Glucophage 500 mg and 850 mg film coated tablets

1. Name Of The Medicinal Product

Glucophage 500 mg film-coated tablet

Glucophage 850 mg film-coated tablet

2. Qualitative And Quantitative Composition

Glucophage 500 mg: One film-coated tablet contains 500mg metformin hydrochloride corresponding to 390 mg metformin base.

Glucophage 850 mg: One film-coated tablet contains 850mg metformin hydrochloride corresponding to 662.9 mg metformin base.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White, circular, convex film-coated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control.

• In adults, Glucophage may be used as monotherapy or in combination with other oral antidiabetic agents or with insulin.

• In children from 10 years of age and adolescents, Glucophage may be used as monotherapy or in combination with insulin.

A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with metformin as first-line therapy after diet failure (see section 5.1).

4.2 Posology And Method Of Administration

Adults:

Monotherapy and combination with other oral antidiabetic agents:

The usual starting dose is 500 mg or 850 mg metformin hydrochloride 2 or 3 times daily given during or after meals. After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 3 g daily, taken as 3 divided doses.

If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate metformin at the dose indicated above.

Combination with insulin:

Metformin and insulin may be used in combination therapy to achieve better blood glucose control. Metformin hydrochloride is given at the usual starting dose of 500 mg or 850 mg 2 or 3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Elderly:

Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary (see section 4.4).

Children and adolescents:

Monotherapy and combination with insulin

• Glucophage can be used in children from 10 years of age and adolescents.

• The usual starting dose is 500 mg or 850 mg metformin hydrochloride once daily, given during or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 2 g daily, taken as 2 or 3 divided doses.

4.3 Contraindications

• Hypersensitivity to metformin or to any of the excipients.

• Diabetic ketoacidosis, diabetic pre-coma.

• Renal failure or renal dysfunction (creatinine clearance < 60 ml/min).

• Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock.

• Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial infarction, shock.

• Hepatic insufficiency, acute alcohol intoxication, alcoholism.

4.4 Special Warnings And Precautions For Use

Lactic acidosis: Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia. Diagnosis: The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps with digestive disorders as abdominal pain and severe asthenia. This can be followed by acidotic dyspnea, abdominal pain, hypothermia and coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalised immediately (see section 4.9).

Renal function:

As metformin is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) should be determined before initiating treatment and regularly thereafter:

• at least annually in patients with normal renal function,

• at least two to four times a year in patients with creatinine clearance at the lower limit of normal and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID).

Administration of iodinated contrast media:

The intravascular administration of iodinated contrast media in radiologic studies can lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. Metformin must be discontinued prior to, or at the time of the test and not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5).

Surgery:

Metformin must be discontinued 48 hours before elective surgery under general, spinal or peridural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and only if normal renal function has been established.

Children and adolescents:

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated.

No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially prepubescent children, is recommended.

Children aged between 10 and 12 years:

Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of metformin in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.

Other precautions:

All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.

The usual laboratory tests for diabetes monitoring should be performed regularly.

Metformin alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulfonylureas or meglitinides).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use not recommended:

Alcohol:

Acute alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of:

fasting or malnutrition, hepatic insufficiency.

Avoid consumption of alcohol and alcohol-containing medicinal product.

Iodinated contrast media :

Intravascular administration of iodinated contrast media may lead to renal failure, resulting in metformin accumulation and an increased risk of lactic acidosis.

Metformin must be discontinued prior to, or at the time of the test and not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.4).

Combinations requiring precautions for use:

Medicinal products with intrinsic hyperglycaemic activity (e.g. glucocorticoids (systemic and local routes) and sympathomimetics):

More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon its discontinuation.

Diuretics, especially loop diuretics:

They may increase the risk of lactic acidosis due to their potential to decrease renal function.

4.6 Pregnancy And Lactation

Pregnancy

Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality.

A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or fetal development, parturition or postnatal development (see section 5.3).

When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus.

Lactation

Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, breast-feeding is not recommended during metformin treatment.A decision on whether to discontinue breast-feeding should be made, taking into account the benefit of breast-feeding and the potential risk to adverse effects on the child. .

Fertility

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

4.7 Effects On Ability To Drive And Use Machines

Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.

However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (e.g. sulfonylureas, insulin or meglitinides).

4.8 Undesirable Effects

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases. To prevent them, it is recommended to take metformin in 2 or 3 daily doses and to increase slowly the doses.

The following adverse reactions may occur under treatment with metformin. Frequencies are defined as follows: very common: >1/100, <1/10; uncommon >1/1,000, <1/100; rare >1/10,000, <1/1,000; very rare <1/10,000.

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

Metabolism and nutrition disorders:

very rare:

Lactic acidosis (see section 4.4).

Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.

Nervous system disorders:

Common: Taste disturbance

Gastrointestinal disorders:

very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders:

very rare: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders:

very rare: Skin reactions such as erythema, pruritus, urticaria

Paediatric population

In published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year, adverse event reporting was similar in nature and severity to that reported in adults.

4.9 Overdose

Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Blood glucose lowering drugs. Biguanides; ATC code: A10BA02

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin may act via 3 mechanisms:

(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.

(2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization.

(3) and delay of intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.

In clinical studies, use of metformin was associated with either a stable body weight or modest weight loss.

In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

Clinical efficacy:

The prospective randomised study (UKPDS) has established the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes.

Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034;

- a significant reduction of the absolute risk of diabetes-related mortality: metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;

- a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021);

- a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).

Benefit regarding clinical outcome has not been shown for metformin used as second-line therapy, in combination with a sulfonylurea.

In type 1 diabetes, the combination of metformin and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.

Paediatric population

Controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year demonstrated a similar response in glycaemic control to that seen in adults.

5.2 Pharmacokinetic Properties

Absorption:

After an oral dose of metformin hydrochloride tablet, maximum plasma concentration (C_max) is reached in approximately 2.5 hours (t_max). Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear.

At the recommended metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In controlled clinical trials, maximum metformin plasma levels (C_max) did not exceed 5 microgram/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin. Following oral administration of a 850 mg tablet, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.

Distribution:

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 l.

Metabolism:

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination:

Renal clearance of metformin is> 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.

When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

Paediatric population

Single dose study: After single doses of metformin hydrochloride 500 mg paediatric patients have shown similar pharmacokinetic profile to that observed in healthy adults.

Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg twice daily for 7 days in paediatric patients the peak plasma concentration (C_max) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies on safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core

Povidone K 30

Magnesium stearate

Film-coating

Hypromellose.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions

6.5 Nature And Contents Of Container

500mg tablets

1 (x 100), 9, 20, 21, 30, 40, 50, 56, 60, 84, 90, 100, 120, 200, 500, 600 or 1000 tablets in blister packs (PVC-aluminium)

21, 30, 40, 50, 60, 100, 120, 300, 400, 500, 600 or 1000 tablets in plastic bottles (high-density polyethylene) with caps (polypropylene),

Not all pack sizes may be marketed.

850mg tablets:

1 (x 100), 8, 9, 10,14, 20, 21, 30, 40, 50, 56, 60, 84, 90, 100, 120, 300, 600 or 1000 tablets in blister packs (PVC-aluminium)

30, 60, 200, 300 or 600 tablets in plastic bottles (high-density polyethylene) with caps (polypropylene),

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

Merck Serono Limited

Bedfont Cross, Stanwell Road

Feltham, Middlesex

TW14 8NX

United Kingdom

8. Marketing Authorisation Number(S)

PL 11648/0085-0086

9. Date Of First Authorisation/Renewal Of The Authorisation

1st October 2007

10. Date Of Revision Of The Text

10/2010

Gabapentin 800mg film-coated tablets

1. Name Of The Medicinal Product

Gabapentin 800mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 800 mg gabapentin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

A white, capsule shaped, film-coated tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

Epilepsy

Adults and children over 12 years

Gabapentin is an anti-epileptic agent indicated as add-on therapy for partial seizures (with or without secondary generalisation) in patients who have not achieved satisfactory control with, or who exhibit intolerance to, standard anticonvulsants whether used alone or in combination.

Children 6-12 years of age

Gabapentin may be used as add-on therapy for partial seizures (with or without secondary generalisation) in children aged between 6-12 years, who have not achieved satisfactory control with, or who exhibit intolerance to, standard anticonvulsants whether used alone or in combination, if the risk-benefit ratio is considered favourable. Treatment should be initiated and supervised by a neurological specialist.

Children under 6 years of age

The use of gabapentin is not recommended in this age group owing to the lack of sufficient supporting data.

Neuropathic Pain

Gabapentin is indicated for the treatment of neuropathic pain in adults.

4.2 Posology And Method Of Administration

Note:

Gabapentin capsules, of strengths 100mg, 300mg and 400mg, and Gabapentin 600mg tablets are also available for construction of an appropriate patient dosage regimen.

Epilepsy

Adults and children (over 12 years)

Gabapentin tablets are administered orally, and may be taken with or without food.

The anti-epileptic effect of gabapentin generally occurs at a daily dose of 900 to 1200mg. It is not necessary to monitor gabapentin plasma concentrations to optimise therapy.

An effective dose can be achieved rapidly by titration over a few days, by administering 300mg once a day on the first day, 300mg twice a day on the second day and 300mg three times a day on the third day (refer to Table 1 below).

Table 1:Dosing chart for initial titration

Dose	Day 1	Day 2	Day 3
900mg	300mg   once a day	300mg   two times a day	300mg   three times a day

Dosage can be increased subsequently with increments of 300mg per day given in three equally divided doses, to a daily maximum of 2400mg. The maximum time between doses in a three times daily schedule should not be more than 12 hours.

Discontinuation of gabapentin, and/or addition of an alternative anticonvulsant medicinal product to the treatment regimen, should be accomplished gradually over a minimum period of one week.

Elderly

Dosage adjustment may be necessary in elderly patients, due to declining renal function with age (refer to Table 2).

Children 6-12 years of age

The recommended dose of gabapentin is 25mg/kg/day to 35 mg/kg/day, given in divided doses three times a day. An effective dose can be achieved by titration over three days, by administering 10 mg/kg/day on the first day, 20 mg/kg/day on the second day and 25mg/kg/day to 35 mg/kg/day on the third day. A suggested maintenance dosing schedule is given below:

Weight Range (kg)	Total mg daily dose
26 - 36	900
37 - 50	1200

Neuropathic Pain

Adults (over 18 years)

Gabapentin tablets are administered orally, and may be taken with or without food.

Gabapentin should be titrated to a maximum dose of 1800mg per day. An effective dose can be achieved rapidly by titration over a few days, by administering 300mg once a day on the first day, 300mg twice a day on the second day and 300mg three times a day on the third day (refer to Table 1).

Dosage can be increased subsequently with increments of 300mg per day to a daily maximum of 1800mg, given in three divided doses. There is no need to divide the doses equally when titrating gabapentin, and it is not necessary to monitor gabapentin plasma concentrations to optimise therapy. The maximum time between doses in a three times daily schedule should not be more than 12 hours.

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.

Discontinuation of gabapentin, dosage reduction or substitution with an alternative medicinal product, should be achieved gradually during a minimum period of one week.

Elderly

It may be necessary to adjust the dose in elderly patients, due to declining renal function with age (refer to Table 2).

Patients with impaired renal function or undergoing haemodialysis

It is recommended that a dose adjustment is made for patients with impaired renal function and those undergoing haemodialysis. The dosage recommendations for impaired renal function are summarised in Table 2 overleaf.

For patients undergoing haemodialysis who have not previously been given gabapentin, a loading dose of 300 to 400mg is recommended, with a further 200 to 300mg of gabapentin following each 4 hours of haemodialysis.

Table 2:Maintenance dosage of gabapentin in patients with impaired renal function

Renal function (creatinine clearance, ml/min)	Total daily dose1 mg/day
> 80	900	1200	2400
50-79	600	600	1200
30-49	300	300	600
15-29	1502	300	300
< 153	1502	1502	1502

¹ Total daily dose should be administered as a three times daily regimen. For patients with normal renal function (creatine clearance>80 ml/min), the daily dose will range from 900 - 2400mg. Dosage reduction is recommended for patients with impaired renal function (creatinine clearance <79 ml/min).

² To be administered as 300mg on alternate days.

³ 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 gabapentin, or to any of the excipients of gabapentin tablets.

4.4 Special Warnings And Precautions For Use

Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsant agents in epileptic patients may precipitate status epilepticus. When, in the judgement of the clinician, there is a need for dose reduction, discontinuation or substitution of alternative anticonvulsant medicinal products, this should be effected gradually over a period of at least one week.

Gabapentin is not considered effective against primary generalised 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.

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

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.

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.

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.

Patients taking gabapentin can be the subject of mood and behavioural disturbances. Such reports have been noted in patients receiving gabapentin, although a causal link has not been established.

Caution is recommended in patients with a history of psychotic illness. On commencing treatment with gabapentin, psychotic episodes have been reported in some patients with, and rarely without, a history of psychotic illness. Most of these events resolved when gabapentin was discontinued, or the dosage reduced.

Suicide/suicidal thoughts:

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agent in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic drugs has 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 behaviour 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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In a study involving healthy volunteers (N=12), when a 60mg controlled-release morphine capsule was administered 2 hours prior to a 600mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.

The anticonvulsant effect of antiepileptics is antagonised by tricyclic antidepressants, selective-serotonin re-uptake inhibitors (SSRIs) and mefloquine, and may be antagonised by monoamine oxidase inhibitors (MAOIs) and tricyclic-related antidepressants. There is a possibility of increased risk of convulsions when antiepileptics are given with chloroquine and hydroxychloroquine.

Gabapentin may be used in combination with other anti-epileptic medicinal products, without concern for alteration of the plasma concentrations of gabapentin or the serum concentrations of other anti-epileptic active substances.

There are no interactions between gabapentin and phenytoin, valproic acid, carbamazepine or phenobarbitone. Steady-state pharmacokinetics of gabapentin are similar in healthy subjects and in patients with epilepsy receiving anti-epileptic agents.

Co-administration of gabapentin with oral contraceptives including norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either component.

In a clinical study where gabapentin was given at the same time as an aluminium and magnesium containing antacid, the bioavailability of gabapentin was reduced by up to 24%. It is recommended that gabapentin should be taken about two hours following any such antacid administration.

The renal excretion of gabapentin is not altered by probenecid, whereas a slight decrease in renal excretion of gabapentin is observed when co-administered with cimetidine. However, this is not expected to be of clinical importance.

False positive readings have been reported with the Ames N-Multistix SG^® dipstick test when gabapentin was added to other anticonvulsant drugs. The more specific sulphosalicylic acid precipitation procedure is recommended to determine urinary protein.

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 acts on the central nervous system and may produce drowsiness, dizziness, or related symptoms. Whilst these adverse events are otherwise mild or moderate, they pose a potential danger for patients who are driving or operating machinery, particularly until such time as the individual patient's experience with gabapentin is characterised. 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 the post-marketing experience are included as frequency Not known (cannot be estimated from the available data)

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

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)

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:	convulsions, hyperkinesias, dysarthria, amnesia, tremor, insomnia, headache, sensations such as paraesthesia, hypaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes
Uncommon:	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 disorder

Common:

hypertension, vasodilatation

Respiratory, thoracic and mediastinal disorders

Common:

dyspnoea, bronchitis, pharyngitis, cough, rhinitis

Gastrointestinal disorders

Common:	vomiting, nausea, dental abnormalities, gingivitis, diarrhoea, 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

Musculoskeletal, connective tissue and bone disorders

Common:	arthralgia, myalgia, back pain, twitching
Not known:	myoclonus

Renal and urinary disorders

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:	generalised oedema
Not known:	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:	WBC (white blood cell count) decreased, weight gain
Uncommon:	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 in overdoses with gabapentin of up to 49 grams. Symptoms of overdose 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 thus 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 group: Other antiepileptics, ATC code: N03A X12

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 radiolabelled gabapentin have characterised 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

Based on the results of bioavailability studies performed with gabapentin tablets, 600 and 800mg tablets are bioequivalent to gabapentin capsules. 600mg gabapentin tablets were found to be bioequivalent to 2 x 300mg capsules based on a similar rate and extent of drug absorption. Likewise, 800mg tablets were found to be bioequivalent to 2 x 400mg capsules.

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 T_1/2), are best described by linear pharmacokinetics. Steady state plasma gabapentin concentrations are predictable from single-dose data.

5.3 Preclinical Safety Data

Carcinogenicity

Gabapentin was administered in the diet to mice at 200, 600, and 2000mg/kg/day and to rats at 250, 1000, and 2000mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell tumours was noted only in male rats at the highest dose. Peak plasma drug concentrations and areas under the concentration time curve in rats at 2000mg/kg are 10 times higher than plasma concentrations in humans receiving 3600mg/day.

The pancreatic acinar cell tumours in male rats were low-grade malignancies, without effect on survival, which did not metastasise or invade surrounding tissue. These tumours were similar to those seen in concurrent controls. The relevance of pancreatic acinar cell tumours in male rats to carcinogenic risk in humans is therefore of uncertain significance.

Mutagenesis

Gabapentin has no genotoxic potential. It was not mutagenic in the Ames bacterial plate incorporation assay, or at the HGPRT locus in mammalian cells in the presence or absence of metabolic activation. Gabapentin did not induce structural chromosome aberrations in mammalian cells in vitro or in vivo, and did not induce micronucleus formation in the bone marrow of hamsters.

Impairment of Fertility

No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately five times the maximum daily human dose on a mg/m2 of body surface area basis).

Teratogenesis

Gabapentin did not increase the incidence of malformations, compared to controls, in the offspring of mice, rats, or rabbits at doses up to 50, 30 and 25 times respectively, the daily human dose of 3600 mg, (four, five or eight times, respectively, the human daily dose on a mg/m2 basis).

Gabapentin induced delayed ossification in the skull, vertebrae, forelimbs, and hindlimbs in rodents, indicative of fetal growth retardation. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during organogenesis and in rats given 500, 1000, or 2000 mg/kg prior to and during mating and throughout gestation. These doses are approximately 1 to 5 times the human dose of 3600 mg on a mg/m2 basis.

No effects were observed in pregnant mice given 500 mg/kg/day (approximately 1/2 of the daily human dose on a mg/m2 basis).

An increased incidence of hydroureter and/or hydronephrosis was observed in rats given 2000 mg/kg/day in a fertility and general reproduction study, 1500 mg/kg/day in a teratology study, and 500, 1000, and 2000 mg/kg/day in a perinatal and postnatal study. The significance of these findings is unknown, but they have been associated with delayed development. These doses are also approximately 1 to 5 times the human dose of 3600 mg on a mg/m2 basis.

In a teratology study in rabbits, an increased incidence of post-implantation foetal loss, occurred in doses given 60, 300, and 1500 mg/kg/day during organogenesis. These doses are approximately 1/4 to 8 times the daily human dose of 3600 mg on a mg/m2 basis.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablets Core:

Macrogol 4000

Pre-gelatinised starch

Colloidal anhydrous silica

Magnesium stearate

Tablet film coating:

Polyvinyl alcohol

Titanium dioxide (E171)

Talc

Lecithin

Xanthan gum

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Store below 25ºC.

6.5 Nature And Contents Of Container

PVC/Aluminium blister pack. Supplied in pack

Antalgil

Antalgil may be available in the countries listed below.

Ingredient matches for Antalgil

Ibuprofen

Ibuprofen is reported as an ingredient of Antalgil in the following countries:

• Italy

International Drug Name Search

Youtolon

Youtolon may be available in the countries listed below.

Ingredient matches for Youtolon

Diflucortolone

Diflucortolone 21-valerate (a derivative of Diflucortolone) is reported as an ingredient of Youtolon in the following countries:

• Japan

International Drug Name Search

Goddards Muscle Lotion

Goddards Muscle Lotion

(turpentine oil, dilute acetic acid, dilute ammonia)

Important information about Goddards Muscle Lotion

• This medicine relieves symptoms of rheumatic and muscular pains.


• It can be used by adults, the elderly and children.

Do not use on broken skin

Now read the rest of the leaflet before you use this medicine. It includes other information which might be especially important for you.

• Keep this leaflet. You may need to read it again.


• Ask your pharmacist if you need any more information or advice.


• If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

What the medicine is for

Goddards Muscle Lotion is a topical emulsion which has warming and soothing properties. It is used to relieve the symptoms of muscle pain and stiffness, including backache, sciatica, lumbago, fibrositis, rheumatic pain and pain caused by bruises, sprains, strains, stiff
muscles and unbroken chilblains.

Before you use this medicine

Do not use the medicine if you or your child have broken skin.

Pregnant or breastfeeding

Ask your doctor or pharmacist for advice before using this medicine if you are pregnant, might be pregnant or are breastfeeding. Goddards Muscle Lotion should not be used in pregnancy unless the doctor has told you to do so.

How to use this medicine

Apply it to the skin

Adults, the elderly and children

• Shake the bottle thoroughly.


• Pour enough muscle lotion into the palm of your hand and rub into the affected area until dry, once or twice a day.


• Avoid contact with eyes and sensitive areas of the skin.


• Wash hands well after use.

For external use only.

If your symptoms persist you should ask your doctor for advice.

If you swallow some

If you accidentally swallow some, see a doctor straight away. Take the pack with you to show which medicine you have swallowed.

Possible side effects

There are no known side effects from using this medicine when used as directed.

If you notice any side effects, stop use and tell your doctor or pharmacist. They will tell you what to do.

Storing this medicine

• Keep it out of the reach and sight of children.


• There are no special conditions for storing this medicine.


• Do not use after the expiry date shown on the carton. The expiry date refers to the last day of that month.


• Medicine should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of any unused medicine. These measures will help to protect the environment.

Further information

What is in this medicine

The active ingredients are: turpentine oil 22% v/v, dilute acetic acid 30% v/v, dilute ammonia solution 14% v/v.

The other ingredients are: arlacel 83 V (sorbitan sesquioleate), PEG-8 oleate and purified water.

What the medicine looks like

Goddards Muscle Lotion is a creamy coloured emulsion which smells of turpentine and ammonia.

It is supplied in 200ml bottles.

Marketing authorisation holder

Actavis Group PTC ehf

Reykjavikurvegi 76-78

220 Hafnarfjordur

Iceland

Manufacturer

Thornton and Ross Ltd.

Huddersfield

HD7 5QH

UK

Goddards is a trade mark of Actavis Group PTC ehf.

This leaflet was revised in March 2009

GANfort

GANFORT 300 micrograms/ml + 5 mg/ml eye drops, solution

bimatoprost and timolol maleate

Read all of this leaflet carefully before you start using this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, please ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What GANFORT is and what it is used for


• 2. Before you use GANFORT


• 3. How to use GANFORT


• 4. Possible side effects


• 5 How to store GANFORT


• 6. Further information

What Ganfort Is And What It Is Used For

GANFORT is an eye drop that is used to control glaucoma. It contains two different active substances (bimatoprost and timolol) that both reduce high pressure in the eye. Bimatoprost belongs to a group of medicines called prostamides. Timolol belongs to a group of medicines called beta-blockers. GANFORT is prescribed to reduce high pressure in the eye.

Your eye contains a clear, watery liquid that feeds the inside of the eye. Liquid is constantly being drained out of the eye and new liquid is made to replace this. If the liquid cannot drain out quickly enough, the pressure inside the eye builds up and could eventually damage your sight. GANFORT works by reducing the production of liquid and also increasing the amount of liquid that is drained. This reduces the pressure inside the eye.

Before You Use Ganfort

Do not use GANFORT:

• if you are allergic (hypersensitive) to bimatoprost, timolol or any of the other ingredients of GANFORT


• if you have any breathing illnesses such as asthma or a history of asthma, or severe chronic obstructive lung disease


• if you have heart problems such as heart weakness or heart beat disorders

Take special care with GANFORT:

Before you use this medicine, tell your doctor

• if you have now or have had in the past
  
  
  • heart, blood pressure or breathing problems
  • overactivity of the thyroid
  • diabetes or low blood sugar levels (hypoglycaemia)
  • severe allergic reactions
  • liver or kidney problems
  • known risk factors for macular oedema (swelling of the retina within the eye leading to worsening vision), for example, cataract surgery

GANFORT may cause your eyelashes to darken and grow, and cause the skin around the eyelid to darken too. The colour of your iris may also go darker over time. These changes may be permanent. The change may be more noticeable if you are only treating one eye.

GANFORT should not be used in people under 18 unless your doctor still recommends it.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

If you use GANFORT with another eye medicine, leave at least 5 minutes between putting in GANFORT and the other medicine. Use any eye ointment or eye gel last.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine. Tell your doctor if you are pregnant or planning to become pregnant. GANFORT should not be used during pregnancy unless your doctor still recommends it.

GANFORT should not be used if you are breast-feeding.

Driving and using machines

GANFORT may cause blurred vision in some patients. Do not drive or use machinery until the symptoms have cleared.

Important information about some of the ingredients of GANFORT

Do not use the drops while your contact lenses are in your eyes. Wait at least 15 minutes after using the eye drops before putting your lenses back in your eyes. A preservative in GANFORT (benzalkonium chloride) may cause eye irritation and is also known to discolour soft contact lenses.

How To Use Ganfort

Always use GANFORT exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. The usual dose is one drop in the morning in each eye that needs treatment. However, your doctor may recommend you apply the drop in the evening instead.

Instructions for use

You must not use the bottle if the tamper-proof seal on the bottle neck is broken before you first use it.

• 1. Wash your hands. Tilt your head back and look at the ceiling.


• 2. Gently pull down the lower eyelid until there is a small pocket.


• 3. Turn the bottle upside down and squeeze it to release one drop into each eye that needs treatment.


• 4. Let go of the lower lid, and close your eye for 30 seconds.

If a drop misses your eye, try again.

To avoid contamination, do not let the tip of the bottle touch your eye or anything else. Put the cap back on and close the bottle straight after you have used it.

If you use more GANFORT than you should

If you use more GANFORT than you should, it is unlikely to cause you any serious harm. Put your next dose in at the usual time. If you are worried, talk to your doctor or pharmacist.

If you forget to use GANFORT

If you forget to use GANFORT, use a single drop as soon as you remember, and then go back to your regular routine. Do not use a double dose to make up for a forgotten dose.

If you stop using GANFORT

GANFORT should be used every day to work properly.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

GANfort Side Effects

Like all medicines, GANFORT can cause side effects, although not everybody gets them. The chance of having a side effect is described by the following categories:

Very common: May occur in more than one person in every 10 people

Common: Occurs in up to nine people in every 100 people

Uncommon: Occurs in up to nine people in every 1000 people

Not known: Cannot be estimated from the available data

The following eye side effects may be seen with GANFORT:

Very common: eye redness, longer eyelashes

Common: burning, itching, stinging, sensitivity to light, eye pain, sticky eyes, dry eyes, a feeling of something in the eye, small breaks in the surface of the eye with or without inflammation, difficulty in seeing clearly, redness and itching of the eyelids, darkening of the eyelids

Uncommon: watery eyes, swollen or painful eyelids, tired eyes, in-growing eyelashes, headache, runny nose, hair growing around the eye

Not known: cystoid macular oedema (swelling of the retina within the eye leading to worsening vision)

The following side effects have been seen with bimatoprost or timolol and so may possibly be seen with GANFORT: Allergic reaction in the eye, cataract, darkening of the eyelashes, darkening of the iris colour, dizziness, high blood pressure, an increase in blood test results that show how your liver is working, cold, effects on the heart beat, heart failure, increased heart rate, low blood pressure, skin rash, cough, dry mouth, hair loss, nightmares, reduced sexual urge, memory loss, tiredness, ringing in the ears and a worsening of myasthenia gravis (increased muscle weakness).

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Ganfort

Keep out of the reach and sight of children.

Do not use GANFORT after the expiry date which is stated on the bottle label and the carton after EXP:. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Once opened, solutions may become contaminated, which can cause eye infections. Therefore, you must throw away the bottle 4 weeks after you first opened it, even if some solution is left. To help you remember, write down the date that you opened it in the space on the carton.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What GANFORT contains

• The active substances are bimatoprost 0.3 mg/ml and timolol 5 mg/ml corresponding to timolol maleate 6.8 mg/ml.


• The other ingredients are benzalkonium chloride (a preservative), sodium chloride, sodium phosphate dibasic heptahydrate, citric acid monohydrate and purified water. Small amounts of hydrochloric acid or sodium hydroxide may be added to bring the solution to the correct pH level.

What GANFORT looks like and contents of the pack

GANFORT is a colourless, clear eye drop solution in a plastic bottle. Each pack contains either 1 or 3 plastic bottles each with a screw-cap. Each bottle is about half full and contains 3 millilitres of solution. This is enough for 4 weeks’ usage. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Allergan Pharmaceuticals Ireland

Castlebar Road

Westport

Co. Mayo

Ireland

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

United Kingdom

Allergan Ltd

1^st Floor

Marlow International

The Parkway

Marlow

Bucks

SL7 1YL

UK

Tel:+ 44 (0) 1628 494026

E-mail:uk_medinfo@allergan.com

This leaflet was last approved in January 2010.

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu/.

UK-PIL-GANFORT-2010-01-11