GABAergic medicated inhibition in the brain.

Tiagabine lacks significant affinity for other neurotransmitter receptor binding sites and/or uptake sites.

5.2 Pharmacokinetic Properties

Tiagabine is rapidly and virtually completely absorbed from Gabitril tablets, with an absolute bioavailability of 89%. Administration with food results in a decreased rate and not extent of absorption.

The volume of distribution is approximately 1 L/kg.

Plasma protein binding of tiagabine is about 96%.

Renal clearance is negligible. Hepatic metabolism is the principle route for elimination of tiagabine. Less than 2% of the dose is excreted unchanged in urine and faeces. No active metabolites have been identified. Other anti-epileptic drugs such as phenytoin, carbamazepine, phenobarbital and primidone induce hepatic drug metabolism and the hepatic clearance of tiagabine is increased when given concomitantly with these drugs.

There is no evidence that tiagabine causes clinically significant induction or inhibition of hepatic drug metabolising enzymes at clinical doses.

The plasma elimination half-life of tiagabine is 7–9 hours, except in induced patients where it is 2-3 hours.

Absorption and elimination of tiagabine are linear within the therapeutic dose range.

Hepatic insufficiency

A study in patients with mild and moderate impaired liver function has shown a 50% increase of the plasma concentration peak (Cmax) and a 70% increase of the area under the curve (AUC) for total (free plus bound) tiagabine in impaired individuals as compared to individuals with normal hepatic function. The fraction of unbound drug was greater in patients with moderate hepatic impairment and, as a result, exposure to unbound drug was increased to a greater extent (up to 2-fold) in moderately impaired individuals as compared to individuals with normal hepatic function. Tiagabine half-life (T_1/2) is prolonged in patients with impaired liver function with the extent of prolongation increasing with increased level of hepatic impairment. Due to adverse events observed in the patients with moderate impairment, patients with severe hepatic impairment were not studied (see Section 4.3).

The dosage of tiagabine should be carefully titrated in patients with epilepsy and reduced hepatic function. Lower doses or longer dosing intervals may be required in patients with mild to moderate impairment in liver function (see Section 4.2).

5.3 Preclinical Safety Data

Animal safety data carried out in the rat, mouse and dog gave no clear evidence of specific organ toxicity nor any findings of concern for the therapeutic use of tiagabine. The dog appears to be particularly sensitive to the pharmacological actions of tiagabine and clinical signs such as sedation, insensibility, ataxia and visual impairment reflecting CNS effects were seen at daily doses of 0.5 mg/kg and above in a dose related manner. The results of a wide range of mutagenicity tests showed that tiagabine is unlikely to be genotoxic to humans. Clastogenic activity was seen only at cytotoxic concentrations (>>200-fold human plasma levels) using the in-vitro human lymphocyte test in the absence of a metabolising system. In long-term carcinogenicity studies conducted in the rat and mouse, only the rat study revealed slightly increased incidences of hepatocellular adenomas in females and benign Leydig cell tumours in the high dose (200 mg/kg/day) group only. These changes are considered to be rat-specific and macrophages and inflammation were seen at a higher incidence than normal. The significance of this latter finding is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet Core:

Cellulose, microcrystalline (E460)

Ascorbic acid (E300)

Lactose, anhydrous

Starch, pregelatinised (maize)

Crospovidone

Silica, colloidal anhydrous (E551)

Hydrogenated vegetable oil (Type 1)

Stearic acid

Magnesium stearate

Film-coating:

Hypromellose

Hydroxypropylcellulose (E463)

Titanium Dioxide (E171)

6.2 Incompatibilities

None.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not refrigerate or freeze. Store in the original package.

6.5 Nature And Contents Of Container

Child resistant, white polyethylene bottles with white polypropylene screw closures. Each bottle contains a high density polyethylene canister of activated clay desiccant.

Packs containing 50 and 100 tablets. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special instructions

7. Marketing Authorisation Holder

Cephalon UK Limited

1 Albany Place

Hyde Way

Welwyn Garden City

Hertfordshire

AL7 3BT

United Kingdom

8. Marketing Authorisation Number(S)

Gabitril 5 mg PL 16260/0009

Gabitril 10 mg PL 16260/0010

Gabitril 15 mg PL 16260/0011

9. Date Of First Authorisation/Renewal Of The Authorisation

30^th September 2002

10. Date Of Revision Of The Text

June 2011

LEGAL CATEGORY

POM

Gyno-Pevaryl Cream

1. Name Of The Medicinal Product

Gyno-Pevaryl™ Cream.

2. Qualitative And Quantitative Composition

Each 100 g of cream contains 1 g econazole nitrate Ph.Eur. (1% w/w).

3. Pharmaceutical Form

Vaginal Cream.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of mycotic vulvovaginitis and mycotic balanitis.

4.2 Posology And Method Of Administration

Route of Administration

For vaginal/penile administration.

Females: One applicator full (approximately 5 g) intravaginally once daily at night for not less than 14 days. The cream should also be applied to the vulva. The full 14 days treatment should be carried out even if the symptoms of vaginal itching or discharge have disappeared.

Males: Apply the cream to the penis, including under the foreskin, once daily for not less than 14 days.

The sexual partner should also be treated.

4.3 Contraindications

Hypersensitivity to any imidazole preparation, other vaginal antifungal products or to any of the ingredients of Gyno-Pevaryl cream.

4.4 Special Warnings And Precautions For Use

Not for ophthalmic or oral use.

Hypersensitivity has rarely been recorded; if it should occur administration should be discontinued.

Contact between contraceptive diaphragms or condoms and this product must be avoided since the rubber may be damaged by the preparation.

Patients using spermicidal contraceptives should consult their physician since any local vaginal treatment may inactivate the spermicidal contraceptive.

Gyno-Pevaryl Cream should not be used in conjunction with other internal or external treatment of the genitalia

Gyno-Pevaryl Cream is not indicated for use in children under the age of 16 years.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Although not studied, based on the chemical similarity of econazole with other imidazole compounds, a theoretical potential for competitive interaction with compounds metabolized by CYP3A4/2C9 exists. Due to the limited systemic availability after vaginal application (see 5.2. Pharmacokinetic Properties), clinically relevant interactions are unlikely to occur. In patients on oral anticoagulants, such as warfarin and acenocoumarol, caution should be exercised and the anticoagulant effect should be monitored more frequently considered.

Adjustment of the oral anticoagulant dosage may be necessary during and after the treatment with econazole.

4.6 Pregnancy And Lactation

Pregnancy

In animals, econazole nitrate has shown no teratogenic effects but is foetotoxic at high doses. The significance of this to man is unknown as there is no evidence of an increased risk when taken in human pregnancy. However, because there is vaginal absorption, as with other imidazoles, econazole should be used in pregnancy only if the practitioner considers it to be necessary.

Lactation

Following oral administration of econazole nitrate to lactating rats, econazole and/or metabolites were excreted in milk and were found in nursing pups. It is not known whether econazole nitrate is excreted in human milk. Caution should be exercised when using Gyno-Pevaryl Cream if the patient is breast-feeding

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The most frequently reported adverse events in clinical trials were application site reactions, such as burning and stinging sensations, pruritus, and erythema.

Including the above mentioned adverse drug reactions (ADRs), the following table displays ADRs that have been reported with the use of Gynaecological Formulation from either clinical trial or postmarketing experiences. The displayed frequency categories use the following convention:

Very common (

Adverse Drug Reactions

System Organ Class	Adverse Drug Reactions
Frequency Category
		Not known
Skin and Subcutaneous Tissue Disorders			Angioedema Rash Urticaria Erythema Pruritus Burning sensation Hypersensitivity

4.9 Overdose

Overdose with econazole nitrate has not been reported to date. In the event of accidental ingestion, nausea, vomiting and diarrhoea may occur. If necessary treat symptomatically.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification: (Antiinfectives and antiseptics, excl. combinations with corticosteroids, imidazole derivatives)

ATC code: G01A F05

Econazole nitrate has no anti-inflammatory action, no effect on circulation, no central or autonomic nervous effects, no effects on respiration, no effect on α or β receptors, no anticholinergic or antiserotonergic reactions.

A broad spectrum of antimycotic activity has been demonstrated against dermatophytes, yeasts and moulds. A clinically relevant action against Gram positive bacteria has also been found.

Econazole acts by damaging cell membranes. The permeability of the fungal cell is increased. Sub-cellular membranes in the cytoplasm are damaged. The site of action is most probably the unsaturated fatty acid acyl moiety of membrane phospholipids.

5.2 Pharmacokinetic Properties

Econazole nitrate is poorly absorbed from the vagina and skin. If given orally, peak plasma levels occur six hours after dosing. About 90% of the absorbed dose is bound to plasma proteins. Metabolism is limited, but primarily occurs in the liver, the metabolites excreted in the urine.

Five major and two minor metabolites have been identified.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tefose 63

Labrafil M 1944 CS

Mineral oil

Butylated hydroxyanisole

Benzoic acid

Purified water

6.2 Incompatibilities

None stated.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Aluminium lacquered tubes.

Pack sizes 78 g, 30g, 15g.

Gyno-Pevaryl Cream (PL 0242/0229) is also contained in:

Gyno-Pevaryl 150 Combined Vaginal Pessaries and Cream

(PL 0242/0227 & PL 0242/0229)

Gyno-Pevaryl 1 C.P. PACK Vaginal Pessary and Cream

(PL 0242/0226 & PL 0242/0229)

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Janssen-Cilag Limited

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 00242/0229

9. Date Of First Authorisation/Renewal Of The Authorisation

22 September 1995/June 2003

10. Date Of Revision Of The Text

23 March 2011

Glimepiride 3mg Tablet

1. Name Of The Medicinal Product

Glimepiride 3mg Tablet

2. Qualitative And Quantitative Composition

Each tablet contains 3mg glimepiride.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

The tablets are pale yellow, oblong and scored on both sides.

4. Clinical Particulars

4.1 Therapeutic Indications

Glimepiride is indicated for the treatment of type II diabetes mellitus, when diet, physical exercise and weight reduction alone are not adequate.

4.2 Posology And Method Of Administration

For oral administration.

The basis for successful treatment of diabetes is a good diet, regular physical activity, as well as routine checks of blood and urine. Tablets or insulin cannot compensate if the patient does not keep to the recommended diet.

Dosage is determined by the results of blood and urinary glucose determinations.

The starting dose is 1 mg glimepiride per day. If good control is achieved this dosage should be used for maintenance therapy.

For the different dosage regimens appropriate strengths are available.

If control is unsatisfactory the dosage should be increased, based on the glycaemic control, in a stepwise manner with an interval of about 1 to 2 weeks between each step, to 2, 3 or 4 mg glimepiride per day.

A dosage of more than 4 mg glimepiride per day gives better results only in exceptional cases. The maximum recommended dose is 6 mg glimepiride per day.

In patients not adequately controlled with the maximum daily dose of metformin, concomitant glimepiride therapy can be initiated.

While maintaining the metformin dose, the glimepiride therapy is started with a low dose, and is then titrated up depending on the desired level of metabolic control up to the maximum daily dose. The combination therapy should be initiated under close medical supervision.

In patients not adequately controlled with the maximum daily dose of glimepiride, concomitant insulin therapy can be initiated if necessary. While maintaining the glimepiride dose, insulin treatment is started at low dose and titrated up depending on the desired level of metabolic control. The combination therapy should be initiated under close medical supervision.

Normally a single daily dose of glimepiride is sufficient. It is recommended that this dose be taken shortly before or during a substantial breakfast or

If a dose is forgotten, this should not be corrected by increasing the next dose. Tablets should be swallowed whole with some liquid.

If a patient has a hypoglycaemic reaction on 1 mg glimepiride daily, this indicates that they can be controlled by diet alone.

In the course of treatment, as an improvement in control of diabetes is associated with higher insulin sensitivity, glimepiride requirements may fall. To avoid hypoglycaemia timely dose reduction or cessation of therapy must therefore be considered. Change in dosage may also be necessary, if there are changes in weight or life style of the patient, or other factors that increase the risk of hypo-or hyperglycaemia.

Switch over from other oral hypoglycaemic agents to glimepiride

A switch over from other oral hypoglycaemic agents to glimepiride can generally be done. For the switch over to glimepiride the strength and the half-life of the previous medicinal product has to be taken into account. In some cases, especially in antidiabetics with a long half-life (e.g. chlorpropamide), a wash out period of a few days is advisable in order to minimise the risk of hypoglycaemic reactions due to the additive effect.

The recommended starting dose is 1 mg glimepiride per day. Based on the response the glimepiride dosage may be increased stepwise, as indicated earlier.

Switch over from Insulin to glimepiride

In exceptional cases, where type 2 diabetic patients are regulated on insulin, a changeover to glimepiride may be indicated. The changeover should be undertaken under close medical supervision.

Special Populations

Patients with renal or hepatic impairment:

See section 4.3.

Children and adolescents:

There are no data available on the use of glimepiride in patients under 8 years of age. For children aged 8 to 17 years, there are limited data on glimepiride as monotherapy (see sections 5.1 and 5.2).

The available data on safety and efficacy are insufficient in the paediatric population and therefore such use is not recommended.

4.3 Contraindications

Glimepiride is contraindicated in patients with the following conditions:

• hypersensitivity to glimepiride, other sulfonylureas or sulfonamides or to any of the excipients,

• insulin dependent diabetes,

• diabetic coma,

• ketoacidosis,

• severe renal or hepatic function disorders.In case of severe renal or hepatic function disorders, a change over to insulin is required.

4.4 Special Warnings And Precautions For Use

Glimepiride must be taken shortly before or during a meal.

When meals are taken at irregular hours or skipped altogether, treatment with glimepiride may lead to hypoglycaemia. Possible symptoms of hypoglycaemia include: headache, ravenous hunger, nausea, vomiting, lassitude, sleepiness, disordered sleep, restlessness, aggressiveness, impaired concentration, alertness and reaction time, depression, confusion, speech and visual disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral convulsions, somnolence and loss of consciousness up to and including coma, shallow respiration and bradycardia. In addition, signs of adrenergic counter-regulation may be present such as sweating, clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.

The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.

Symptoms can almost always be promptly controlled by immediate intake carbohydrates (sugar). Artificial sweeteners have no effect.

It is known from other sulfonylureas that, despite initially successful countermeasures, hypoglycaemia may recur.

Severe hypoglycaemia or prolonged hypoglycaemia, only temporarily controlled by the usual amounts of sugar, require immediate medical treatment and occasionally hospitalisation.

Factors favouring hypoglycaemia include:

• unwillingness or (more commonly in older patients) incapacity of the patient to cooperate,

• undernutrition, irregular mealtimes or missed meals or periods of fasting,

• alterations in diet,

• imbalance between physical exertion and carbohydrate intake,

• consumption of alcohol, especially in combination with skipped meals,

• impaired renal function,

• serious liver dysfunction,

• overdosage with glimepiride,

• certain uncompensated disorders of the endocrine system affecting carbohydrate metabolism or counterregulation of hypoglycaemia (as for example in certain disorders of thyroid function and in anterior pituitary or adrenocortical insufficiency), concurrent administration of certain other medicinal products (see section 4.5).

Treatment with glimepiride requires regular monitoring of glucose levels in blood and urine. In addition determination of the proportion of glycosylated haemoglobin is recommended.

Regular hepatic and haematological monitoring (especially leucocytes and thrombocytes) are required during treatment with glimepiride.

In stress-situations (e.g. accidents, acute operations, infections with fever, etc.) a temporary switch to insulin may be indicated.

No experience has been gained concerning the use of glimepiride in patients with severe impairment of liver function or dialysis patients. In patients with severe impairment of renal or liver function change over to insulin is indicated.

Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to hemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.

Glimepiride tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

If glimepiride is taken simultaneously with certain other medicinal products, both undesired increases and decreases in the hypoglycaemic action of glimepiride can occur. For this reason, other medicinal products should only be taken with the knowledge (or at the prescription) of the doctor.

Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). Its metabolism is known to be influenced by concomitant administration of CYP2C9 inducers (e.g rifampicin) or inhibitors (e.g fluconazole).

Results from an vivo interaction study reported in literature show that glimepiride AUC is increased approximately 2-fold by fluconazole, one of the most potent CYP2C9 inhibitors.

Based on the experience with glimepiride and with other sulfonylureas the following interactions have to be mentioned.

Potentiation of the blood-glucose-lowering effect and, thus, in some instances hypoglycaemia may occur when one of the following medicinal products is taken, for example:

- phenylbutazone, azapropazon and oxyfenbutazone,
- insulin and oral antidiabetic products, such as metformin
- salicylates and p
- anabolic steroids and male sex hormones,
- chloramphenicol, certain long acting sulfonamides, tetracyclines, quinolone antibiotics and clarithromycin
- coumarin anticoagulants,
- fenfluramine,
- fibrates,
- ACE inhibitors,
- fluoxetine, MAO-inhibitors,
- allopurinol, probenecid, sulfinpyrazone,
- sympatholytics,
- cyclophosphamide, trophosphamide and iphosphamides,
- miconazol, fluconazole,
- pentoxifylline (high dose parenteral),
- tritoqualine.

Weakening of the blood-glucose-lowering effect and, thus raised blood glucose levels may occur when one of the following medicinal products is taken, for example:

oestrogens and progestogens,

saluretics, thiazide diuretics,

thyroid stimulating agents, glucocorticoids,

phenothiazine derivatives, chlorpromazine,

adrenaline and sympathicomimetics,

nicotinic acid (high dosages) and nicotinic acid derivatives,

laxatives (long term use),

phenytoin, diazoxide,

glucagon, barbiturates and rifampicin,

acetazolamide.

H₂ antagonists, betablockers, clonidine and reserpine may lead to either potentiation or weakening of the blood glucose lowering effect.

Under the influence of sympatholytic medicinal products such as betablockers, clonidine, guanethidine and reserpine, the signs of adrenergic counterregulation to hypoglycaemia may be reduced or absent.

Alcohol intake may potentiate or weaken the hypoglycaemic action of glimepiride in an unpredictable fashion.

Glimepiride may either potentiate or weaken the effects of coumarin derivatives

4.6 Pregnancy And Lactation

Pregnancy

Risk related to the diabetes

Abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities and perinatal mortality. So the blood glucose level must be closely monitored during pregnancy in order to avoid the teratogenic risk. The use of insulin is required under such circumstances. Patients who consider pregnancy should inform their physician.

Risk related to glimepiride

There are no adequate data from the use of glimepiride in pregnant women. Animal studies have shown reproductive toxicity which likely was related to the pharmacologic action (hypoglycaemia) of glimepiride (see section 5.3).

Consequently, glimepiride should not be used during the whole pregnancy.

In case of treatment by glimepiride, if the patient plans to become pregnant or if a pregnancy is discovered, the treatment should be switched as soon as possible to insulin therapy.

Lactation

The excretion in human milk is unknown. Glimepiride is excreted in rat milk. As other sulfonylureas are excreted in human milk and because there is a risk of hypoglycaemia in nursing infants, breast-feeding is advised against during treatment with glimepiride.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or operate machinery in these circumstances.

4.8 Undesirable Effects

The following adverse reactions from clinical investigations are based on experience with glimepiride and other sulfonylureas, and are listed below by system organ class and in order of decreasing incidence (very common:

Blood and lymphatic system disorders

Rare: thrombocytopenia, leukopenia, , granulocytopenia, agranulocytosis, erythropenia, haemolytic anaemia and pancytopenia, which are in general reversible upon discontinuation of medication.

Immune system disorders

Very rare: leukocytoclastic vasculitis, mild hypersensitivity reactions that may develop into serious reactions with dyspnoea, fall in blood pressure and sometimes shock.

Not known:cross-allergenicity with sulfonylureas, sulfonamides or related substances is possible.

Metabolism and nutrition disorders

Rare: hypoglycaemia.

These hypoglycaemic reactions mostly occur immediately, may be severe and are not always easy to correct.The occurrence of such reactions depends, as with other hypoglycaemic therapies, on individual factors such as dietary habits and the dosage (see further under section 4.4).

Eye disorders

Not known:visual disturbances, transient, may occur especially on initiation of treatment, due to changes in blood glucose levels.

Gastrointestinal disorders

Very rare: nausea, vomiting, diarrhoea, abdominal distension, abdominal discomfort and abdominal pain, which seldom lead to discontinuation of therapy.

Hepato-biliary disorders

Not known:hepatic enzymes increased.

Very rare: hepatic function abnormal (e.g. with cholestasis and jaundice) , hepatitis and hepatic failure.

Skin and subcutaneous tissue disorders

Not known:hypersensitivity reactions of the skin may occur as pruritus, rash urticaria and photosensitivity.

Investigations

Very rare: blood sodium decrease.

4.9 Overdose

After ingestion of an overdosage hypoglycaemia may occur, lasting from 12 to 72 hours, and may recur after an initial recovery. Symptoms may not be present for up to 24 hours after ingestion. In general observation in hospital is recommended. Nausea, vomiting and epigastric pain may occur. The hypoglycaemia may in general be accompanied by neurological symptoms like restlessness, tremor, visual disturbances, co-ordination problems, sleepiness, coma and convulsions.

Treatment primarily consists of preventing absorption by inducing vomiting and then drinking water or lemonade with activated charcoal (adsorbent) and sodium-sulphate (laxative). If large quantities have been ingested, gastric lavage is indicated, followed by activated charcoal and sodium-sulphate. In case of (severe) overdosage hospitalisation in an intensive care department is indicated. Start the administration of glucose as soon as possible, if necessary by a bolus intravenous injection of 50 ml of a 50% solution, followed by an infusion of a 10% solution with strict monitoring of blood glucose. Further treatment should be symptomatic.

In particular when treating hypoglycaemia due to accidental intake of Glimepiride Winthrop in infants and young children, the dose of glucose given must be carefully controlled to avoid the possibility of producing dangerous hyperglycaemia. Blood glucose should be closely monitored.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Blood glucose lowering drugs, excl. insulins: Sulfonamides, urea derivatives. ATC Code: A10B B12.

Glimepiride is an orally active hypoglycaemic substance belonging to the sulfonylurea group. It may be used in non-insulin dependent diabetes mellitus.

Glimepiride acts mainly by stimulating insulin release from pancreatic beta cells.

As with other sulfonylureas this effect is based on an increase of responsiveness of the pancreatic beta cells to the physiological glucose stimulus. In addition, glimepiride seems to have pronounced extrapancreatic effects also postulated for other sulfonylureas.

Insulin release

Sulfonylureas regulate insulin secretion by closing the ATP-sensitive potassium channel in the beta cell membrane. Closing the potassium channel induces depolarisation of the beta cell and results

This leads to insulin release through exocytosis.

Glimepiride binds with a high exchange rate to a beta cell membrane protein which is associated with the ATP-sensitive potassium channel but which is different from the usual sulfonylurea binding site.

Extrapancreatic activity

The extrapancreatic effects are for example an improvement of the sensitivity of the peripheral tissue for insulin and a decrease of the insulin uptake by the liver.

The uptake of glucose from blood into peripheral muscle and fat tissues occurs via special transport proteins, located in the cells membrane. The transport of glucose in these tissues is the rate limiting step in the use of glucose. Glimepiride increases very rapidly the number of active glucose transport molecules in the plasma membranes of muscle and fat cells, resulting in stimulated glucose uptake.

Glimepiride increases the activity of the glycosyl-phosphatidylinositol-specific phospholipase C which may be correlated with the drug-induced lipogenesis and glycogenesis in isolated fat and muscle cells.

Glimepiride inhibits the glucose production in the liver by increasing the intracellular concentration of fructose-2,6

General

In healthy persons, the minimum effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute physical exercise, reduction of insulin secretion, is still present under glimepiride.

There was no significant difference in effect regardless of whether the medicinal product was given 30 minutes or immediately before a meal. In diabetic patients, good metabolic control over 24 hours can be achieved with a single daily dose.

Although the hydroxy metabolite of glimepiride caused a small but significant decrease in serum glucose in healthy persons, it accounts for only a minor part of the total drug effect.

Combination therapy with metformin

Improved metabolic control for concomitant glimepiride therapy compared to metformin alone in patients not adequately controlled with the maximum dosage of metformin has been shown in one study.

Combination therapy with insulin

Data for combination therapy with insulin are limited. In patients not adequately controlled with the maximum dosage of glimepiride, concomitant insulin therapy can be initiated. In two studies, the combination achieved the same improvement in metabolic control as insulin alone; however, a lower average dose of insulin was required in combination therapy.

Special populations

Children and adolescents

An active controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2,000 mg daily) of 24 weeks duration was performed in 285 children (8-17 years of age) with type 2 diabetes.

Both glimepiride and metformin exhibited a significant decrease from baseline in HbA_1c (glimepiride -0.95 (se 0.41); metformin -1.39 (se 0.40)). However, glimepiride did not achieve the criteria of non-inferiority to metformin in mean change from baseline of HbA_1c. The difference between treatments was 0.44% in favour of metformin. The upper limit (1.05) of the 95% confidence interval for the difference was not below the 0.3% non-inferiority margin.

Following glimepiride treatment, there were no new safety concerns noted in children compared to adult patients with type 2 diabetes mellitus. No long-term efficacy and safety data are available in paediatric patients.

5.2 Pharmacokinetic Properties

Absorption: The bioavailability of glimepiride after oral administration is complete. Food intake has no relevant influence on absorption, only absorption rate is slightly diminished. Maximum serum concentrations (C_max) are reached approx. 2.5 hours after oral intake (mean 0.3 µg/ml during multiple dosing of 4 mg daily) and there is a linear relationship between dose and both C_max and AUC (area under the time/concentration curve).

Distribution: Glimepiride has a very low distribution volume (approx. 8.8 litres) which is roughly equal to the albumin distribution space, high protein binding (>99%), and a low clearance (approx. 48 ml/min).

In animals, glimepiride is excreted in milk. Glimepiride is transferred to the placenta. Passage of the blood brain barrier is low.

Biotransformation and elimination: Mean dominant serum half-life, which is of relevance for the serum concentrations under multiple-dose conditions, is about 5 to 8 hours. After high doses, slightly longer half-lives were noted.

After a single dose of radiolabelled glimepiride, 58% of the radioactivity was recovered in the urine, and 35% in the faeces. No unchanged substance was detected in the urine. Two metabolites

Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics, and the intraindividual variability was very low. There was no relevant accumulation.

Special populations

Pharmacokinetics were similar in males and females, as well as in young and elderly (above 65 years) patients. In patients with low creatinine clearance, there was a tendency for glimepiride clearance to increase and for average serum concentrations to decrease, most probably resulting from a more rapid elimination because of lower protein binding. Renal elimination of the two metabolites was impaired. Overall no additional risk of accumulation is to be assumed in such patients.

Pharmacokinetics in five non-diabetic patients after bile duct surgery were similar to those in healthy persons.

Children and adolescents

A fed study investigating the pharmacokinetics, safety, and tolerability of a 1 mg single dose of glimepiride in 30 paediatric patients (4 children aged 10-12 years and 26 children aged 12-17 years) with type 2 diabetes showed mean AUC_(0-last) , Cmax and t_1/2 similar to that previously observed in adults.

5.3 Preclinical Safety Data

Preclinical effects observed occurred at exposures sufficiently in excess of the maximum human exposure as to indicate little relevance to clinical use, or were due to the pharmacodynamic action (hypoglycaemia) of the compound. This finding is based on conventional safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and reproduction toxicity studies. In the latter (covering embryotoxicity, teratogenicity and developmental toxicity), adverse effects observed were considered to be secondary to the hypoglycaemic effects induced by the compound in dams and in offspring.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate

sodium starch glycollate (type A)

magnesium stearate

microcrystalline cellulose

povidone 25000

Colouring agents

Yellow iron oxide (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30 °C.

Store in the original package in order to protect from moisture.

6.5 Nature And Contents Of Container

White/opaque PVC/Aluminium blisters or clear/bluish PVC/Aluminium blisters.

15, 20, 30, 50, 60, 90 and 120 tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 17780/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

26/01/2010

10. Date Of Revision Of The Text

January 2010

Legal status

POM